HUGO ID Detailed Result 9605

PMID	Match String	Actual String	Score	Flanking text	Edited by	Edit
11220737	COX-2	Cox-2	1.8	of the disease the expression of cyclooxygenase type 2 (Cox-2), Cox-2 a key enzyme in the synthesis of prostanoids which are
11220737	COX-2	Cox-2	1.8	in the anterior horn of the spinal cord exhibit robust Cox-2 immunoreactivity
11220737	COX-2	Cox-2	1.8	Cox-2 mRNA and protein levels and catalytic activity are also significantly
11220737	COX-2	Cox-2	1.8	The time course of the spinal cord Cox-2 upregulation parallels that of motor neuronal loss in transgenic mSOD1
11220737	COX-2	Cox-2	1.8	We also show that Cox-2 activity is dramatically increased in postmortem spinal cord samples from
11220737	COX-2	Cox-2	1.8	We speculate that Cox-2 upregulation through its pivotal role in inflammation is instrumental in
11220737	COX-2	Cox-2	1.8	inflammation is instrumental in the ALS neurodegenerative process and that Cox-2 inhibition may be a valuable therapeutic avenue for the treatment
12362410	COX-2	COX-2	1.0	and a sharp upregulation of the enzyme cyclooxygenase 2 (COX-2) COX-2
12362410	COX-2	COX-2	1.0	COX-2 is a particularly attractive target because of its marked increase
14511332	COX	COX	2.2	are produced by two different isoforms of the cyclooxygenase (COX) COX enzyme namely COX-1 and COX-2	Junguk Hur
14511332	COX-2	COX-2	13.4	two different isoforms of the cyclooxygenase (COX) COX enzyme namely COX-1 and COX-2
14511332	COX-2	COX-2	13.4	isoforms of the cyclooxygenase (COX) COX enzyme namely COX-1 and COX-2
14511332	COX-2	COX-2	13.4	In particular COX-2 was demonstrated to be crucial for PG-synthesis in inflammation
14511332	COX-2	COX-2	13.4	Recently inhibition of COX-2 was shown to prevent the loss of motor neurons in
14511332	COX-2	COX-2	13.4	Furthermore spinal COX-2 expression was shown to be increased in transgenic mice that
14511332	COX-2	COX-2	13.4	Therefore we investigated the expression of COX-1 and COX-2 in the spinal cord of seven human sporadic
14511332	COX-2	COX-2	13.4	Therefore we investigated the expression of COX-1 and COX-2 in the spinal cord of seven human sporadic ALS patients
14511332	COX-2	COX-2	13.4	COX-2 expression was dramatically increased in the spinal cord of patients
14511332	COX-2	COX-2	13.4	Statistical analysis showed a significantly higher expression of COX-2 in ALS for both neurons and glia
14511332	COX	COX	2.2	prostaglandin E2 (PG PG E 2 as a marker for COX activity in the cerebrospinal fluid of nine patients diagnosed for	Junguk Hur
14511332	COX-2	COX-2	13.4	The results of our study corroborate a potential role for COX-2 in the pathogenesis of motor neuron death in ALS
14511332	COX-2	COX-2	13.4	Selective COX-2 inhibition might therefore offer a new possibility in the treatment
14511332	COX-2	COX-2	13.4	However to determine the exact role of COX-2 in human ALS will require further research
14511332	COX-2	COX-2	13.4	Very recently the proinflammatory enzyme cyclooxygenase-2 (COX-2) COX-2 was reported to be highly expressed in the spinal cord
14511332	COX	COX	2.2	Currently two COX isoforms are known namely COX-1 and COX-2 ( Vane et	Junguk Hur
14511332	COX-2	COX-2	13.4	Currently two COX isoforms are known namely COX-1 and COX-2 ( Vane et al . 1998
14511332	COX-2	COX-2	13.4	Currently two COX isoforms are known namely COX-1 and COX-2 ( Vane et al . 1998
14511332	COX-2	COX-2	13.4	Whereas COX-1 mainly subserves _amp_#8216 house-keeping_amp_#8217 functions COX-2 is the product of an _amp_#8216 immediate-early gene_amp_#8217 that is
14511332	COX-2	COX-2	13.4	Under normal conditions COX-2 expression is highly restricted to distinct organ systems including the
14511332	COX-2	COX-2	13.4	and the eye ( Maihofner et al . 2001 but COX-2 expression can be dramatically increased in various tissues following the
14511332	COX	COX	2.2	Recently one of us demonstrated the constitutive expression of both COX isoforms in the spinal cord of rodents and a dramatic	Junguk Hur
14511332	COX-2	COX-2	13.4	spinal cord of rodents and a dramatic induction of spinal COX-2 protein following peripheral nociceptive stimulation ( Maihofner et al .
14511332	COX-2	COX-2	13.4	Very recently inhibition of COX-2 was protective in a glutamate-mediated in vitro model of sALS
14511332	COX-2	COX-2	13.4	et al . (2001 2001 described the immunohistochemical distribution of COX-2 in the spinal cord of mSOD1 mice over the progression
14511332	COX-2	COX-2	13.4	post mortem samples of ALS cases as a marker for COX-2 activity
14511332	COX	COX	2.2	However the cellular localization and expression of both COX isoforms in human sALS remains unclear	Junguk Hur
14511332	COX-2	COX-2	13.4	Therefore we compared the spinal expression of COX-1 and COX-2 in sALS and control patients by means of
14511332	COX-2	COX-2	13.4	Therefore we compared the spinal expression of COX-1 and COX-2 in sALS and control patients by means of immunohistochemistry
14511332	COX-2	COX-2	13.4	We here demonstrate a high expression of COX-2 protein in spinal cord specimens of human sALS cases
14511332	COX-2	COX-2	13.4	The increased expression of COX-2 was corroborated by a significantly higher concentration of PG E
14511332	COX-2	COX-2	13.4	Briefly goat polyclonal antisera raised against human COX-1 and COX-2 protein (Santa Santa Cruz Biotechnology Santa Cruz CA
14511332	COX-2	COX-2	13.4	Briefly goat polyclonal antisera raised against human COX-1 and COX-2 protein (Santa Santa Cruz Biotechnology Santa Cruz CA were employed
14511332	COX-2	COX-2	13.4	To further differentiate the cellular distributions of COX-1 and COX-2 proteins a double staining procedure using a mouse
14511332	COX-2	COX-2	13.4	To further differentiate the cellular distributions of COX-1 and COX-2 proteins a double staining procedure using a mouse monoclonal antihuman
14511332	COX-2	COX-2	13.4	Specimens were coded and assessed observer-blinded for presence of COX-1 and COX-2 immunoreactivity (IR) IR
14511332	COX-2	COX-2	13.4	were coded and assessed observer-blinded for presence of COX-1 and COX-2 immunoreactivity (IR) IR
14511332	COX-2	COX-2	13.4	Membranes were probed with polyclonal goat antihuman COX-1 or COX-2 serum (diluted diluted 1 1000 followed by a horseradish peroxidase
14511332	COX-2	COX-2	13.4	immunohistochemistry we performed Western blotting experiments for the detection of COX-1 and COX-2 protein with spinal protein extracts from human donors
14511332	COX-2	COX-2	13.4	performed Western blotting experiments for the detection of COX-1 and COX-2 protein with spinal protein extracts from human donors with no
14511332	COX-2	COX-2	13.4	the results of a similar experiment for the detection of COX-2 protein
14511332	COX-2	COX-2	13.4	lane from human spinal cords were separated alongside purified sheep COX-2 protein (right right lane by SDS-PAGE blotted onto nitrocellulose membranes
14511332	COX-2	COX-2	13.4	SDS-PAGE blotted onto nitrocellulose membranes and incubated with the same COX-2 antibody as that used for immunohistochemistry
14511332	COX-2	COX-2	13.4	Unpurified COX-2 proteins derived from either cell lysates or tissues typically produce
14511332	COX-2	COX-2	13.4	single band at 75 kDa was detected for the purified COX-2 protein
14511332	COX	COX	2.2	To exclude potential crossreactions between the antibodies for the two COX isoforms we determined the specifity with purified COX-1 and COX-2	Junguk Hur
14511332	COX-2	COX-2	13.4	the two COX isoforms we determined the specifity with purified COX-1 and COX-2 protein by Western blotting
14511332	COX-2	COX-2	13.4	COX isoforms we determined the specifity with purified COX-1 and COX-2 protein by Western blotting
14511332	COX-2	COX-2	13.4	antihuman polyclonal COX-1 antibody exclusively detected COX-1 protein and not COX-2 protein
14511332	COX-2	COX-2	13.4	from a similar experiment in which the goat antihuman polyclonal COX-2 antibody detected only COX-2 protein and not COX-1 protein
14511332	COX-2	COX-2	13.4	in which the goat antihuman polyclonal COX-2 antibody detected only COX-2 protein and not COX-1 protein
14511332	COX	COX-immunoreactivity	0.0	COX-immunoreactivity	Junguk Hur
14511332	COX-2	COX-2	13.4	only a few motor neurons and interneurons were immunoreactive for COX-2 protein ( Fig 2B
14511332	COX	COX-2-positive	0.0	number of neurons with COX-2-IR was counted the percentage of COX-2-positive motor neurons and interneurons was found to be significantly increased	Junguk Hur
14511332	COX-2	COX-2	13.4	Furthermore expression of COX-2 was found to be enhanced in sALS cases compared to
14511332	COX-2	COX-2	13.4	As demonstrated by the coexpression with GFAP glial COX-2 expression was predominantly found in astrocytes ( Fig 2H
14511332	COX-2	COX-2	13.4	Overall the glial expression of COX-2 was significantly increased in sALS cases (0.71 0.71 _amp_plusmn 0.5
14511332	COX-2	COX-2	13.4	reduction of neurons in the spinal cord the percentage of COX-2 expressing motor neurons and interneurons was increased in sALS
14511332	COX-2	COX-2	13.4	Secondly glial expression of COX-2 was enhanced in sALS
14511332	COX-2	COX-2	13.4	COX-2 overexpression in sALS
14511332	COX-2	COX-2	13.4	Expression of COX-2 in human diseases is a topic of considerable interest with
14511332	COX-2	COX-2	13.4	of considerable interest with regard to the recent development of COX-2 selective inhibitors ( Hawkey 1999
14511332	COX-2	COX-2	13.4	( Drachman _amp_ Rothstein 2000 demonstrated a beneficial effect of COX-2 inhibition in an in vitro model while Almer et al
14511332	COX-2	COX-2	13.4	(2001 2001 demonstrated a role for COX-2 in mutant SOD1 mice and Yasojima et al
14511332	COX-2	COX-2	13.4	(2001 2001 showed up-regulation of COX-2 mRNA in spinal cord specimens of sALS cases
14511332	COX-2	COX-2	13.4	Recently two animal studies demonstrated a beneficial effect of selective COX-2 inhibition in mouse models of ALS ( Drachman et al
14511332	COX-2	COX-2	13.4	However the cellular origin of COX-2 up-regulation in human sALS has so far not been delineated
14511332	COX-2	COX-2	13.4	we provide immunohistochemical evidence for a dramatic increase in spinal COX-2 expression in motor neurons interneurons and glial cells in sALS
14511332	COX-2	COX-2	13.4	COX-2 was also observed in motor neurons of control specimens the
14511332	COX-2	COX-2	13.4	This agrees with reports on the constitutive expression of COX-2 in the spinal cord of rodents and the localization of
14511332	COX-2	COX-2	13.4	in the spinal cord of rodents and the localization of COX-2 protein determined electron microscopically ( Maihofner et al . 2000b
14511332	COX-2	COX-2	13.4	In normal conditions COX-2 derived PGs are assumed to play homeostatic functions ( Beiche
14511332	COX-2	COX-2	13.4	Nevertheless the reason for the dramatic COX-2 overexpression in sALS is unknown
14511332	COX-2	COX-2	13.4	In pain models COX-2 protein was induced following glutamatergic stimulation ( Maihofner et al
14511332	COX-2	COX-2	13.4	NF-kappa B NF-kappa B in particular is crucial for COX-2 induction in several cell types ( Vane et al .
14511332	COX-2	COX-2	13.4	Cytokines could also contribute to high expression of COX-2 in sALS particularly IL-1beta and IL-6
14511332	COX-2	COX-2	13.4	Both are known inducers of COX-2 expression and their concentrations are elevated in the CSF of
14511332	COX-2	COX-2	13.4	Consistently we demonstrated a significantly higher expression of COX-2 in glial cells
14511332	COX-2	COX-2	13.4	in transgenic mSOD1 mice ( Almer et al . 2001 COX-2 was found to be predominantly expressed in astrocytes and not
14511332	COX-2	COX-2	13.4	might be explained by the capability of IL-1beta to induce COX-2 in astrocytes but not in microglia cells ( Vane et
14511332	COX-2	COX-2	13.4	COX-2 expression in the astroglia of rodents has been shown previously
14511332	COX-2	COX-2	13.4	reduction in the number of interneurons in our sALS cases COX-2 expression was also found to be increased in this cell
14511332	COX	COX	2.2	match those of a previous study investigating the expression of COX proteins in mSOD1 mice	Junguk Hur
14511332	COX-2	COX-2	13.4	(2001 2001 also found that COX-2 was present in motor neurons and predominantly in astroglia although
14511332	COX-2	COX-2	13.4	that misclassification of neurons led to the high expression of COX-2 protein in sALS presented here
14511332	COX-2	COX-2	13.4	. 2003 and were shown to be specific for the COX-1 and COX-2 protein respectively
14511332	COX-2	COX-2	13.4	and were shown to be specific for the COX-1 and COX-2 protein respectively
14511332	COX	COX	2.2	of the antibodies and their capability to detect the respective COX isoforms in human spinal cord extracts by Western blotting	Junguk Hur
14511332	COX-2	COX-2	13.4	have intentionally focused on the in situ expression of both COX-1 and COX-2 proteins in human ALS spinal cords
14511332	COX-2	COX-2	13.4	focused on the in situ expression of both COX-1 and COX-2 proteins in human ALS spinal cords
14511332	COX	COX	2.2	Therefore this study provides necessary data regarding the expression of COX isoforms in human ALS	Junguk Hur
14511332	COX	COX-activity	0.0	Therefore measurement of PG-E 2 as a marker for COX-activity may serve as an additional independent method	Junguk Hur
14511332	COX-2	COX-2	13.4	with the results of two recent animal studies where selective COX-2 inhibition was found to be protective against motor neuron death
14511332	COX-2	COX-2	13.4	A role for COX-2 in the pathogenesis of sALS
14511332	COX-2	COX-2	13.4	What is the significance of COX-2 overexpression in ALS
14511332	COX-2	COX-2	13.4	There are several lines of evidence that COX-2 might play a role in the pathogenesis of ALS
14511332	COX-2	COX-2	13.4	Firstly application of a selective COX-2 inhibitor in an in vitro organotypic model of ALS protected
14511332	COX-2	COX-2	13.4	in two in vivo studies where application of a selective COX-2 inhibitor protected against motor neuron degeneration and prolonged survival in
14511332	COX-2	COX-2	13.4	Thirdly based on the action of PGs COX-2 could promote inflammatory processes in ALS
14511332	COX-2	COX-2	13.4	Therefore COX-2 derived PGs could play a role in glutamate excitotoxicity which
14511332	COX-2	COX-2	13.4	potentiation of kainic acid induced excitotoxicity in transgenic mice overexpressing COX-2 protein
14511332	COX-2	COX-2	13.4	Fourthly COX-2 may also be involved in the production of reactive oxygen
14511332	COX	COX	2.2	COX enzymes are bifunctional proteins	Junguk Hur
14511332	COX	COX	2.2	The peroxidase activity of COX is nonspecific and can reduce several different hydroperoxides while co-oxidizing	Junguk Hur
14511332	COX-2	COX-2	13.4	Finally COX-2 appears to be involved in neuronal cell cycle regulation
14511332	COX-2	COX-2	13.4	kinase (INK) INK p18INK4 is a downstream target of neuronal COX-2 expression p18INK4 inhibits CDK 4 6 which is in turn
14511332	COX-2	COX-2	13.4	Therefore COX-2 inhibition might attenuate apoptotic damage in neurodegenerative diseases
14511332	COX-2	COX-2	13.4	However the specifity of COX-2 expression for ALS has to be questioned
14511332	COX-2	COX-2	13.4	Increased COX-2 levels were also shown for Alzheimer's disease Parkinson's disease epilepsy
14511332	COX-2	COX-2	13.4	Therefore we would explicitly like to state that COX-2 expression seems to be a common endpoint in neurodegeneration rather
14511332	COX-2	COX-2	13.4	Furthermore there is the possibility that COX-2 expression might be protective and antiapoptotic
14511332	COX-2	COX-2	13.4	of us was able to show that the expression of COX-2 in CRC parallels the expression of IL-1 beta and IL-6
14511332	COX-2	COX-2	13.4	In this context COX-2 is thought to be actively involved in carcinogenesis and antiapoptosis
14511332	COX-2	COX-2	13.4	by the immunohistochemical results presented here the exact role of COX-2 in the pathogenesis of human ALS still remains to be
14511332	COX-2	COX-2	13.4	North-east ALS consortium to test a potential benefit of selective COX-2 inhibition in human ALS
14511332	COX-2	COX-2	13.4	In contrast to the COX-2 protein COX-1 expression was predominantly found in microglia cells and
14511332	COX-2	COX-2	13.4	Alzheimer disease ( Pasinetti _amp_ Aisen 1998 where COX-2 was found to be the pivotal isoform involved in the
14511332	COX	COX	2.2	for the first time the in situ expression of both COX proteins in the spinal cords of human sALS specimens	Junguk Hur
14511332	COX-2	COX-2	13.4	Expression of COX-2 protein was markedly increased in the motoneurons interneurons and glial
14511332	COX-2	COX-2	13.4	Based on the beneficial effects of selective COX-2 inhibition in models of ALS the results of this and
14511332	COX-2	COX-2	13.4	rationale for clinical investigations on potential positive effects of selective COX-2 inhibitors in human sALS
14511332	COX	COX	2.2	ALS amyotrophic lateral sclerosis COX cyclooxygenase CSF cerebrospinal fluid GFAP glial fibrillary acidic protein IR	Junguk Hur
14720207	COX-2	COX-2	1.3	We investigated the therapeutic effects of cyclooxygenase 2 (COX-2) COX-2 inhibitors both alone and in combination with creatine in the
14720207	COX-2	COX-2	1.3	The administration of COX-2 inhibitors significantly reduced prostaglandin E2 levels at 110 days of
14720207	COX-2	COX-2	1.3	The combination of creatine with COX-2 inhibitors produced additive neuroprotective effects and extended survival by approximately
14720207	COX-2	COX-2	1.3	The COX-2 inhibitors significantly protected against depletion of anterior horn motor neurons
14720207	COX-2	COX-2	1.3	against depletion of anterior horn motor neurons and creatine with COX-2 inhibitors showed greater protection than COX-2 inhibitors alone
14720207	COX-2	COX-2	1.3	neurons and creatine with COX-2 inhibitors showed greater protection than COX-2 inhibitors alone
15081582	COX	COX	0.3	Inflammatory pathways involving the cyclooxygenase (COX) COX enzymes and subsequent generation of prostaglandins are potential target sites	Junguk Hur
15081582	COX	COX	0.3	In the CNS COX enzymes are localized to neurons astrocytes and microglia and can	Junguk Hur
15081582	COX	COX	0.3	to be a dual role for the prostaglandin products of COX enzymes in the nervous system	Junguk Hur
15081582	COX	COX	0.3	In this review the pathways of COX activity and prostaglandin production form the center of the debate	Junguk Hur
15081582	COX	COX	0.3	many aspects to neuroinflammation the pathways involving the cyclooxygenase (COX) COX enzyme and subsequent generation of prostaglandins clearly play a role	Junguk Hur
15081582	COX	COX	0.3	In this review the COX and prostaglandin pathways are used to frame the debate regarding	Junguk Hur
15081582	COX	COX	0.3	The significance of the COX pathway having both positive and negative outcomes in neurodegenerative disease	Junguk Hur
15081582	COX	COX	0.3	COX prostaglandins and neuroinflammation	Junguk Hur
15081582	COX	COX	0.3	Cyclooxygenase (COX) COX is the rate-limiting step in the production of prostaglandins	Junguk Hur
15081582	COX	COX	0.3	Arachidonic acid is the principal substrate for COX ( O'Banion 1999	Junguk Hur
15081582	COX	COX	0.3	There are two distinct COX isoenzymes known as COX-1 and COX-2 that are 65% homologous	Junguk Hur
15081582	COX-2	COX-2	3.8	There are two distinct COX isoenzymes known as COX-1 and COX-2 that are 65% homologous
15081582	COX-2	COX-2	3.8	There are two distinct COX isoenzymes known as COX-1 and COX-2 that are 65% homologous
15081582	COX-2	COX-2	3.8	Conversely COX-2 was initially characterized as an inducible enzyme that is expressed
15081582	COX-2	COX-2	3.8	COX-2 is now known to be constitutively expressed in the kidney
15081582	COX-2	COX-2	3.8	Many cellular factors induce COX-2 expression including multiple growth factors cytokines interleukin (IL)-1_amp_#x3b2; IL -1_amp_#x3b2
15081582	COX-2	COX-2	3.8	One transcription factor that influences COX-2 expression following exposure to these cellular factors is NF-_amp_#x3ba B
15081582	COX-2	COX-2	3.8	COX-2 has an NF-_amp_#x3ba B binding site in its promoter region
15081582	COX-2	COX-2	3.8	Specific inhibition of COX-2 upregulation can be achieved by factors that inhibit NF-_amp_#x3ba B
15081582	COX	COX	0.3	The COX enzymes (COX-1 COX-1 and COX-2 are more completely termed prostaglandin	Junguk Hur
15081582	COX-2	COX-2	3.8	The COX enzymes (COX-1 COX-1 and COX-2 are more completely termed prostaglandin G/H G H
15081582	COX-2	COX-2	3.8	The COX enzymes (COX-1 COX-1 and COX-2 are more completely termed prostaglandin G/H G H synthases (1
15081582	COX	COX	0.3	Next the peroxidase action of the COX enzyme rapidly converts PGG 2 to prostaglandin H (PGH PGH	Junguk Hur
15081582	COX-2	COX-2	3.8	The second peroxidase step of the COX-2 reaction produces the free radical superoxide which may cause damage
15081582	COX-2	COX-2	3.8	Although it is unlikely that upregulation of COX-2 activity alone produces enough free radicals to account for the
15081582	COX	COX	0.3	Both COX isoforms are detectable in various cell types in the CNS	Junguk Hur
15081582	COX	COX	0.3	Identification of the patterns of COX enzyme expression will permit us to form a hypothesis regarding	Junguk Hur
15081582	COX-2	COX-2	3.8	permit us to form a hypothesis regarding the roles of COX-1 and -2 under normal conditions and during disease
15081582	COX	COX	0.3	Analysis of the expression of COX isoforms in ALS models is expected to not only determine	Junguk Hur
15081582	COX	COX	0.3	we will better understand the pathogenic and protective implications of COX activity in ALS	Junguk Hur
15081582	COX	COX	0.3	COX and neurons	Junguk Hur
15081582	COX-2	COX-2	3.8	Immunoreactivity for COX-2 is present in the dendritic spines of cortical neurons and
15081582	COX-2	COX-2	3.8	display a distinct alteration in the laminar pattern of cortical COX-2 immunoreactivity ( Kaufmann et al. 1996
15081582	COX-2	COX-2	3.8	COX-2 immunoreactivity also is observed in the soma and throughout the
15081582	COX-2	COX-2	3.8	Constitutive COX-2 is in the spinal dorsal and ventral horns as well
15081582	COX	COX	0.3	Indeed the antihyperalgesic activity of COX inhibitors is associated with regulation of constitutive COX-2 in the	Junguk Hur
15081582	COX-2	COX-2	3.8	activity of COX inhibitors is associated with regulation of constitutive COX-2 in the spinal cord ( Svensson and Yaksh 2002
15081582	COX-2	COX-2	3.8	Although a role for COX-2 in healthy cells is not clear under pathological conditions the
15081582	COX-2	COX-2	3.8	cells is not clear under pathological conditions the induction of COX-2 in neurons has been well demonstrated
15081582	COX-2	COX-2	3.8	COX-2 was originally localized in neurons using in situ hybridization
15081582	COX-2	COX-2	3.8	Following a single maximal electroconvulsive seizure COX-2 is rapidly induced in hippocampal and cortical neurons peaking between
15081582	COX-2	COX-2	3.8	the N -methyl--aspartic acid (NMDA) NMDA receptor completely inhibits the COX-2 induction implying that NMDA receptor activation is involved in the
15081582	COX-2	COX-2	3.8	that NMDA receptor activation is involved in the upregulation of COX-2 in these neurons
15081582	COX-2	COX-2	3.8	In addition administration of the glucocorticoid dexamethasone markedly decreases COX-2 induction but only in the neocortex ( Yamagata et al.
15081582	COX-2	COX-2	3.8	This study suggests that COX-2 upregulation in neurons is dependent upon glutamatergic activity at the
15081582	COX-2	COX-2	3.8	basalis can induce seizures in a rat and subsequently upregulate COX-2
15081582	COX-2	COX-2	3.8	(1997) 1997 showed that COX-2 induction overlaps with the development of neuronal apoptosis 8 h
15081582	COX-2	COX-2	3.8	that precede neuronal death and correlates with the induction of COX-2 mRNA
15081582	COX-2	COX-2	3.8	prostaglandin production and subsequent cell death is attenuated by a COX-2 inhibitor but not with a COX-1 selective inhibitor ( Hewett
15081582	COX-2	COX-2	3.8	In addition genetic studies show that transgenic mice overexpressing COX-2 specifically in neurons are more susceptible to excitotoxicity ( Kelley
15081582	COX-2	COX-2	3.8	In contrast COX-2 knockout mice experience reduced neuronal death compared to wild-type mice
15081582	COX-2	COX-2	3.8	COX-2 is induced in models of cerebral ischemia
15081582	COX-2	COX-2	3.8	but especially the penumbra region show a significant increase in COX-2 mRNA in the ischemic area ipsilateral to the occlusion 4
15081582	COX-2	COX-2	3.8	There is a direct correlation between the extent of COX-2 mRNA induction at 4 h and the severity of subsequent
15081582	COX-2	COX-2	3.8	the glutamate antagonist agent MK-801 significantly prevents the induction of COX-2 in the penumbra region ( Collaco-Moraes et al. 1996
15081582	COX-2	COX-2	3.8	studies provide evidence of a linkage between glutamate activity subsequent COX-2 induction and finally apoptotic death in neurons
15081582	COX-2	COX-2	3.8	Although increased extracellular glutamate regardless of its source can induce COX-2 in neurons the full consequences of this induction in neurons
15081582	COX-2	COX-2	3.8	COX-2 activity correlates with apoptosis in certain models however from studies
15081582	COX-2	COX-2	3.8	conducted thus far it is not clear which products of COX-2 induction are contributing to neuronal death which are helping neurons
15081582	COX	COX	0.3	COX and astrocytes	Junguk Hur
15081582	COX-2	COX-2	3.8	In the nervous system COX-2 induction following cell activation or injury is not restricted to
15081582	COX-2	COX-2	3.8	injury is not restricted to neurons since astrocytes also upregulate COX-2
15081582	COX-2	COX-2	3.8	IL-1_amp_#x3b2 causes a rapid induction of COX-2 peaking at 2 h and returning to baseline by 24
15081582	COX-2	COX-2	3.8	Dexamethasone can attenuate IL-1_amp_#x3b2 -mediated PGE 2 secretion and COX-2 expression ( O'Banion et al. 1996
15081582	COX-2	COX-2	3.8	Astrocytic COX-2 is also induced by LPS TNF basic fibroblast growth factor
15081582	COX-2	COX-2	3.8	Although there is strong evidence for the induction of COX-2 in astrocytes in vitro there are few studies that confirm
15081582	COX-2	COX-2	3.8	COX-2 immunoreactive astrocytes have been observed in the hippocampus at 1_amp_#x2013
15081582	COX-2	COX-2	3.8	the cortex in Alzheimer's disease in situ hybridization with a COX-2 riboprobe revealed signal in a small proportion of GFAP-positive astrocytes
15081582	COX-2	COX-2	3.8	In addition COX-2 colocalizes with GFAP in infarcted human brains ( Sairanen et
15081582	COX-2	COX-2	3.8	Most in vitro studies are short-term and demonstrate COX-2 induction in the order of hours after the insult
15081582	COX-2	COX-2	3.8	vitro models may skew attempts to ascertain the significance of COX-2 activity in neurodegenerative disease
15081582	COX-2	COX-2	3.8	In the context of neurodegenerative diseases the chronic induction of COX-2 will be more pathophysiologically relevant
15081582	COX	COX	0.3	COX and microglia	Junguk Hur
15081582	COX	COX	0.3	The significance of the different isoform of COX expression in this cell type is not clear	Junguk Hur
15081582	COX-2	COX-2	3.8	mechanisms than macrophages fibroblasts and synovial cells that can induce COX-2 via the cytokines TNF IL-1_amp_#x3b2 and IL-6
15081582	COX-2	COX-2	3.8	None of these agents induce COX-2 or NF-_amp_#x3ba B expression in na_amp_#xef ve microglial cells
15081582	COX-2	COX-2	3.8	In cultured rat brain microglia LPS induces COX-2 expression that is prevented in the presence of inhibitors of
15081582	COX-2	COX-2	3.8	Thus NF-_amp_#x3ba B is involved in LPS-stimulated microglial COX-2 expression ( Bauer et al. 1997
15081582	COX-2	COX-2	3.8	injury paradigms there are little data indicating the expression of COX-2 in microglia in vivo
15081582	COX-2	COX-2	3.8	(1998) 1998 showed COX-2 immunostaining of cells with a microglial-like morphology in infarcted human
15081582	COX	COX	0.3	After examining the locations and activity of the COX enzymes throughout the CNS a discussion of the potential actions	Junguk Hur
15081582	COX-2	COX-2	3.8	In a carrageenin-induced pleurisy model in rats COX-2 induction peaks at 2 h with maximal PGE 2 production
15081582	COX-2	COX-2	3.8	At a later time COX-2 increases again but this time with increased levels of PGD
15081582	COX-2	COX-2	3.8	different inflammatory responses are modulated by the addition of a COX-2 inhibitor that causes inhibition of the early inflammatory response but
15081582	COX-2	COX-2	3.8	to be a dual role for the products of the COX-2 enzyme in the nervous system
15081582	COX-2	COX-2	3.8	In these models inhibition of COX-2 can delay disease onset and progression
15081582	COX-2	COX-2	3.8	Thus prostaglandin products of COX-2 appear to play a critical role in the development of
15081582	COX-2	COX-2	3.8	Addition of COX-2 inhibitors prevents both PGE 2 production and kainic acid-induced neuronal
15081582	COX-2	COX-2	3.8	-induced glutamate may lead to further excitatory cell activation and COX-2 induction
15081582	COX-2	COX-2	3.8	This mechanism is highlighted in a model of COX-2 overexpression that displays acceleration of glutamate-mediated neuronal apoptosis ( Mirjany
15081582	COX	COX	0.3	of prostaglandins also are different depending upon the presence of COX inhibitors	Junguk Hur
15081582	COX-2	COX-2	3.8	Independently these cells are protected from death by the COX-2 inhibitor APHS
15081582	COX-2	COX-2	3.8	on cell survival in the presence or absence of a COX-2 inhibitor may be because COX-2 activity results in the generation
15081582	COX-2	COX-2	3.8	presence or absence of a COX-2 inhibitor may be because COX-2 activity results in the generation of multiple prostaglandins with potentially
15081582	COX-2	COX-2	3.8	When COX-2 is inhibited both the pro- and anti-apoptotic products are lost
15081582	COX-2	COX-2	3.8	However when COX-2 is not inhibited multiple prostaglandins are present that can act
15081582	COX-2	COX-2	3.8	2 all can suppress NF-_amp_#x3ba B activation and thus suppress COX-2 induction as well as other inflammatory mediators including inducible nitric
15081582	COX-2	COX-2	3.8	in which the significance of the differential expression of the COX-1 and COX-2 isoforms may arise
15081582	COX-2	COX-2	3.8	the significance of the differential expression of the COX-1 and COX-2 isoforms may arise
15081582	COX-2	COX-2	3.8	microglial origin can regulate the activity of NF-_amp_#x3ba B and COX-2 in adjacent neurons without the same feedback regulation affecting the
15081582	COX	COX	0.3	COX prostaglandins and ALS	Junguk Hur
15081582	COX-2	COX-2	3.8	COX-2 activity appears to play an important role in ALS
15081582	COX-2	COX-2	3.8	In many different models COX-2 upregulation occurs concurrently with ALS disease events
15081582	COX-2	COX-2	3.8	COX-2 and PGE 2 are significantly elevated upwards of sevenfold in
15081582	COX-2	COX-2	3.8	human SOD1-expressing (mSOD1) mSOD1 mice there is increased expression of COX-2 but not COX-1 mRNA
15081582	COX-2	COX-2	3.8	COX-2 mRNA and protein levels COX catalytic activity and PGE 2
15081582	COX	COX	0.3	COX-2 mRNA and protein levels COX catalytic activity and PGE 2 levels are all increased in	Junguk Hur
15081582	COX-2	COX-2	3.8	COX-2 levels in mSOD1 mice are increased in both early symptomatic
15081582	COX-2	COX-2	3.8	Selective inhibition of COX-2 with SC236 protects motor neurons in an organotypic cell culture
15081582	COX	COX	0.3	In addition several drugs that inhibit COX isoforms directly prevent the death of motor neurons in enriched	Junguk Hur
15081582	COX	COX	0.3	This suggests that the motor neurons activate COX during an injury and the mechanisms of protection by COX	Junguk Hur
15081582	COX	COX	0.3	COX during an injury and the mechanisms of protection by COX inhibitors in mixed culture or in vivo is not mediated	Junguk Hur
15081582	COX	COX	0.3	In the transgenic mSOD1 mouse the nonselective COX inhibitor acetylsalicylate delays the appearance of motor deficits ( Barneoud	Junguk Hur
15081582	COX-2	COX-2	3.8	This delayed onset is recapitulated when the selective COX-2 inhibitor nimesulide is administered prophylactically in these mice ( Pompl
15081582	COX-2	COX-2	3.8	Treatment with Celecoxib a different selective COX-2 inhibitor also prolongs survival in the mSOD1 mouse model of
15081582	COX-2	COX-2	3.8	It seems that neuroinflammation proceeds albeit more slowly in COX-2 inhibitor-treated animals possibly through the slower microglial COX-1 upregulation and
15081582	COX-2	COX-2	3.8	Experiments that demonstrate protective abilities of COX-2 inhibition imply that COX-2 activation contributes to neuronal vulnerability and
15081582	COX-2	COX-2	3.8	Experiments that demonstrate protective abilities of COX-2 inhibition imply that COX-2 activation contributes to neuronal vulnerability and apoptosis by an undefined
15081582	COX	COX-dependent	0.0	It may be that the COX-dependent production of reactive oxygen species during the peroxidase step of	Junguk Hur
15081582	COX	COX	0.3	not known whether the amount of ROS produced by the COX enzyme is sufficient to cause neuronal death	Junguk Hur
15081582	COX-2	COX-2	3.8	In addition some of the prostaglandin products of the COX-2 enzyme cause direct damage to neurons as well as act
15081582	COX-2	COX-2	3.8	It is clear that neuroinflammation particularly COX-2 upregulation and prostaglandin production plays a significant role in neurodegenerative
15081582	COX-2	COX-2	3.8	It seems likely that COX-2 inhibitors can delay the progression of symptoms and clinical studies
15081582	COX-2	COX-2	3.8	Although treatment of neurodegenerative diseases such as ALS with COX-2 inhibitors is likely to produce some symptomatic benefit it is
15081582	COX-2	COX-2	3.8	activate NF-_amp_#x3ba B leading to a paradoxical activation of the COX-2 enzyme that is clearly a problem for this therapeutic approach
15081582	COX-2	COX-2	3.8	prostaglandins that feedback on NF-_amp_#x3ba B to regulate transcription of COX-2
15081582	COX-2	COX-2	3.8	Certain downstream products of the COX-2 enzyme are pro-apoptotic while others are neuroprotective
15081582	COX-2	COX-2	3.8	Inhibiting COX-2 will block both the neurodegenerative and neuroprotective products of this
15081582	COX-2	COX-2	3.8	in the development of future therapies rather than broadly targeting COX-2 or even further upstream at the level of NF-_amp_#x3ba B
15081582	COX-2	COX-2	3.8	of NF-_amp_#x3ba B to target specific prostaglandin synthases downstream of COX-2
15081582	COX	COX	0.3	Thorough understanding of the individual roles of prostaglandins COX isoforms and neuroprotective mechanisms of COX inhibitors are essential to	Junguk Hur
15081582	COX	COX	0.3	individual roles of prostaglandins COX isoforms and neuroprotective mechanisms of COX inhibitors are essential to further these therapeutic developments	Junguk Hur
15210305	COX-2	COX-2	2.0	COX-2 and CD11B (a a specific marker of microglia activation have
15210305	COX-2	COX-2	2.0	The significant up-regulation of COX-2 in ALS spinal cord compared to control tissues including patients
15210305	COX-2	COX-2	2.0	COX-2 mRNA up-regulation was restricted to pathologically affected tissue and this
15210305	COX-2	COX-2	2.0	to pathologically affected tissue and this was accompanied by increased COX-2 protein levels
15453089	COX	COX	0.6	Cyclooxygenase (COX) COX catalyses the first committed step in the synthesis of prostanoids	Junguk Hur
15453089	COX	COX	0.6	COX exists as constitutive and inducible isoforms	Junguk Hur
15453089	COX-2	COX-2	4.4	COX-2 is the inducible isoform rapidly expressed in several cell types
15453089	COX-2	COX-2	4.4	Since its discovery in the early 1990s COX-2 has emerged as a major player in inflammatory reactions in
15453089	COX-2	COX-2	4.4	By extension COX-2 expression in brain has been associated with pro-inflammatory activities thought
15453089	COX-2	COX-2	4.4	First in the central nervous system COX-2 is expressed under normal conditions and contributes to fundamental brain
15453089	COX-2	COX-2	4.4	the last decade the evidence of a direct role of COX-2 in neurodegenerative events is still controversial
15453089	COX-2	COX-2	4.4	Furthermore the emerging role of COX-2 in behavioral and cognitive functions will be discussed
15453089	COX	COX	0.6	Cyclooxygenase (COX), COX also known as prostaglandin (PG) PG H synthase catalyses the	Junguk Hur
15453089	COX	COX	0.6	COX has become a very popular enzyme since 1971 when it	Junguk Hur
15453089	COX	COX	0.6	(NSAIDs) NSAIDs exert their anti-inflammatory properties through the inhibition of COX enzymatic activity thus preventing PG synthesis ( 1	Junguk Hur
15453089	COX	COX	0.6	class of drugs affects many other important cellular targets nonetheless COX remains central to the development of anti-inflammatory treatments of a	Junguk Hur
15453089	COX	COX	0.6	COX is a unique enzyme	Junguk Hur
15453089	COX	COX	0.6	production of free radicals which are in part utilized by COX itself ( Fig 1	Junguk Hur
15453089	COX	COX	0.6	two enzymatic activities occur at distinct interacting sites on the COX molecule and external factors can affect each of them independently	Junguk Hur
15453089	COX	COX	0.6	Second during the cyclooxygenase activity COX undergoes a conformational rearrangement leading to an unstable intermediate which	Junguk Hur
15453089	COX	COX	0.6	COX is an integral membrane glycoprotein consisting of a homodimer with	Junguk Hur
15453089	COX-2	COX-2	4.4	to mediate physiological responses a second and inducible isoform termed COX-2 was identified in the early 1990s ( 4
15453089	COX-2	COX-2	4.4	COX-2 is rapidly expressed in several cell types in response to
15453089	COX-2	COX-2	4.4	COX-1 and COX-2 are coded by 2 distinct genes located on
15453089	COX-2	COX-2	4.4	COX-1 and COX-2 are coded by 2 distinct genes located on human chromosome
15453089	COX-2	COX-2	4.4	The COX-2 gene is characterized by the presence of a TATA box
15453089	COX-2	COX-2	4.4	its promoter region which account for the complex regulation of COX-2 expression
15453089	COX-2	COX-2	4.4	determinant or as translation inhibitory element suggesting post-transcriptional control of COX-2 expression
15453089	COX-2	COX-2	4.4	2 isoenzymes which could account for the different sensitivities of COX-1 and COX-2 to specific inhibitors ( 5
15453089	COX-2	COX-2	4.4	which could account for the different sensitivities of COX-1 and COX-2 to specific inhibitors ( 5
15453089	COX-2	COX-2	4.4	the 2 isoforms is the 18-amino acid insert near the COX-2 C-terminus which is not present in COX-1 and has allowed
15453089	COX	COX	0.6	The distribution of the 2 COX isoforms has been extensively studied in rat and human tissues	Junguk Hur
15453089	COX-2	COX-2	4.4	However in brain testes and kidney macula densa cells both COX-1 and COX-2 are expressed under physiological conditions ( 2
15453089	COX-2	COX-2	4.4	brain testes and kidney macula densa cells both COX-1 and COX-2 are expressed under physiological conditions ( 2
15453089	COX-2	COX-2	4.4	In rat brain COX-1 and COX-2 immunoreactivities are present in discrete neuronal populations distributed
15453089	COX-2	COX-2	4.4	In rat brain COX-1 and COX-2 immunoreactivities are present in discrete neuronal populations distributed in distinct
15453089	COX-2	COX-2	4.4	Similarly mRNAs for both COX-1 and COX-2 are present in several regions of human brain
15453089	COX-2	COX-2	4.4	Similarly mRNAs for both COX-1 and COX-2 are present in several regions of human brain although COX-2
15453089	COX-2	COX-2	4.4	COX-2 are present in several regions of human brain although COX-2 is the prominent isoform particularly in the hippocampus ( 8
15453089	COX-2	COX-2	4.4	The relative contribution of COX-1 and COX-2 activity to brain pathology and physiology has been
15453089	COX-2	COX-2	4.4	The relative contribution of COX-1 and COX-2 activity to brain pathology and physiology has been recently questioned
15453089	COX-2	COX-2	4.4	been overlooked on the other side mandatory evidence suggests that COX-2 plays a special role in normal neuronal function and in
15453089	COX-2	COX-2	4.4	the popular paradigm by which COX-1 serves physiological functions and COX-2 is responsible for _amp_#147 pathological_amp_#148 PGs cannot explain an increasing
15453089	COX	COX	0.6	Recently a third variant of COX named COX-3 and 2 partial COX-1 proteins (PCOX-1 PCOX-1 proteins	Junguk Hur
15453089	COX2	COX2	1.8	Recently a third variant of COX named COX-3 and 2 partial COX-1 proteins (PCOX-1 PCOX-1 proteins have been
15453089	COX	COX	0.6	Thus COX-3 could represent the brain-specific COX isoform the existence of which was hypothesized a few decades	Junguk Hur
15453089	COX	COX	0.6	of paracetamol in spite of its poor ability to inhibit COX from peripheral tissues ( 12	Junguk Hur
15453089	COX	COX	0.6	The potential role of COX isoforms and PGs in brain diseases has been extensively reviewed	Junguk Hur
15453089	COX-2	COX-2	4.4	Over-expression of COX-2 has been associated with neurotoxicity in acute conditions such as
15453089	COX-2	COX-2	4.4	However the beneficial or detrimental role played by COX-2 in inflammatory and neurodegenerative brain pathologies is still controversial
15453089	COX-2	COX-2	4.4	First the emerging role of COX-2 in cognitive functions will be discussed since understanding the role
15453089	COX-2	COX-2	4.4	cognitive functions will be discussed since understanding the role of COX-2 in brain function is an important prerequisite to fully understanding
15453089	COX-2	COX-2	4.4	to fully understanding how to exploit the potential benefits of COX-2 inhibition in disabling neurological diseases
15453089	COX-2	COX-2	4.4	In mammalian brain COX-2 is constitutively expressed in specific neuronal populations under normal physiological
15453089	COX-2	COX-2	4.4	In rat brain COX-2 mRNA and immunoreactivity were detected in dentate gyrus granule cells
15453089	COX-2	COX-2	4.4	This _amp_#147 constitutive_amp_#148 neuronal COX-2 expression should be more correctly regarded as _amp_#147 dynamically_amp_#148 regulated
15453089	COX-2	COX-2	4.4	The dependence of COX-2 expression on natural excitatory synaptic activity is supported by the
15453089	COX-2	COX-2	4.4	natural excitatory synaptic activity is supported by the presence of COX-2 immunoreactivity in distal dendrites and dendritic spines which are involved
15453089	COX-2	COX-2	4.4	distribution within a neuronal population is compatible with induction of COX-2 in subsets of neurons in response to natural excitatory synaptic
15453089	COX-2	COX-2	4.4	The involvement of COX-2 in synaptic activity is further supported by the developmental profile
15453089	COX-2	COX-2	4.4	synaptic activity is further supported by the developmental profile of COX-2 expression
15453089	COX-2	COX-2	4.4	In rat brain COX-2 expression follows developmental gradients and coincides with the critical period
15453089	COX-2	COX-2	4.4	and abnormalities of dendritic branching_amp_#151 the laminar pattern of cortical COX-2 immunoreactivity is disrupted in that COX-2-positive neurons are decreased in
15453089	COX	COX-2-positive	0.0	laminar pattern of cortical COX-2 immunoreactivity is disrupted in that COX-2-positive neurons are decreased in number and randomly distributed ( 18	Junguk Hur
15453089	COX-2	COX-2	4.4	neurons during the first post-natal week showed decreased levels of COX-2 but not COX-1 in the hippocampus at adulthood
15453089	COX-2	COX-2	4.4	of hippocampal cholinergic input may impact on the expression of COX-2 in hippocampal neurons and on the functional role of PGs
15453089	COX-2	COX-2	4.4	Indirect evidence of COX-2 involvement in synaptic plasticity has been obtained in the recent
15453089	COX	COX	0.6	plasticity has been obtained in the recent years by using COX inhibitors in in vivo and in vitro models of synaptic	Junguk Hur
15453089	COX-2	COX-2	4.4	COX-2 inhibitors but not COX-1 selective inhibitors administered systemically shortly after
15453089	COX	COX	0.6	Similarly intracerebral injection of COX inhibitors in chicks attenuated memory of a passive avoidance response	Junguk Hur
15453089	COX-2	COX-2-specific	1.8	In addition pre-training infusion of a COX-2-specific inhibitor (celecoxib) celecoxib in the hippocampus of adult rats impaired
15453089	COX-2	COX-2	4.4	acquisition of the Morris water maze suggesting that in rats COX-2 activity in the hippocampus is necessary for both memory and
15453089	COX	COX	0.6	keeping with these findings systemic administration of ibuprofen a non-selective COX inhibitor caused deficits in spatial learning in the water maze	Junguk Hur
15453089	COX	COX	0.6	through an increase in BDNF levels supporting the hypothesis that COX activity plays a permissive role in synaptic plasticity and spatial	Junguk Hur
15453089	COX	COX-2-inhibitor	0.0	not PGD 2 reversed the suppression of LTP induced by COX-2-inhibitor in hippocampal dentate granule neurons in vitro ( 24	Junguk Hur
15453089	COX-2	COX-2	4.4	2 which is preferentially formed during the enzymatic activity of COX-2 rather than of COX-1 could participate to synaptic plasticity through
15453089	COX-2	COX-2	4.4	neocortical blood flow in response to vibrissal stimulation by the COX-2 inhibitor NS398
15453089	COX	COX-2-derived	0.0	Moreover COX-2-derived PGs are involved in the coupling of synaptic plasticity with	Junguk Hur
15453089	COX-2	COX-2	4.4	hyperemic response was also impaired in mutant mice lacking of COX-2 ( 26
15453089	COX-2	COX-2	4.4	spite of the emerging evidence of a physiological role for COX-2 in brain development and function COX-2 knockout mice show no
15453089	COX-2	COX-2	4.4	a physiological role for COX-2 in brain development and function COX-2 knockout mice show no gross abnormalities of brain anatomy
15453089	COX-2	COX-2	4.4	In this light the expression of COX-2 and its contribution to the pathogenic events in MS have
15453089	COX-2	COX-2	4.4	COX-2 immunoreactivity has been found in experimental autoimmune encephalomyelitis (EAE), EAE
15453089	COX-2	COX-2	4.4	proteolipid protein revealed that during the acute phase of EAE COX-2 expression is confined within infiltrating macrophages and ramified microglia close
15453089	COX-2	COX-2	4.4	Very rare reactive astrocytes expressed COX-2 in this phase but their number significantly increased during relapse
15453089	COX-2	COX-2	4.4	but their number significantly increased during relapse phase suggesting that COX-2 induction in astrocytes could be due to soluble factors i.e
15453089	COX-2	COX-2	4.4	a peptide of another myelin protein the myelin basic protein COX-2 immunoreactivity was exclusively found associated with neurons and endothelial cells
15453089	COX	COX-2-positive	0.0	The number of COX-2-positive endothelial cells increased with the progression of the disease most	Junguk Hur
15453089	COX	COX-2-positive	0.0	the number of COX-1-positive macrophages increased along with that of COX-2-positive cells	Junguk Hur
15453089	COX-2	COX-2	4.4	brain parenchyma breakdown of BBB primary demyelination and axon damage COX-2 expression was restricted to major infiltrating hematogenous cell populations such
15453089	COX-2	COX-2	4.4	macrophages but the possibility that some endothelial cells also expressed COX-2 could not be ruled out
15453089	COX-2	COX-2	4.4	Neuronal COX-2 was not affected by the ongoing inflammation
15453089	COX-2	COX-2	4.4	broad area surrounding the inflammatory lesions there was no obvious COX-2 staining in these cells indicating that the upregulation of COX-2
15453089	COX-2	COX-2	4.4	COX-2 staining in these cells indicating that the upregulation of COX-2 expression in this model of chronic immune-mediated lesions is remarkably
15453089	COX-2	COX-2	4.4	A similar restricted COX-2 expression has been described in brain tissues from 7 MS
15453089	COX-2	COX-2	4.4	these specimens characterized by the presence of chronic active lesions COX-2 expression was studied by sophisticated confocal microscopy analysis
15453089	COX	COX-2-positive	0.0	COX-2-positive cells were present in all chronic active lesions examined and	Junguk Hur
15453089	COX-2	COX-2	4.4	COX-2 immunoreactivity was largely but not exclusively associated with cells expressing
15453089	COX-2	COX-2	4.4	However not all CD64-positive cells expressed COX-2
15453089	COX-2	COX-2	4.4	Expression of COX-2 was frequently associated with that of inducible NO synthase (iNOS),
15453089	COX-2	COX-2	4.4	The authors also propose that the colocalization of COX-2 and iNOS may be functionally linked to oligodendroglial excitotoxic death
15453089	COX-2	COX-2	4.4	Nonetheless a protective role of COX-2 in MS cannot be excluded
15453089	COX	COX-derived	0.0	co-administration of misoprostol a PGE 2 analog suggesting that distinct COX-derived products (i.e i.e ROS and PGs may have protective or	Junguk Hur
15453089	COX-2	COX-2	4.4	The well-established role of COX-2 in inflammation and in glutamate-dependent neurotoxicity has set the basis
15453089	COX-2	COX-2	4.4	glutamate-dependent neurotoxicity has set the basis for the hypothesis of COX-2 involvement in ALS pathogenesis
15453089	COX-2	COX-2	4.4	COX-2 mRNA and protein were increased in postmortem spinal cords of
15453089	COX-2	COX-2	4.4	of PGE 2 tissue levels paralleled the increased expression of COX-2 ( 43
15453089	COX-2	COX-2	4.4	The cell types expressing COX-2 have been identified in both animal and human specimens
15453089	COX-2	COX-2	4.4	Under normal conditions COX-2 is expressed in neurons in the spinal cord dorsal and
15453089	COX-2	COX-2	4.4	In postmortem spinal cord of ALS patients COX-2 expression was markedly increased and localized to both neurons and
15453089	COX	COX-2-positive	0.0	The number of COX-2-positive motor neurons and interneurons was significantly increased in spite of	Junguk Hur
15453089	COX-2	COX-2	4.4	In addition COX-2 was associated with astrocytes and and to a much lesser
15453089	COX-2	COX-2	4.4	A similar pattern of COX-2 expression was reported for the mutated SOD1 transgenic mice (
15453089	COX-2	COX-2	4.4	The role of COX-2 activity in ALS was examined by using selective COX-2 inhibitors
15453089	COX-2	COX-2	4.4	of COX-2 activity in ALS was examined by using selective COX-2 inhibitors
15453089	COX-2	COX-2	4.4	In the first study the COX-2 inhibitor SC236 significantly protected motor neurons in an organotypic spinal
15453089	COX-2	COX-2	4.4	These findings suggested that COX-2 could take part in the excitotoxic damage caused by elevated
15453089	COX-2	COX-2	4.4	same group showed that treatment of SOD1 transgenic mice with COX-2 inhibitor celecoxib significantly delayed the onset of disease prolonged the
15453089	COX-2	COX-2	4.4	These studies suggest that inhibition of COX-2 could have therapeutic benefits by altering the cascade of events
15453089	COX-2	COX-2	4.4	However in these studies mice received the COX-2 inhibitor treatment beginning several weeks before the onset of disease
15453089	COX-2	COX-2	4.4	Thus the efficacy of COX-2 inhibition in the presence of overt clinical signs of disease
15453089	COX-2	COX-2	4.4	Several mechanisms could be triggered by COX-2 overexpression
15453089	COX-2	COX-2	4.4	to the enhancing effect of PGE 2 on glutamate release COX-2 could contribute to oxidative stress-mediated damage by producing oxidizing reactive
15453089	COX-2	COX-2	4.4	In transgenic mutated SOD1 mice COX-2 and iNOS are induced with a similar temporal pattern and
15453089	COX-2	COX-2	4.4	COX-2 could also contribute to ALS by promoting inflammatory processes
15453089	COX	COX	0.6	been related to free radical scavenging effects rather then to COX inhibition or attenuation of inflammation ( 51 52	Junguk Hur
15453089	COX	COX	0.6	Two studies have investigated the expression of COX isoforms in postmortem PD specimens or in PD experimental models	Junguk Hur
15453089	COX-2	COX-2	4.4	The first study reported an increased expression of COX-2 in ameboid or activated microglial cells in the substantia nigra
15453089	COX-2	COX-2	4.4	nigra from 11 idiopathic PD patients whereas neuronal and astroglial COX-2 expression was not different in the control and PD groups
15453089	COX-2	COX-2	4.4	that the greater potential for PG synthesis is associated to COX-2 and microglial cells ( 53
15453089	COX-2	COX-2	4.4	the second and more recent study ( 52 showed that COX-2 is specifically induced in substantia nigra dopaminergic neurons in postmortem
15453089	COX-2	COX-2	4.4	The involvement of COX-2 in PD neurodegeneration was further suggested by the observation that
15453089	COX-2	COX-2	4.4	suggested by the observation that MPTP neurodegeneration was mitigated in COX-2 but not in COX-1 knock out mice
15453089	COX-2	COX-2	4.4	PGE 2 levels was associated with a strong induction of COX-2 expression which increased with the progression of disease and was
15453089	COX-2	COX-2	4.4	sporadic CJD ( 57 suggesting that the selective upregulation of COX-2 in microglial cells is not characteristic of a specific prion
15453089	COX-2	COX-2	4.4	results were reported in a recent study in which both COX-1 and COX-2 were increased in sporadic CJD cortex ( 58
15453089	COX-2	COX-2	4.4	reported in a recent study in which both COX-1 and COX-2 were increased in sporadic CJD cortex ( 58
15453089	COX-2	COX-2	4.4	COX-1 immunoreactivity was present in macrophages/microglial macrophages microglial cells whereas COX-2 was predominantly in neurons mRNAs and proteins of both isoforms
15453089	COX	COX	0.6	Increased COX activity in prion diseases was confirmed by 2 studies (	Junguk Hur
15453089	COX-2	COX-2	4.4	the CSF of CJD patients and the high expression of COX-2 in microglial cells in experimental prion diseases suggest that PGE
15453089	COX-2	COX-2	4.4	cells with apoptotic neurons has been reported to selectively promote COX-2 expression and PGE 2 synthesis ( 61
15453089	COX	COX	0.6	By contrast the non-selective COX inhibitor indomethacin had no significant effect on onset of clinical	Junguk Hur
15453089	COX	COX	0.6	The concept of a pathogenic role of COX in AD is deeply rooted in epidemiological studies reporting an	Junguk Hur
15453089	COX-2	COX-2	4.4	Over the last 10 years several analyses of COX-1 and COX-2 expressions have been carried out in animal models
15453089	COX-2	COX-2	4.4	Over the last 10 years several analyses of COX-1 and COX-2 expressions have been carried out in animal models and postmortem
15453089	COX-2	COX-2	4.4	still controversial body of evidence pointing to the involvement of COX-2 in the cascade of events leading to neurodegeneration in AD
15453089	COX-2	COX-2	4.4	COX-2 mRNA levels in AD brains were reported as either decreased
15453089	COX-2	COX-2	4.4	9 65 66 possibly because of the short half-life of COX-2 transcripts or individual variability of inflammatory-related processes ( 67
15453089	COX-2	COX-2	4.4	Several studies reported increased neuronal COX-2 immunoreactivity compared to control brain tissues ( 9 68
15453089	COX-2	COX-2	4.4	However in other studies in which COX-2 expression was related to specific hallmarks of the disease such
15453089	COX	COX-2-positive	0.0	dementia rating and Braak stage of disease the number of COX-2-positive neurons decreased with the severity of dementia	Junguk Hur
15453089	COX	COX-2-positive	0.0	In end stage AD COX-2-positive neurons were significantly fewer than in non-demented controls ( 68	Junguk Hur
15453089	COX-2	COX-2	4.4	more recent study ( 70 the number of neurons expressing COX-2 negatively correlated with the Braak score for amyloid deposits although
15453089	COX-2	COX-2	4.4	Braak score for amyloid deposits although a moderate albeit non-significant COX-2 increase was found at Braak stage A corresponding to the
15453089	COX-2	COX-2	4.4	COX-2 immunoreactivity did not correlate with Braak staging for neurofibrillary changes
15453089	COX-2	COX-2	4.4	These recent studies suggest that COX-2 expression varies with the disease stage and this may explain
15453089	COX-2	COX-2	4.4	also reported a colocalization and a significant correlation of neuronal COX-2 expression with cell cycle regulators involved in controlling the G
15453089	COX-2	COX-2	4.4	Although there are some indications that COX-2 might regulate cell cycle progression ( 70 the functional link
15453089	COX-2	COX-2	4.4	regulate cell cycle progression ( 70 the functional link between COX-2 and cell cycle alteration remains elusive
15453089	COX-2	COX-2	4.4	Nonetheless it can be suggested that COX-2 and cell cycle proteins are involved in early steps leading
15453089	COX-2	COX-2	4.4	In contrast to COX-2 the levels of COX-1 mRNA and protein were not significantly
15453089	COX	COX-2-positive	0.0	is consistent with the slight increase in the number of COX-2-positive neurons at Braak stage A as well as with the	Junguk Hur
15453089	COX	COX-2-positive	0.0	Braak stage A as well as with the reduction in COX-2-positive neurons reported in patients with severe dementia and Braak end-stage	Junguk Hur
15453089	COX-2	COX-2	4.4	The moderate increase in COX-2 expression and activity at very early stages of AD could
15453089	COX-2	COX-2	4.4	Upregulation of neuronal COX-2 is associated with ischemia and excitotoxicity suggesting that COX-2 is
15453089	COX-2	COX-2	4.4	neuronal COX-2 is associated with ischemia and excitotoxicity suggesting that COX-2 is involved in neurotoxic mechanisms
15453089	COX-2	COX-2	4.4	Increased susceptibility to excitotoxicity in COX-2 over-expressing neurons and neuroprotection by COX-2 inhibition has been shown
15453089	COX-2	COX-2	4.4	susceptibility to excitotoxicity in COX-2 over-expressing neurons and neuroprotection by COX-2 inhibition has been shown in several experimental models ( 64
15453089	COX-2	COX-2	4.4	Nonetheless increased COX-2 expression could be an adaptive reaction to pathological events such
15453089	COX-2	COX-2	4.4	Taking into account the positive and negative effects of increased COX-2 activity and the emerging role of COX-2-derived PGs in brain
15453089	COX-2	COX-2	4.4	is difficult to predict the final outcome of long-term therapeutic COX-2 inhibition
15453089	COX	COX-2-derived	0.0	effects of increased COX-2 activity and the emerging role of COX-2-derived PGs in brain function it is difficult to predict the	Junguk Hur
15453089	COX-2	COX-2	4.4	At present clinical trials of selective COX-2 inhibitors have not been as convincing as expected but these
15453089	COX-2	COX-2	4.4	the peroxisome proliferator-activated receptor- gamma suggesting that selective inhibition of COX-2 may not be the optimal therapeutic strategy ( 64
15453089	COX-2	COX-2	4.4	Since its discovery in early 1990s COX-2 has emerged as a major player in inflammatory reactions in
15453089	COX-2	COX-2	4.4	Evidence from several laboratories indicates that COX-2 is induced in various inflammatory settings is the main source
15453089	COX-2	COX-2	4.4	By extension COX-2 expression in brain has been associated with pro-inflammatory activities thought
15453089	COX-2	COX-2	4.4	should be borne in mind when considering the significance of COX-2 activity in brain diseases
15453089	COX-2	COX-2	4.4	First COX-2 is expressed under normal conditions and contributes to fundamental brain
15453089	COX-2	COX-2	4.4	the last decade the evidence of a direct role of COX-2 in neurodegenerative events is still controversial and further experimental and
15453089	COX-2	COX-2	4.4	are required to improve our knowledge of how and when COX-2 inhibition may have beneficial effects for patients suffering from inflammatory
15453089	COX-2	COX-2	4.4	neurons glia endothelial cells and infiltrating blood cells can express COX-2 in brain
15453089	COX-2	COX-2	4.4	Over-expression of COX-2 in each of these cells may have different functional consequences
15453089	COX-2	COX-2	4.4	outcome is likely to depend on the prevailing product of COX-2 activity including PGs with different functions and free radicals
15453089	COX-2	COX-2	4.4	particularly susceptible to damage caused by free radicals generated through COX-2 peroxidase activity whereas glial cells are more resistant
15453089	COX-2	COX-2	4.4	Specific signals seem responsible for COX-2 induction and/or and or over-expression in particular cell types such
15453089	COX-2	COX-2	4.4	The beneficial effects of specific and non-specific COX-2 inhibitors in several experimental models and epidemiological studies are an
15453089	COX-2	COX-2	4.4	studies are an indirect proof of the causative role of COX-2 in neurodegeneration as COX-independent mechanisms cannot be excluded
15453089	COX	COX-independent	0.0	proof of the causative role of COX-2 in neurodegeneration as COX-independent mechanisms cannot be excluded	Junguk Hur
15572176	COX-2	COX-2	1.0	forms of nitric oxide synthase (iNOS) iNOS and cyclooxygenase (COX-2), COX-2 display nitrotyrosine immunoreactivity and downregulate the glutamate transporter EAAT2
15572176	COX-2	COX-2	1.0	binding protein S100_amp_#x3b2 85 and express inflammatory makers such as COX-2 81 iNOS and neuronal NOS 5 and 115
15572176	COX-2	COX-2	1.0	For example reactive astrocytes in ALS express COX-2 an enzyme that catalyzes the synthesis of the inflammatory prostaglandin
15572176	COX-2	COX-2	1.0	Treatment of ALS mice with the COX-2 inhibitor Celecoxib delayed the onset of the disease and increased
15572176	COX-2	COX-2	1.0	Interestingly cytokine signaling can induce iNOS COX-2 and NMDA receptor subunit phosphorylation with different consequences in glial
15572176	COX-2	COX-2	1.0	tumour necrosis factor-alpha (TNF-_amp_#x3b1;), TNF-_amp_#x3b1 IL-1_amp_#x3b2 and IFN_amp_#x3b3 induces IL-6 COX-2 and iNOS and makes the cells vulnerable to undergo apoptosis
15691215	COX-2	COX-2	1.0	transfer of VEGF or glial cell-line derived neurotrophic factor anti-inflammatory COX-2 inhibitors and minocycline have had particularly promising results in mice
15799549	COX-2	COX-2	1.8	in ALS spinal cord showed strong expression of cyclooxygenase-2 (COX-2) COX-2 (one one log greater than control tissues and inducible nitric
15799549	COX	COX-2-negative	0.0	hemispheric cerebral infarction macrophage infiltration of the white matter was COX-2-negative and restricted to lateral and anterior corticospinal tracts	Junguk Hur
15804265	COX-2	COX-2	1.0	Inhibition of a key mediator of inflammation cyclooxygenase 2 (COX-2), COX-2 represents a promising therapeutic approach in ALS
15804265	COX-2	COX-2	1.0	Here we tested the in vivo effects of a specific COX-2 inhibitor Rofecoxib administered by intraperitoneal injection in the SOD1(G93A SOD1
15974901	COX	COX	0.0	are reports suggesting that NSAIDs act independently of cyclooxygenase (COX) COX inhibition but only at higher doses	Junguk Hur
16101543	COX-2	COX-2	1.3	by two isoforms of the cyclooxygenase (COX) COX enzyme namely COX-1 and COX-2
16101543	COX-2	COX-2	1.3	isoforms of the cyclooxygenase (COX) COX enzyme namely COX-1 and COX-2
16101543	COX	COX	0.0	acid (AA) AA by two isoforms of the cyclooxygenase (COX) COX enzyme namely COX-1 and COX-2	Junguk Hur
16101543	COX-2	COX-2	1.3	In particular the action of COX-2 and PGs in CNS inflammation has gained much attention recently
16101543	COX	COX	0.0	However accumulating evidence also shows that COX inhibitors alleviate various types of brain damage via suppressing inflammatory	Junguk Hur
16101543	COX	COX	0.0	Accordingly the roles of two COX enzymes in mediating inflammation and anti-inflammation have recently been debated	Junguk Hur
16101543	COX	COX	0.0	findings indicating that the reciprocal interaction of glial cell activation COX enzymes and PGs mediates neurodegeneration and neuroprotection during brain inflammation	Junguk Hur
16120782	COX-2	COX-2	2.0	astrocytes as well as the expression of cyclooxygenase 2 (COX-2) COX-2 and nitric oxide synthase (iNOS) iNOS in the spinal cord
16120782	COX-2	COX-2	2.0	For the analysis of iNOS and COX-2 100 microg of protein samples was separated in 10% SDS
16120782	COX-2	COX-2	2.0	murine iNOS Santa Cruz Biotechology Heidelberg Germany or a polyclonal COX-2 antibody at a 1 600 dilution (rabbit rabbit polyclonal antibody
16120782	COX-2	COX-2	2.0	dilution (rabbit rabbit polyclonal antibody to synthetic peptide from murine COX-2 Cayman Ann Arbor MI
16120782	COX-2	COX-2	2.0	The specificities of the iNOS and COX-2 antibodies have been confirmed by positive controls containing iNOS or
16120782	COX-2	COX-2	2.0	antibodies have been confirmed by positive controls containing iNOS or COX-2 protein (data data not shown
16120782	COX-2	COX-2	2.0	Coinduction of COX-2 and iNOS were described in several neurodegenerative disorders including ALS
16120782	COX-2	COX-2	2.0	analysis of lumbar spinal cord lysates from 90-d-old mice confirmed COX-2 expression in wild-type mice ( n = 4 and revealed
16120782	COX-2	COX-2	2.0	revealed that SOD1-G93A mice ( n = 4 showed elevated COX-2 levels ( Fig 3 b
16120782	COX-2	COX-2	2.0	In both cases Pio treatment significantly decreased COX-2 and iNOS expression in SOD1-G93A mice ( n = 4
16120782	COX-2	COX-2	2.0	wt-Pio n = 5 for SOD1 and SOD1-Pio and of COX-2 and iNOS Western blots ( n = 4 for all
16120782	COX-2	COX-2	2.0	We found a marked reduction in the expression of COX-2 and iNOS two major proinflammatory enzymes after Pio treatment
16120782	COX-2	COX-2	2.0	by similar or identical stimulators (O'Banion, O'Banion 1999 because the COX-2 and iNOS promoters share several binding sites for signal transduction
16120782	COX	COX-2-generated	0.0	from the detrimental action of either iNOS-derived excess NO or COX-2-generated proinflammatory prostanoids the dual inhibition of both enzymes observed in	Junguk Hur
16120782	COX-2	COX-2	2.0	Thus NO may increase the catalytic activity of COX-2 thereby increasing the production of proinflammatory prostanoids (Nogawa Nogawa et
16120782	COX-2	COX-2	2.0	signal transduction pathway is also involved in the iNOS and COX-2 gene regulation after inflammatory stimulation
16120782	COX-2	COX-2	2.0	JAK-STAT pathway contributes to the observed suppression of iNOS and COX-2 expression
16380619	COX-2	COX-2	1.0	mediator and a major downstream product of cyclooxygenase 2 (COX-2) COX-2
16380619	COX-2	COX-2	1.0	Increased levels of PGE-2 and COX-2 were described in patients with ALS
16380619	COX-2	COX-2	1.0	PGE-2 and COX-2 presented both angiogenic properties and reciprocal interactions between COX-2/PGE-2 COX-2
16380619	COX-2	COX-2	1.0	COX-2 presented both angiogenic properties and reciprocal interactions between COX-2/PGE-2 COX-2 PGE-2 and VEGF are described
16380619	COX-2	COX-2	1.0	findings suggest that increased levels of IL-6 TNF-alpha PGE-2 and COX-2 observed in patients with ALS parallel motor neuronal loss and
16380619	COX-2	COX-2	1.0	We hypothesize that COX-2 inhibitors may even be harmful in patients with ALS because
16624536	COX-2	COX-2	1.5	An increased expression of pro-inflammatory cytokines COX-2 29 30 and 31 and of microglia-mediated protein oxidative pathology
16624536	COX-2	COX-2	1.5	This process is associated with an increased level of COX-2 mRNA and protein and an increase in PGE 2 content
16624536	COX-2	COX-2	1.5	excitotoxicity in organotypic spinal cord cultures can be suppressed by COX-2 inhibition 52
16624536	COX-2	COX-2	1.5	as well as decreased mRNA expression of inflammatory products including COX-2 iNOS and I_amp_#x3ba B (an an inhibitor of NF-_amp_#x3ba B
16624536	COX-2	COX-2	1.5	Like microglia reactive astrocytes express inflammatory markers including iNOS and COX-2 114 and can produce proinflammatory mediators including prostaglandins 115 IL-6
16624536	COX-2	COX-2	1.5	Celecoxib (Celebrex) Celebrex and rofecoxib are inhibitors of COX-2
16624536	COX-2	COX-2	1.5	Treatment with these COX-2 inhibitors combined with creatine increased survival by up to 30%
16624536	COX	COX	0.6	mice 139 140 and 141 while treatment with a non-specific COX inhibitor (sulindac) sulindac extended survival by roughly 10% 142	Junguk Hur
16624536	COX	COX	0.6	should be noted however that to date none of the COX inhibitors tested have shown efficacy in human ALS patients	Junguk Hur
16647138	COX	COX	2.9	Thus cyclooxygenases (COX), COX lipoxygenases (LOX), LOX and epoxygenases (EPOX) EPOX metabolize AA to	Junguk Hur
16647138	COX	COX	2.9	In contrast COX and LOX metabolize DHA to resolvins docosatrienes and neuroprotectins	Junguk Hur
16647138	COX	COX	2.9	and non-neural tissues express several different isoforms of PLA 2 COX and LOX under normal or stimulated situations ( Kis et	Junguk Hur
16647138	COX	COX	2.9	How the isoforms of PLA 2 COX and LOX enzymes interact with each other remains to be	Junguk Hur
16647138	COX	COX	2.9	Eicosanoid synthesis through COX and LOX enzymes may involve different AA substrate pools and	Junguk Hur
16647138	COX	COX	2.9	stimulation and modulation of PLA 2 PLC and PLD and COX activities	Junguk Hur
16647138	COX	COX	2.9	In addition to the abovementioned lipid mediators COX LOX and EPOX-catalyzed reactions also produce reactive oxygen species (ROS)	Junguk Hur
16647138	COX	COX	2.9	summarize studies on the multiplicity properties regulation and roles of COX LOX and EPOX in brain tissue	Junguk Hur
16647138	COX	COX	2.9	this discussion would initiate more studies on the importance of COX LOX EPOX and their lipid mediators in neurological disorders	Junguk Hur
16647138	COX	COX	2.9	The inhibition of COX LOX and EPOX activities may provide an attractive approach for	Junguk Hur
16647138	COX	COX	2.9	Cyclooxygenases (COX) COX	Junguk Hur
16647138	COX	COX	2.9	PGG 2 to generate a radical intermediate that begins the COX reaction ( Jiang et al. 2004	Junguk Hur
16647138	COX	COX	2.9	Three forms of COX enzymes designated as COX-1 COX-2 and COX-3 occur in mammalian	Junguk Hur
16647138	COX-2	COX-2	16.2	Three forms of COX enzymes designated as COX-1 COX-2 and COX-3 occur in mammalian tissues
16647138	COX-2	COX-2	16.2	such as cytokines growth factors and bacterial endotoxin rapidly induce COX-2 which is normally undetectable in healthy tissues
16647138	COX-2	COX-2	16.2	COX-2 is constitutively expressed in the kidney stomach and brain (
16647138	COX-2	COX-2	16.2	COX-1 and COX-2 are homodimers
16647138	COX-2	COX-2	16.2	COX-1 and COX-2 are homodimers
16647138	COX-2	COX-2	16.2	COX-1 contains Val at the 434 and 523 positions whereas COX-2 has Ile at positions 434 and 523
16647138	COX-2	COX-2	16.2	larger and more flexible substrate and inhibitor binding sites in COX-2 than in COX-1 ( Kurumbail et al. 1996
16647138	COX-2	COX-2	16.2	The amino acid sequences of COX-1 and COX-2 also differ from each other at the N-
16647138	COX-2	COX-2	16.2	The amino acid sequences of COX-1 and COX-2 also differ from each other at the N- and C-termini
16647138	COX-2	COX-2	16.2	COX-2 lacks a 17 amino acid sequence at the N-terminus but
16647138	COX-2	COX-2	16.2	Thus the active site of COX-2 is larger and more accommodating than that of COX-1 and
16647138	COX-2	COX-2	16.2	This property may be responsible for greater eicosanoid production by COX-2 when the AA concentration is low ( Smith et al.
16647138	COX-2	COX-2	16.2	AA is the preferred substrate for COX-1 and COX-2
16647138	COX-2	COX-2	16.2	AA is the preferred substrate for COX-1 and COX-2
16647138	COX	COX	2.9	The action of COX enzymes on eicosapentaenoic acid generates the 3-series of prostaglandins and	Junguk Hur
16647138	COX	COX	2.9	All isoforms of COX enzymes have been cloned ( DeWitt and Smith 1988 and	Junguk Hur
16647138	COX-2	COX-2	16.2	The COX-2 gene is 8.3 kb whereas the COX-1 gene is much
16647138	COX-2	COX-2	16.2	COX-1 mRNA is approximately 2.8 kb while COX-2 mRNA is approximately 4.0 kb
16647138	COX-2	COX-2	16.2	Analysis of the 5_amp_#x2032 -flanking untranslated regions of COX-1 and COX-2 indicates that the COX-1 gene is associated with
16647138	COX-2	COX-2	16.2	Analysis of the 5_amp_#x2032 -flanking untranslated regions of COX-1 and COX-2 indicates that the COX-1 gene is associated with housekeeping activities
16647138	COX-2	COX-2	16.2	the COX-1 gene is associated with housekeeping activities whereas the COX-2 gene is involved in response-related activities
16647138	COX-2	COX-2	16.2	The 5_amp_#x2032 -flanking region of the COX-2 gene has a TATA box 30 base pairs upstream from
16647138	COX-2	COX-2	16.2	The COX-2 gene also contains a number of putative regulatory sites including
16647138	COX-2	COX-2	16.2	activity such as IL-4 IL-10 and IL-13 can specifically inhibit COX-2 upregulation
16647138	COX-2	COX-2	16.2	location of these sites differs considerably from those in the COX-2 gene
16647138	COX-2	COX-2	16.2	COX-1 does not respond to NF-_amp_#x3ba B as intensely as COX-2
16647138	COX-2	COX-2	16.2	In rat and ovine brain COX-1 and COX-2 immunoreactivities are present in discrete neuronal populations distributed
16647138	COX-2	COX-2	16.2	In rat and ovine brain COX-1 and COX-2 immunoreactivities are present in discrete neuronal populations distributed in distinct
16647138	COX-2	COX-2	16.2	midbrain pons and medulla ( Breder et al. 1995 whereas COX-2 immunoreactivity prevails in neurons and glial cells of hippocampus hypothalamus
16647138	COX-2	COX-2	16.2	In neurons astrocytes and microglial cells COX-2 immunoreactivity is localized to the perinuclear regions ( Tomimoto et
16647138	COX-2	COX-2	16.2	The expression of COX-2 is markedly increased in microglial cells after intraperitoneal administration of
16647138	COX-2	COX-2	16.2	cells after intraperitoneal administration of lipopolysaccharide (LPS), LPS whereas neuronal COX-2 remains unchanged ( Elmquist et al. 1997
16647138	COX-2	COX-2	16.2	In microglial cells COX-2 expression and ability to release PGE 2 TXA 2 and
16647138	COX-2	COX-2	16.2	COX-2 induction in microglia by proinflammatory stimuli is apparently similar to
16647138	COX	COX	2.9	COX-3 is a new acetaminophen-sensitive isoform of the COX family	Junguk Hur
16647138	COX-2	COX-2	16.2	properties have been described for COX-3 compared with COX-1 or COX-2 enzymes many investigators consider it to be a splice variant
16647138	COX-2	COX-2	16.2	Comparison of canine COX-3 activity with murine COX-1 and COX-2 demonstrates that analgesic/antipyretic analgesic antipyretic drugs such as
16647138	COX-2	COX-2	16.2	Comparison of canine COX-3 activity with murine COX-1 and COX-2 demonstrates that analgesic/antipyretic analgesic antipyretic drugs such as acetaminophen phenacetin
16647138	COX-2	COX-2	16.2	a 127-amino-acid open reading frame with no sequence similarity with COX-2 ( Snipes et al. 2005
16647138	COX	COX	2.9	This is in contrast to the canine COX-3 which has COX activity	Junguk Hur
16647138	COX	COX	2.9	COX genes may produce a number of splice variants some with	Junguk Hur
16647138	COX	COX	2.9	number of splice variants some with and others without any COX activity ( Kis et al. 2005 Simmons et al. 2005	Junguk Hur
16647138	COX-2	COX-2	16.2	of affecting the cerebral circulation in a comparable manner to COX-1 and 2 pathways
16647138	COX	COX	2.9	In addition to the COX and LOX pathways the cytochrome P450 (CYP450) CYP450 pathways also	Junguk Hur
16647138	COX-2	COX-2	16.2	endothelial cells result in endothelial cell tube formation by stimulating COX-2 expression and prostacyclin production ( Michaelis et al. 2005
16647138	COX	COX	2.9	Roles of COX LOX and EPOX in brain tissue	Junguk Hur
16647138	COX	COX	2.9	COX LOX and EPOX are important enzymes involved in the generation	Junguk Hur
16647138	COX	COX	2.9	COX enzymes catalyze the conversion of AA into prostaglandins and thromboxanes	Junguk Hur
16647138	COX	COX	2.9	to release AA metabolites by reactions catalyzed by PLA 2 COX LOX and EPOX depends upon not only on neural cell	Junguk Hur
16647138	COX-2	COX-2	16.2	the generation of PGE 2 LTB 4 and PAF through COX-2 LOX and acetyl-CoA acetyltransferase reactions respectively
16647138	COX-2	COX-2	16.2	PLA 2 COX-2 and LOX inhibitors have been used to treat acute inflammation
16647138	COX	COX	2.9	Involvement of COX and LOX in neurodegeneration	Junguk Hur
16647138	COX	COX	2.9	to neuronal degeneration by the activation of caspases PLA 2 COX and LOX resulting in apoptotic cell death	Junguk Hur
16647138	COX	COX	2.9	supported by the observation that inhibitors of caspases PLA 2 COX and LOX block apoptosis ( Farooqui et al. 2004 Farooqui	Junguk Hur
16647138	COX	COX	2.9	Collective evidence suggests that all isoforms of PLA 2 COX and LOX along with caspases are involved in apoptotic cell	Junguk Hur
16647138	COX	COX	2.9	The stimulation of COX and LOX isoforms and oxidation of arachidonic acid is harmful	Junguk Hur
16647138	COX	COX	2.9	Involvement of COX and LOX in pain state	Junguk Hur
16647138	COX	COX	2.9	The action of COX enzymes on AA generates these metabolites	Junguk Hur
16647138	COX-2	COX-2	16.2	COX-1 and COX-2 play a central role in the induction of
16647138	COX-2	COX-2	16.2	COX-1 and COX-2 play a central role in the induction of nociception produced
16647138	COX-2	COX-2	16.2	An increase in the expression of COX-2 activity accompanies the induction of nociception ( Svensson and Yaksh
16647138	COX-2	COX-2	16.2	COX-2 expression and its activity in neuropathic pain are controversial
16647138	COX-2	COX-2	16.2	COX-2 levels in the dorsal spinal cord increase following a L5/L6
16647138	COX-2	COX-2	16.2	Zhao et al. 2000 and intrathecal or local injections of COX-2 inhibitors prevent the development of nociception
16647138	COX-2	COX-2	16.2	In contrast only a very small change in spinal cord COX-2 mRNA and protein expression follows the spared nerve injury model
16647138	COX-2	COX-2	16.2	model of partial nerve injury in the rat and selective COX-2 inhibition does not alter the nociception
16647138	COX-2	COX-2	16.2	This indicates that COX-2 does not play a role in the development and maintenance
16647138	COX	COX-2-generated	0.3	as well as peripheral nociceptive mechanisms and both mechanisms involve COX-2-generated metabolites	Junguk Hur
16647138	COX	COX-isozyme-deficient	0.3	(hot-plate) hot-plate and slowly developing diffuse pain (writhing) writhing with COX-isozyme-deficient mice indicate that COX-3 plays an important role in chronic	Junguk Hur
16647138	COX	COX	2.9	Collective evidence suggests that all isoforms of COX enzymes are involved in pain transmission processes in brain and	Junguk Hur
16647138	COX	COX	2.9	Involvement of COX and LOX in synaptic plasticity	Junguk Hur
16647138	COX-2	COX-2	16.2	NMDA receptor-dependent synaptic activity dynamically regulates the expression of the COX-2 gene in brain
16647138	COX-2	COX-2	16.2	most abundant prostaglandins generated in the brain through COX-1/COX-2 COX-1 COX-2 pathways (PGE PGE 2 PGF 2a and PGD 2 are
16647138	COX-2	COX-2	16.2	The observation that COX-2 inhibitors block the induction of LTP in hippocampal dentate granules
16647138	COX-2	COX-2-mediated	2.3	PGE 2 but not PGD 2 or PGF 2_amp_#x3b1 reverses COX-2-mediated suppression of LTP
16647138	COX-2	COX-2-induced	2.3	These studies suggest that PGE 2 is the effector of COX-2-induced synaptic plasticity
16647138	COX-2	COX-2	16.2	The translocation of COX-2 to the nuclear envelope during neural cell stimulation generates eicosanoids
16647138	COX	COX-	1.8	In brain tissue COX- and LOX-generated metabolites of AA may modulate synaptic plasticity not	Junguk Hur
16647138	COX-2	COX-2	16.2	into the cell ( Kadoya et al. 2003 4-HNE induces COX-2 expression in macrophages
16647138	COX-2	COX-2	16.2	The expression of COX-2 plays an important role in the intensification of inflammatory responses
16647138	COX	COX	2.9	A nonenzymic mechanism analogous to the formation of prostaglandins by COX enzymes forms the isoprostanes	Junguk Hur
16647138	COX-2	COX-2	16.2	PAF also stimulates the inducible isoform of COX-2 ( Bazan et al. 1993
16647138	COX-2	COX-2	16.2	An immediate early gene encodes COX-2 which is responsible for prostaglandin synthesis in neuropathological processes
16647138	COX-2	COX-2	16.2	50730 blocks stimulation of the immediate early gene responsible for COX-2 ( Bazan et al. 1997
16647138	COX-2	COX-2	16.2	The COX-2 inhibitor NS-398 was ineffective as were two cytochrome P450 antagonists
16647138	COX-2	COX-2	16.2	two cytochrome P450 antagonists (MS-PPOH MS-PPOH and miconazole suggesting that COX-2 and P450 metabolites do not play a significant role in
16647138	COX-2	COX-2	16.2	(2006) 2006 observed dense immunohistochemical staining for COX-1 but not COX-2 in the astrocytic endfeet that ensheath cortical arterioles as well
16647138	COX-2	COX-2	16.2	COX-2 expression and prostaglandin E2 production are enhanced in the spinal
16647138	COX-2	COX-2	16.2	Constitutive levels of COX-2 in the spinal cord are low but peripheral inflammation upregulates
16647138	COX-2	COX-2	16.2	In the brain synaptic activity regulates the basal expression of COX-2
16647138	COX-2	COX-2	16.2	Furthermore COX-2 is localized in neuronal dendritic spines where active synapses are
16647138	COX-2	COX-2	16.2	Kaufmann et al. 1996 implying that both constitutive and inducible COX-2 may participate in synaptic plasticity
16647138	COX-2	COX-2	16.2	Selective COX-2 inhibition significantly reduced postsynaptic excitability back-propagation of dendritic action-potential-associated Ca
16647138	COX-2	COX-2	16.2	consistent with a likely role of PGE 2 generated by COX-2 in the regulation of membrane excitability and long-term synaptic plasticity
16647138	COX	COX-2-synthesized	0.3	COX-2-synthesized PGE 2 may act on PG receptors within the same	Junguk Hur
16647138	COX-2	COX-2	16.2	Administration of a selective COX-2 inhibitor to eliminate endogenous PGE 2 reduced somatic and dendritic
16647138	COX-2	COX-2	16.2	amplitude and temporal summation in slices previously treated with a COX-2 inhibitor ( Chen and Bazan 2005
16647138	COX-2	COX-2	16.2	is a profound difference between NSAIDs with different selectivities for COX-1 and COX-2 with regard to their effects on the synthesis
16647138	COX-2	COX-2	16.2	profound difference between NSAIDs with different selectivities for COX-1 and COX-2 with regard to their effects on the synthesis of endogenous
16647138	COX-2	COX-2	16.2	an inhibitory action on COX-1 increased brain KYNA formation whereas COX-2 selective inhibitors had the opposite effect
16647138	COX	COX	2.9	and lowering in brain KYNA levels following the administration of COX inhibitors suggesting that PGs tonically modulate KYNA metabolism	Junguk Hur
16647138	COX	COX	2.9	Gene deletion studies_amp_#x2014 COX and LOX	Junguk Hur
16647138	COX	COX	2.9	The development of COX deficient mice has allowed investigators to study the individual roles	Junguk Hur
16647138	COX-2	COX-2	16.2	has allowed investigators to study the individual roles of the COX-1 and COX-2 isoforms
16647138	COX-2	COX-2	16.2	investigators to study the individual roles of the COX-1 and COX-2 isoforms
16647138	COX	COX-2-deficient	0.3	COX-2-deficient mice have poor survival rates reduced resolution of gastrointestinal ulcers	Junguk Hur
16647138	COX-2	COX-2	16.2	these lists and that for the maintenance of normal physiology COX-2 appears to play a more critical role
16647138	COX	COX	2.9	which there is evidence for a central role of both COX enzymes is hypophagia (a a reduction in feeding in mice	Junguk Hur
16647138	COX-2	COX-2	16.2	reduction in milk intake in comparison with wild-type mice whereas COX-2 mice responded more like wild-type animals
16647138	COX-2	COX-2	16.2	However at 90 to 120 min after IL-1_amp_#x3b2 administration COX-2 KO mice showed only small responses while COX-1 KO mice
16647138	COX-2	COX-2	16.2	is primarily involved in the early phase of milk intake COX-2 is more responsible for the later phase ( Swiergiel and
16647138	COX-2	COX-2-	2.3	demonstrated reduced and increased susceptibility to ischemic brain injury in COX-2- and COX-1-deficient mice respectively
16647138	COX	COX-2-deficient	0.3	level of neuronal injury produced by transient global ischemia in COX-2-deficient mice in comparison with wild-type mice	Junguk Hur
16647138	COX-2	COX-2	16.2	Various lines of evidence implicate COX-2 in fever production
16647138	COX-2	COX-2	16.2	lipopolysaccharide (LPS) LPS or intravenous and intracerebral IL-1_amp_#x3b2 administration whereas COX-2 inhibitors suppress the fever induced by these pyrogens ( Cao
16647138	COX	COX-2-deficient	0.3	febrile response to injection of intraperitoneal LPS in COX-1 and COX-2-deficient mice	Junguk Hur
16647138	COX-2	COX-2	16.2	LPS with a 1_amp_#xb0 C rise in temperature whereas the COX-2 _amp_#x2212;/_amp_#x2212; _amp_#x2212 _amp_#x2212 mice displayed no increase in temperature indicating
16647138	COX-2	COX-2	16.2	_amp_#x2212 _amp_#x2212 mice displayed no increase in temperature indicating that COX-2 is necessary for LPS-induced fever production
16647138	COX-2	COX-2	16.2	Endocannabinoids and COX-2
16647138	COX-2	COX-2	16.2	these hydrolytic pathways endocannabinoids can be selectively oxygenated by a COX-2 pathway ( Kozak and Marnett 2002 and Yu et al.
16647138	COX-2	COX-2	16.2	Inhibition of COX-2 can potentiate the action of these endocannabinoids ( Kim and
16647138	COX-2	COX-2	16.2	Furthermore metabolites of AEA and 2-AG derived from COX-2 possess biological activity including the activation of protein kinase C
16647138	COX-2	COX-2	16.2	significantly more stable metabolically than free acid PGs suggesting that COX-2 action on endocannabinoids may provide oxygenated lipids with sufficiently long
16647138	COX-2	COX-2	16.2	2 production induced by either AEA or MAEA a selective COX-2 inhibitor indicating induction of COX-2
16647138	COX-2	COX-2	16.2	AEA or MAEA a selective COX-2 inhibitor indicating induction of COX-2
16647138	COX-2	COX-2	16.2	AEA and MAEA increased the expression of COX-2 protein an action that AM-251 a selective cannabinoid receptor-1-agonist partially
16647138	COX-2	COX-2	16.2	Additionally AEA increased COX-2 promoter activity
16647138	COX-2	COX-2	16.2	(2005) 2005 suggested that AEA increases COX-2 expression at the transcriptional level through a cannabinoid-receptor-1-mediated mechanism in
16647138	COX-2	COX-2	16.2	(2005) 2005 concluded that oxidation of eCB by COX-2 decreases their level in the hippocampus thus enhancing LTP eCBs
16647138	COX-2	COX-2	16.2	Conversely inhibition of COX-2 prevented LTP in hippocampal dentate neurons ( Kim and Alger
16647138	COX-2	COX-2	16.2	( Kim and Alger 2004 leading to the conclusion that COX-2 regulates the formation of CB1 ligands that negatively regulate LTP
16647138	COX	COX	2.9	Early indications of an involvement of COX and LOX in traumatic brain injury arose from studies on	Junguk Hur
16647138	COX-2	COX-2	16.2	COX-2 is an important mediator of neuroinflammation ( Feng et al.
16647138	COX-2	COX-2	16.2	of the rat cerebral cortex caused a bilateral induction of COX-2 mRNA in the cortex and dentate gyrus
16647138	COX-2	COX-2	16.2	COX-2 activity was detectable in these areas and persisted in the
16647138	COX-2	COX-2	16.2	Upregulation of COX-2 mRNA has also been observed in the rat spinal cord
16647138	COX-2	COX-2	16.2	COX-2 immunoreactivity in this instance was observed only in endothelial cells
16647138	COX-2	COX-2	16.2	(1998) 1998 observed trauma-induced COX-2 mRNA expression in spinal cord neurons and around blood vessels
16647138	COX-2	COX-2	16.2	(2000) 2000 found COX-2 protein almost exclusively in neurons
16647138	COX-2	COX-2	16.2	The effects of COX-2 inhibition on recovery following traumatic brain injury (TBI) TBI in
16647138	COX-2	COX-2	16.2	worsening of motor but not cognitive performance and suggested that COX-2 induction following TBI may play a protective role
16647138	COX-2	COX-2	16.2	Studies on COX-1 and COX-2 gene deletion provided some information on the roles
16647138	COX-2	COX-2	16.2	Studies on COX-1 and COX-2 gene deletion provided some information on the roles of these
16647138	COX	COX-2-deficient	0.3	COX-2-deficient mice displayed a reduced susceptibility to ischemic brain injury and	Junguk Hur
16647138	COX-2	COX-2	16.2	Conversely mice with neuronal overexpression of COX-2 had increased levels of PGE 2 with significant increases in
16647138	COX-2	COX-2	16.2	Clinical trials have recently revealed that long-term therapy with COX-2 inhibitors increases the incidence of myocardial infarction and stroke which
16647138	COX-2	COX-2	16.2	PGE 2 may be responsible for the neurotoxic effects of COX-2 ( Manabe et al. 2004
16647138	COX-2	COX-2	16.2	COX-2 mRNA is upregulated in the ischemic rat cerebral hemisphere beginning
16647138	COX-2	COX-2	16.2	Neurons at the medial edge of the ischemic area had COX-2 immunoreactivity and the injured brain had elevated PGE 2 levels
16647138	COX-2	COX-2	16.2	These data would appear to implicate COX-2 in the mechanisms of delayed neuronal death
16647138	COX-2	COX-2	16.2	PLA 2 activation may be converted to prostaglandins by both COX-1 and COX-2 during the immediate response and predominantly by COX-2
16647138	COX-2	COX-2	16.2	activation may be converted to prostaglandins by both COX-1 and COX-2 during the immediate response and predominantly by COX-2 during the
16647138	COX-2	COX-2	16.2	COX-1 and COX-2 during the immediate response and predominantly by COX-2 during the delayed response ( Murakami et al. 2002 sPLA
16647138	COX-2	COX-2	16.2	delayed response ( Murakami et al. 2002 sPLA 2 upregulates COX-2 ( Bidgood et al. 2000 and is functionally coupled with
16647138	COX-2	COX-2	16.2	( Bidgood et al. 2000 and is functionally coupled with COX-2 but not with COX-1 ( Balsinde et al. 1998
16647138	COX-2	COX-2	16.2	Substantial increases in COX-2 mRNA and protein levels occur in the peri-infarct and focal
16647138	COX-2	COX-2	16.2	In the ischemic core significant increases in COX-2 mRNA followed 6 h of ischemia
16647138	COX-2	COX-2	16.2	ischemic core during ischemic periods did not show increases in COX-2 protein
16647138	COX-2	COX-2	16.2	in microglia but weakly in neurons in control brains whereas COX-2 was absent in control autopsied brains
16647138	COX-2	COX-2	16.2	However COX-2 was induced robustly in neurons during the acute phase of
16647138	COX-2	COX-2	16.2	COX-2 was also upregulated in microglia during focal ischemia ( Tomimoto
16647138	COX	COX	2.9	of inhibitors of PLA 2 as well as inhibitors of COX LOX and cytochrome P450 isozymes to reverse the depolarization	Junguk Hur
16647138	COX	COX	2.9	Numerous studies have evaluated the effects of COX inhibitors on stroke injury	Junguk Hur
16647138	COX-2	COX-2	16.2	Pretreatment with indomethacin an inhibitor of COX-1 and COX-2 reduced infarct size following focal ischemia with reperfusion
16647138	COX-2	COX-2	16.2	Pretreatment with indomethacin an inhibitor of COX-1 and COX-2 reduced infarct size following focal ischemia with reperfusion in rats
16647138	COX-2	COX-2	16.2	Ibuprofen which also inhibits both COX-1 and COX-2 reduced neuronal injury and improved cerebral blood flow
16647138	COX-2	COX-2	16.2	Ibuprofen which also inhibits both COX-1 and COX-2 reduced neuronal injury and improved cerebral blood flow and neurological
16647138	COX	COX	2.9	Two other non-selective COX inhibitors piroxicam and flurbiprofen significantly ameliorated delayed (7 7 days	Junguk Hur
16647138	COX-2	COX-2	16.2	The recent development of selective COX-2 inhibitors has stimulated a number of studies of their efficacy
16647138	COX-2	COX-2	16.2	inducible nitric oxide synthase (NOS) NOS gene which suggests that COX-2 reaction products may be another mechanism by which iNOS-derived nitric
16647138	COX-2	COX-2	16.2	Another COX-2 inhibitor nimesulide effectively limited hippocampal damage following forebrain ischemia in
16647138	COX	COX-2-deficient	0.3	degree of hippocampal neuronal injury produced by global ischemia in COX-2-deficient mice was less than that in wild-type mice ( Sasaki	Junguk Hur
16647138	COX-2	COX-2	16.2	Selective inhibition of COX-1 by valerylsalicylate or of COX-2 by rofecoxib was used to assess the relative contributions of
16647138	COX	COX	2.9	was initiated 6 h after ischemia providing evidence that both COX isoforms are involved in the progression of neuronal damage following	Junguk Hur
16647138	COX-2	COX-2	16.2	The highly selective COX-2 inhibitor DFU was neuroprotective when administered several hours after transient
16647138	COX-2	COX-2	16.2	The selective COX-2 inhibitors SC58125 and SC58326 are neuroprotective in rat global and
16647138	COX-2	COX-2	16.2	(2004) 2004 examined whether the selective COX-2 inhibitor celecoxib reduces cerebral inflammation and edema after intracerebral hemorrhage
16647138	COX-2	COX-2	16.2	S-2474 a novel NSAID suppresses COX-2 at low nanomolar levels but does not affect COX-1
16647138	COX	COX	2.9	Two COX inhibitors indomethacin and ibuprofen were less effective on this preparation	Junguk Hur
16647138	COX	COX	2.9	neuronal death which LOX and CY450 inhibitors greatly reduced with COX inhibitors having less of an effect	Junguk Hur
16647138	COX	COX	2.9	Role of COX LOX and EPOX in excitotoxic injury	Junguk Hur
16647138	COX-2	COX-2	16.2	These enzymes include PLA 2 COX-2 LOX and EPOX
16647138	COX-2	COX-2	16.2	Marked increases in COX-2 and 5-LOX mRNA and protein levels occur following kainate injections
16647138	COX-2	COX-2	16.2	This increase in COX-2 and 5-LOX can be prevented by not only glutamate receptor
16647138	COX-2	COX-2	16.2	al. 1999 and Pepicelli et al. 2002 but also by COX-2 and 5-LOX inhibitors ( Manev et al. 2000a and Pepicelli
16647138	COX-2	COX-2	16.2	The role of COX-2 and 5-LOX in excitotoxicity is also supported by microdialysis studies
16647138	COX-2	COX-2	16.2	blocked by the infusion of NMDA antagonists as well as COX-1 and COX-2 inhibitors indicating that both COX-1 and COX-2 contribute
16647138	COX-2	COX-2	16.2	the infusion of NMDA antagonists as well as COX-1 and COX-2 inhibitors indicating that both COX-1 and COX-2 contribute to the
16647138	COX-2	COX-2	16.2	as well as COX-1 and COX-2 inhibitors indicating that both COX-1 and COX-2 contribute to the prostaglandin synthesis and oxidative damage
16647138	COX-2	COX-2	16.2	as COX-1 and COX-2 inhibitors indicating that both COX-1 and COX-2 contribute to the prostaglandin synthesis and oxidative damage in excitotoxicity
16647138	COX-2	COX-2	16.2	it promotes neuronal injury that depends on the magnitude of COX-2 and 5-LOX expression ( Iadecola et al. 2001a Nakayama et
16647138	COX-2	COX-2	16.2	It is likely that increased COX-2 and 5-LOX activities and high levels of their reaction products
16647138	COX-2	COX-2	16.2	The neurochemical consequences of increased COX-2 and 5-LOX activities and high levels of their products include
16647138	COX-2	COX-2	16.2	Our emphasis on the interaction between glutamate receptors and COX-2 and 5-LOX activities and their reaction products does not rule
16647138	COX-2	COX-2-	2.3	appropriate to apply the concept of synergism between glutamate and COX-2- and 5-LOX-generated products and their receptors to neural cell injury
16647138	COX-2	COX-2-	2.3	The synergistic actions of glutamate and COX-2- and 5-LOX-generated products may be rapid whereas in neurodegenerative disorders
16647138	COX-2	COX-2-	2.3	limited extent due to the availability of ATP glutamate and COX-2- and 5-LOX-product-mediated damage may take a longer time to develop
16647138	COX-2	COX-2	16.2	These studies suggest that COX-2 and 5-LOX-generated products along with free radical formation play critical
16647138	COX-2	COX-2	16.2	of cytosolic PLA 2 ( Kajiwara et al. 1996 and COX-2 ( Marcheselli and Bazan 1996
16647138	COX-2	COX-2	16.2	In rat brain COX-2 mRNA is preferentially expressed in neurons where it is developmentally
16647138	COX-2	COX-2	16.2	it is developmentally regulated ( Tocco et al. 1997 and COX-2 expression is induced by kainic-acid-induced seizures ( Chen et al.
16647138	COX-2	COX-2	16.2	rat cortico-hippocampal neurons is also associated with increased expression of COX-2 ( Tocco et al. 1997
16647138	COX-2	COX-2	16.2	Induction of COX-2 but not COX-1 gene expression has been demonstrated to precede
16647138	COX	COX	2.9	( Birkle and Bazan 1987 indicating the stimulation of both COX and LOX activity	Junguk Hur
16647138	COX-2	COX-2	16.2	another seizure model the genetically epilepsy-susceptible E1 mouse expression of COX-2 in the hippocampus was upregulated after an epileptic seizure and
16647138	COX-2	COX-2	16.2	hippocampus was upregulated after an epileptic seizure and indomethacin a COX-2 inhibitor shortened the duration from seizure onset to full recovery
16647138	COX-2	COX-2	16.2	rat hippocampal-kindling model enabled a study of the role of COX-2 in seizure activity
16647138	COX-2	COX-2	16.2	COX-2 encoded in an early-response gene increased in a synaptic-activity-dependent manner
16647138	COX-2	COX-2	16.2	When rats were rekindled 34 days later this spreading of COX-2 expression persisted
16647138	COX-2	COX-2	16.2	The COX-2 selective inhibitor nimesulide attenuated kindling development ( Tu and Bazan
16647138	COX-2	COX-2	16.2	attenuated kindling development ( Tu and Bazan 2003 thus neuronal COX-2 gene induction and cPLA 2 activation are key signaling events
16647138	COX-2	COX-2	16.2	(2003) 2003 examined the effects of COX-2 on the _amp_#x2018 rapid kindling_amp_#x2019 development in COX-2 knockout mice
16647138	COX-2	COX-2	16.2	effects of COX-2 on the _amp_#x2018 rapid kindling_amp_#x2019 development in COX-2 knockout mice and mice treated with nimesulide
16647138	COX-2	COX-2	16.2	They also measured COX-2 mRNA expression and PGE 2 concentrations
16647138	COX-2	COX-2	16.2	Kindling in hippocampal neurons of control mice markedly increased brain COX-2 mRNA levels with a significant increase in PGE 2 levels
16647138	COX-2	COX-2	16.2	Moreover conditions of COX-2 deficiency significantly decreased the incidence of after-discharges total after-discharge duration
16647138	COX-2	COX-2	16.2	total after-discharge duration and seizure behavior induction suggesting that inducible COX-2 facilitates the recurrence of hippocampal seizures
16647138	COX-2	COX-2	16.2	a transgenic mouse model with neuronal overexpression of the human COX-2 to further explore its role in excitotoxicity
16647138	COX-2	hCOX-2	2.3	Overexpression of hCOX-2 potentiated the intensity and lethality of kainic acid excitotoxicity thus
16647138	COX-2	COX-2	16.2	acid excitotoxicity thus demonstrating a cause_amp_#x2013 effect relationship between neuronal COX-2 expression and excitotoxicity
16647138	COX	COX	2.9	in rats gave further evidence of a neuroprotective effect of COX	Junguk Hur
16647138	COX-2	COX-2	16.2	The COX-2 selective inhibitor rofecoxib significantly reduced kainate-induced cell death in the
16647138	COX-2	COX-2	16.2	Another selective COX-2 inhibitor celecoxib was effective in reducing electroshock-induced convulsions in rats
16647138	COX-2	COX-2	16.2	(febrile)-induced febrile -induced seizures no reports on the effects of COX-2 inhibitors on epileptic seizures in humans have appeared
16647138	COX	COX	2.9	The involvement of COX and LOX pathways in AD has been extensively studied in	Junguk Hur
16647138	COX-2	COX-2	16.2	A marked increase of COX-1 and COX-2 expression and immunoreactivity in cerebral cortex and hippocampal
16647138	COX-2	COX-2	16.2	A marked increase of COX-1 and COX-2 expression and immunoreactivity in cerebral cortex and hippocampal regions of
16647138	COX-2	COX-2	16.2	The neuroprotective effects of COX-1 and COX-2 inhibitors (NSAID) NSAID strongly support the view that
16647138	COX-2	COX-2	16.2	The neuroprotective effects of COX-1 and COX-2 inhibitors (NSAID) NSAID strongly support the view that upregulation of
16647138	COX-2	COX-2	16.2	The molecular mechanism by which COX-1 and COX-2 promote amyloidogenic accumulation of _amp_#x3b2 -amyloid peptide is
16647138	COX-2	COX-2	16.2	The molecular mechanism by which COX-1 and COX-2 promote amyloidogenic accumulation of _amp_#x3b2 -amyloid peptide is not fully
16647138	COX-2	COX-2	16.2	COX-1 and COX-2 potentiate _amp_#x3b2 -amyloid peptide generation through mechanisms that
16647138	COX-2	COX-2	16.2	COX-1 and COX-2 potentiate _amp_#x3b2 -amyloid peptide generation through mechanisms that involve _amp_#x3b3
16647138	COX-2	COX-2	16.2	Furthermore COX-2 expression is also involved in regulation of cell cycle activity
16647138	COX-2	COX-2-mediated	2.3	Re-entry into the cell cycle may underlie COX-2-mediated neuronal damage in AD ( Xiang et al. 2002
16647138	COX	COX	2.9	the EPOX inhibitors SKF25A and metyrapone but not by the COX inhibitors indomethacin and NS-398	Junguk Hur
16647138	COX-2	COX-2	16.2	disease is characterized by a prominent neuroinflammatory component upregulation of COX-2 mRNA and oxidative stress ( Yasojima et al. 2001
16647138	COX-2	COX-2	16.2	Upregulation of COX-2 mRNA also occurs in SOD1 transgenic mice at the onset
16647138	COX-2	COX-2	16.2	cell culture model of ALS the addition of a selective COX-2 inhibitor SC236 blocked the destruction of motor neurons ( Drachman
16647138	COX-2	COX-2	16.2	of motor neurons ( Drachman and Rothstein 2000 suggesting that COX-2 may play an important role in inflammatory processes in ALS
16647138	COX-2	COX-2	16.2	Similarly treatment with celecoxib another COX-2 inhibitor prolongs the survival of neurons in the SOD1 mouse
16647138	COX-2	COX-2	16.2	Although upregulation of COX-2 and PGE 2 levels may not be the root cause
16647138	COX-2	COX-2	16.2	At present nothing is known about the expression of COX-2 in patients with PD
16647138	COX-2	COX-2	16.2	However involvement of COX-2 in the pathogenesis of PD has been explored in an
16647138	COX-2	COX-2	16.2	2 3 6 tetrahydropyridine (MPTP) MPTP as well as in COX-2 gene knockout mice ( Feng et al. 2003 and Teismann
16647138	COX	COX-2-deficient	0.3	mortality rate has been reported after MPTP injection in heterozygous COX-2-deficient mice than in the wild-type mice and inhibition of COX-2	Junguk Hur
16647138	COX-2	COX-2	16.2	COX-2-deficient mice than in the wild-type mice and inhibition of COX-2 protein expression decreases the lesions caused by MPTP and protects
16647138	COX-2	COX-2-mediated	2.3	The molecular mechanism associated with COX-2-mediated neurodegeneration in animal models of PD remains unknown
16647138	COX-2	COX-2	16.2	However COX-2 inhibition may prevent the formation of the oxidant species of
16647138	COX	COX	2.9	Collective evidence suggests that changes in COX LOX and EPOX activities may not be the primary effect	Junguk Hur
16647138	COX-2	COX-2	16.2	Using RT-PCR and Western blotting both COX-1 and COX-2 are significantly increased in brains from CJD patients
16647138	COX-2	COX-2	16.2	Using RT-PCR and Western blotting both COX-1 and COX-2 are significantly increased in brains from CJD patients compared to
16647138	COX-2	COX-2	16.2	and in brain homogenates of scrapie-infected mice the upregulation of COX-1 and COX-2 is accompanied by a several-fold increase in concentrations
16647138	COX-2	COX-2	16.2	brain homogenates of scrapie-infected mice the upregulation of COX-1 and COX-2 is accompanied by a several-fold increase in concentrations of PGE
16647138	COX-2	COX-2	16.2	In contrast indomethacin a COX-1 and COX-2 inhibitor and baicalein a 12-LOX inhibitor do not
16647138	COX-2	COX-2	16.2	In contrast indomethacin a COX-1 and COX-2 inhibitor and baicalein a 12-LOX inhibitor do not affect PrP106_amp_#x2013
16647138	COX	COX	2.9	Future perspectives interactions among multiple forms of COX LOX and EPOX and their relationship to upstream PLA 2	Junguk Hur
16647138	COX	COX	2.9	Although transcripts activities and immunoreactive proteins for COX LOX and EPOX are widely expressed throughout the brain very	Junguk Hur
16647138	COX	COX	2.9	The occurrence of isoforms of COX LOX and EPOX enzymes in cytoplasm and other subcellular organelles	Junguk Hur
16647138	COX	COX	2.9	The multiplicity of COX LOX and EPOX enzymes in brain tissue provides diversity in	Junguk Hur
16647138	COX-2	COX-2	16.2	In astrocytes TGF_amp_#x3b2 1 upregulates COX-1 expression and serum increases COX-2 expression
16647138	COX-2	COX-2	16.2	Neither TGF_amp_#x3b2 1 nor serum affects COX-1 and COX-2 expression in neurons
16647138	COX-2	COX-2	16.2	Neither TGF_amp_#x3b2 1 nor serum affects COX-1 and COX-2 expression in neurons
16647138	COX-2	COX-2	16.2	Furthermore COX-1 compensates for the loss of COX-2 in the COX-2 knockout (COX-2 COX-2 _amp_#x2212;/_amp_#x2212; _amp_#x2212 _amp_#x2212 mouse
16647138	COX-2	COX-2	16.2	Furthermore COX-1 compensates for the loss of COX-2 in the COX-2 knockout (COX-2 COX-2 _amp_#x2212;/_amp_#x2212; _amp_#x2212 _amp_#x2212 mouse brain
16647138	COX-2	COX-2	16.2	for the loss of COX-2 in the COX-2 knockout (COX-2 COX-2 _amp_#x2212;/_amp_#x2212; _amp_#x2212 _amp_#x2212 mouse brain
16647138	COX-2	COX-2	16.2	Thus COX-2 _amp_#x2212;/_amp_#x2212; _amp_#x2212 _amp_#x2212 shows a compensatory increase in brain COX-1
16647138	COX	COX	2.9	This behavior complicates the analysis of COX LOX and EPOX function at cellular and subcellular levels	Junguk Hur
16647138	COX	COX	2.9	when one considers the coupling mechanisms of various isoforms of COX LOX and EPOX with different receptors at cellular and subcellular	Junguk Hur
16647138	COX	COX	2.9	Some isoforms of COX LOX and EPOX are constitutively expressed while others are inducible	Junguk Hur
16647138	COX	COX	2.9	The isoforms of COX LOX and EPOX may not function interchangeably but act in	Junguk Hur
16647138	COX	COX	2.9	It is likely that various isoforms of COX LOX and EPOX act on different cellular pools of arachidonic	Junguk Hur
16647138	COX	COX	2.9	Thus the interactions among COX LOX and EPOX-generated metabolites at plasma membrane cytoplasmic and nuclear	Junguk Hur
16647138	COX	COX	2.9	tempting to speculate that coordinated cross talk not only among COX LOX and EPOX isozymes but also with upstream PLA 2	Junguk Hur
16647138	COX	COX	2.9	In the nuclear membrane and nucleus COX LOX and EPOX-mediated signaling has the advantage over plasma membrane	Junguk Hur
16647138	COX	COX	2.9	In brain tissue the activities of COX LOX and EPOX isoforms may depend not only on the	Junguk Hur
16647138	COX	COX	2.9	The ability of COX LOX and EPOX isoforms to orchestrate complex prostaglandin leukotriene HETE	Junguk Hur
16647138	COX	COX	2.9	The activation of COX LOX and EPOX isoforms at a subcellular level in neural	Junguk Hur
16647138	COX	COX	2.9	Therefore a strict regulation of COX LOX and EPOX isozymes is very important for normal brain	Junguk Hur
16647138	COX	COX	2.9	As stated above the regulation of COX LOX and EPOX activities is complex and mediated by several	Junguk Hur
16647138	COX	COX	2.9	To understand the contribution of isoforms of COX LOX and EPOX in physiological and disease processes a systematic	Junguk Hur
16647138	COX	COX	2.9	The enzymic mechanisms include three systems COX isozymes which synthesize prostaglandins LOX isozymes which generate hydroxyl derivatives	Junguk Hur
16647138	COX	COX	2.9	ischemia AD PD ALS and CJD stimulation and upregulation of COX LOX and EPOX isozyme activities and the generation of excessive	Junguk Hur
16647138	COX	COX	2.9	These metabolites not only antagonize the effect of COX LOX and EPOX-generated products but also counteract leukocyte infiltration and	Junguk Hur
16647138	COX	COX	2.9	Elevated activities of isoforms of COX LOX and EPOX at cellular and subcellular levels in ischemia	Junguk Hur
16753239	COX-2	COX-2	1.0	that TZDs block the production of iNOS TNF-_amp_#x3b1 IL-6 and COX-2 by primary rat microglia and astrocytes and protected cortical neurons
16766086	COX-2	COX-2	1.0	These agents suppressed cytokine as well as COX-2 expression
16766086	COX-2	COX-2	1.0	Expression of inflammatory genes such as iNOS cyclooxygenase-2 (COX-2), COX-2 proinflammatory cytokines and intercellular adhesion molecule are upregulated following stroke
16766086	COX-2	COX-2	1.0	associated with reduced expression of inflammatory mediators such as iNOS COX-2 and IL-1_amp_#x3b2 ( Fig 5
16766086	COX-2	COX-2	1.0	mRNA was reduced by approximately 25% for iNOS 30% for COX-2 and 50% for IL-1_amp_#x3b2 ( n = 4 for each
17015226	COX-2	COX-2	1.0	Cyclooxygenase-2 (COX-2), COX-2 produced in abundance by microglia and other inflammatory cells (but
17015226	COX-2	COX-2	1.0	a key role in stimulating production of proinflammatory cytokines and COX-2 expression is induced in spinal cords of ALS patients (
17015226	COX-2	COX-2	1.0	In mice use of a COX-2 inhibitor (celecoxib) celecoxib prolonged survival by slowing disease onset (
17569578	COX2	COX2	2.5	cytokine expression iNOS expression and NO production and inhibition of COX2 and subsequent generation of immunostimulated prostanoid synthesis 38
17569578	COX-2	COX-2	2.8	pioglitazone treated SOD1-G93A mice as were the protein levels of COX-2 and iNOS
17569578	COX2	COX2	2.5	expression as well as elevated expression of adhesion molecules iNOS COX2 and other inflammatory mediators which act to exacerbate the tissue
17569578	COX2	COX2	2.5	of peripheral leukocytes diminished microglial activation and reduction of iNOS COX2 and cytokine expression
17574754	COX-2	COX-2	1.0	Induction of cyclooxygenase-2 (COX-2) COX-2 with production of prostaglandins occurs in a wide spectrum of
17574754	COX-2	COX-2	1.0	Inhibition of the COX-2 pathway and downstream production of prostaglandins protect neurons in rodent
17574754	COX-2	COX-2	1.0	investigating the functions of selected prostaglandin receptor pathways in mediating COX-2 neurotoxicity have demonstrated both toxic and paradoxically neuroprotective effects of
17574754	COX-2	COX-2	1.0	The inducible isoform of cyclooxygenase COX-2 is rapidly upregulated in vivo in hippocampal and cerebral cortical
17574754	COX-2	COX-2	1.0	However in pathologic conditions caused by either excitotoxicity or inflammation COX-2 expression and activity are increased in neurons and glial cells
17574754	COX-2	COX-2	1.0	Thus increased COX-2 activity and prostaglandin production are hallmarks of a wide range
17574754	COX-2	COX-2	1.0	In humans increased COX-2 and prostaglandin production have been observed in AD ALS multiple
17574754	COX-2	COX-2	1.0	Thus COX-2 appears to function physiologically in promoting synaptic activity and pathologically
17574754	COX-2	COX-2	1.0	Because inhibition of COX-2 either genetically or pharmacologically decreases neuronal injury in rodent models
17574754	COX-2	COX-2	1.0	is considerable interest in defining the downstream mechanisms by which COX-2 exerts its neurotoxicity
17574754	COX-2	COX-2	1.0	has been the examination of prostaglandin signaling cascades downstream of COX-2 and the identification of neurotoxic prostaglandin receptors 4
17574754	COX-2	COX-2	1.0	the metabolism of arachidonic acid by COX-1 and the inducible COX-2
17574754	COX-2	COX-2	1.0	COX-2 neurotoxicity is presumed to be mediated by one or more
17574754	COX-2	COX-2	1.0	Induction of COX-2 activity and production of downstream prostaglandins is associated in a
17574754	COX-2	COX-2	1.0	COX-2 inhibition has been shown to be protective in this in
17574754	COX-2	COX-2	1.0	that the DP FP and IP receptors do not mediate COX-2 toxicity in this in vitro model and from our previous
17574754	COX	COX	0.0	A larger question is whether COX inhibition by non-steroidal anti-inflammatory drugs (NSAIDs), NSAIDs which should reduce	Junguk Hur
17574754	COX-2	COX-2	1.0	In models of in vitro and in vivo excitotoxicity COX-2 inhibition is clearly neuroprotective
17901552	COX-2	COX-2	1.0	Function of COX-2 and prostaglandins in neurological disease
17901552	COX-2	COX-2	1.0	Induction of COX-2 expression and enzymatic activity promotes neuronal injury in a number
17901552	COX-2	COX-2	1.0	Inhibition of COX-2 activity either genetically or pharmacologically has been shown to be
17901552	COX	COX	0.0	Inhibition of COX activity with nonsteroidal anti-inflammatory drugs (NSAIDs) NSAIDs reduces inflammation and	Junguk Hur
17901552	COX	COX-mediated	0.0	COX-mediated neuronal injury is presumed be due to downstream effects of	Junguk Hur
17901552	COX-2	COX-2	1.0	that are paradoxically protective when taken in the context that COX-2 induces neuronal injury in the setting of excitotoxicity
18040778	COX-2	COX-2	1.0	Cyclooxygenase-2 (COX-2) COX-2 is an enzyme central to the production of prostaglandins a
18040778	COX-2	COX-2	1.0	COX-2 and prostaglandin E 2 are elevated in the CNS of
18040778	COX-2	COX-2	1.0	implicated in other neuroinflammatory/neurodegenerative neuroinflammatory neurodegenerative diseases and not surprisingly COX-2 has been considered a major therapeutic target
18040778	COX-2	COX-2	1.0	Hypothetically by inhibiting microglial cell cyclooxygenases (COX-1 COX-1 or COX-2 the metabolism of arachadonic acid is curtailed and production of
18040778	COX	COX	0.0	In addition to the suppression of prostaglandin production COX inhibitors may also decrease the formation of AB peptide (Hirohata	Junguk Hur
18040778	COX-2	COX-2	1.0	Although preclinical and early clinical data suggested that COX-2 inhibitors may have a beneficial role in AD results of
18040778	COX-2	COX-2	1.0	subsequent studies and the development of unanticipated side effects of COX-2 inhibitors have dampened enthusiasm for the use of these agents
18464922	COX-2	COX-2	1.0	promoters including those encoding for inflammation (iNOS, iNOS NF-_amp_#x003ba B COX-2 oxidative stress and apoptosis
18464922	COX-2	COX-2	1.0	microglial activation as well as reduction in the expression of COX-2 and iNOS 39
18464925	COX2	COX2	2.5	as well as expression of the inducible enzymes iNOS and COX2 induced in LPS-stimulated astrocyte and microglial cultures 58
18464925	COX-2	COX-2	3.0	the natural ligand 15d-PGJ 2 prevented the IL-1 _amp_#x003b2 -induced COX-2 mRNA accumulation in human astrocytes through a PPAR _amp_#x003b3 -independent
18464925	COX-2	COX-2	3.0	the production of TNF-_amp_#x003b1 IL-1 _amp_#x003b2 and the expression of COX-2 in the same cell system while increasing the expression of
18464925	COX-2	COX-2-specific	2.5	In this cell system COX-2-specific inhibitors failed to promote neuronal survival suggesting protective mechanisms independent
18464925	COX-2	COX-2	3.0	failed to promote neuronal survival suggesting protective mechanisms independent of COX-2 metabolism
18464925	COX-2	COX-2	3.0	of PGJ 2 by directly preventing the enzymatic activity of COX-2 rather than its expression as previously described in activated monocytic
18464925	COX-2	COX-2	3.0	The reduction of COX-2 enzymatic activity could be achieved through the modifications of key
11220737	cox 2	cox 2	1.0	consistent with this view the present study demonstrates that during the course of the disease the expression of cyclooxygenase type 2 cox 2 a key enzyme in the synthesis of prostanoids which are potent mediators of inflammation is dramatically increased.
11220737	cox 2	cox 2	1.0	in both early symptomatic and end stage transgenic msod1 mice neurons and to a lesser extent glial cells in the anterior horn of the spinal cord exhibit robust cox 2 immunoreactivity.
11220737	cox 2	cox 2	1.0	cox 2 mrna and protein levels and catalytic activity are also significantly increased in the spinal cord of the transgenic msod1 mice.
11220737	cox 2	cox 2	1.0	the time course of the spinal cord cox 2 upregulation parallels that of motor neuronal loss in transgenic msod1 mice.
11220737	cox 2	cox 2	1.0	we also show that cox 2 activity is dramatically increased in postmortem spinal cord samples from sporadic als patients.
11220737	cox 2	cox 2	1.0	we speculate that cox 2 upregulation through its pivotal role in inflammation is instrumental in the als neurodegenerative process and that cox 2 inhibition may be a valuable therapeutic avenue for the treatment of als.
12362410	cox 2	cox 2	1.0	nce of numerous molecules characteristic of free radical attack the occurrence of proteins associated with activation of the complement cascade and a sharp upregulation of the enzyme cyclooxygenase 2 cox 2 .
12362410	cox 2	cox 2	1.0	cox 2 is a particularly attractive target because of its marked increase in als spinal cord.
14511332	cox 2	cox 2	1.0	they are produced by two different isoforms of the cyclooxygenase cox enzyme namely cox 1 and cox 2.
14511332	cox 2	cox 2	1.0	in particular cox 2 was demonstrated to be crucial for pg synthesis in inflammation.
14511332	cox 2	cox 2	1.0	recently inhibition of cox 2 was shown to prevent the loss of motor neurons in a model of amyotrophic lateral sclerosis als .
14511332	cox 2	cox 2	1.0	furthermore spinal cox 2 expression was shown to be increased in transgenic mice that produce an als like syndrome.
14511332	cox 2	cox 2	1.0	therefore we investigated the expression of cox 1 and cox 2 in the spinal cord of seven human sporadic als patients by means of immunohistochemistry.
14511332	cox 2	cox 2	1.0	cox 2 expression was dramatically increased in the spinal cord of patients with als.
14511332	cox 2	cox 2	1.0	statistical analysis showed a significantly higher expression of cox 2 in als for both neurons and glia.
14511332	cox 2	cox 2	1.0	the results of our study corroborate a potential role for cox 2 in the pathogenesis of motor neuron death in als.
14511332	cox 2	cox 2	1.0	selective cox 2 inhibition might therefore offer a new possibility in the treatment of human als.
14511332	cox 2	cox 2	1.0	however to determine the exact role of cox 2 in human als will require further research.
14511332	cox 2	cox 2	1.0	very recently the proinflammatory enzyme cyclooxygenase 2 cox 2 was reported to be highly expressed in the spinal cord of msod1 mice almer et al . 2001 .
14511332	cox 2	cox 2	1.0	currently two cox isoforms are known namely cox 1 and cox 2 vane et al . 1998 .
14511332	cox 2	cox 2	1.0	whereas cox 1 mainly subserves _amp_#8216;house keeping_amp_#8217; functions cox 2 is the product of an _amp_#8216;immediate early gene_amp_#8217; that is rapidly inducible and tightly regulated vane et al . 1998 .
14511332	cox 2	cox 2	1.0	under normal conditions cox 2 expression is highly restricted to distinct organ systems including the kidney harris et al . 1994 and the eye maihofner et al . 2001 but cox 2 expression can be dramatically increased in various tissues following the initiation of transcription by activating factors including different proinflammatory cytokines arterial wall sheer forces or
14511332	cox 2	cox 2	1.0	recently one of us demonstrated the constitutive expression of both cox isoforms in the spinal cord of rodents and a dramatic induction of spinal cox 2 protein following peripheral nociceptive stimulation maihofner et al . 2000b .
14511332	cox 2	cox 2	1.0	very recently inhibition of cox 2 was protective in a glutamate mediated in vitro model of sals drachman _amp_ rothstein 2000 .
14511332	cox 2	cox 2	1.0	almer et al . 2001 described the immunohistochemical distribution of cox 2 in the spinal cord of msod1 mice over the progression of the disease.
14511332	cox 2	cox 2	1.0	furthermore they showed an increased prostaglandin e2 pg e 2 level in post mortem samples of als cases as a marker for cox 2 activity.
14511332	cox 2	cox 2	1.0	therefore we compared the spinal expression of cox 1 and cox 2 in sals and control patients by means of immunohistochemistry.
14511332	cox 2	cox 2	1.0	we here demonstrate a high expression of cox 2 protein in spinal cord specimens of human sals cases.
14511332	cox 2	cox 2	1.0	the increased expression of cox 2 was corroborated by a significantly higher concentration of pg e 2 in the cerebrospinal fluid of patients diagnosed with als.
14511332	cox 2	cox 2	1.0	briefly goat polyclonal antisera raised against human cox 1 and cox 2 protein santa cruz biotechnology santa cruz ca were employed.
14511332	cox 2	cox 2	1.0	to further differentiate the cellular distributions of cox 1 and cox 2 proteins a double staining procedure using a mouse monoclonal antihuman antibody to glial fibrillary acidic protein to label astrocytes gfap; dako glostrup denmark and a mouse monoclonal antihuman an
14511332	cox 2	cox 2	1.0	specimens were coded and assessed observer blinded for presence of cox 1 and cox 2 immunoreactivity ir .
14511332	cox 2	cox 2	1.0	membranes were probed with polyclonal goat antihuman cox 1 or cox 2 serum diluted 1 : 1000 followed by a horseradish peroxidase hrp linked donkey antigoat igg secondary antibody diluted 1 : 1000; santa cruz biotechnology .
14511332	cox 2	cox 2	1.0	the normal spinal cord and specifity of the antibodies to assess the specifity of the antibodies used for immunohistochemistry we performed western blotting experiments for the detection of cox 1 and cox 2 protein with spinal protein extracts from human donors with no known neurological diseases two males age 65 and 78 years .
14511332	cox 2	cox 2	1.0	figure 1b demonstrates the results of a similar experiment for the detection of cox 2 protein.
14511332	cox 2	cox 2	1.0	protein extracts left lane from human spinal cords were separated alongside purified sheep cox 2 protein right lane by sds page blotted onto nitrocellulose membranes and incubated with the same cox 2 antibody as that used for immunohistochemistry.
14511332	cox 2	cox 2	1.0	unpurified cox 2 proteins derived from either cell lysates or tissues typically produce a double or triple band in western blot analysis at 68 75 kda fig 1b left lane .
14511332	cox 2	cox 2	1.0	a single band at 75 kda was detected for the purified cox 2 protein.
14511332	cox 2	cox 2	1.0	to exclude potential crossreactions between the antibodies for the two cox isoforms we determined the specifity with purified cox 1 and cox 2 protein by western blotting.
14511332	cox 2	cox 2	1.0	figure 1c shows that the goat antihuman polyclonal cox 1 antibody exclusively detected cox 1 protein and not cox 2 protein.
14511332	cox 2	cox 2	1.0	figure 1d shows the results from a similar experiment in which the goat antihuman polyclonal cox 2 antibody detected only cox 2 protein and not cox 1 protein.
14511332	cox 2	cox 2	1.0	in control specimens only a few motor neurons and interneurons were immunoreactive for cox 2 protein fig 2b .
14511332	cox 2	cox 2	1.0	in most neurons cox 2 ir was absent fig 2c .
14511332	cox 2	cox 2	1.0	the immunoreactive product could be clearly distinguished from lipofuscin like inclusions which had a different staining pattern compared to the reddish cox 2 ir fig 2c .
14511332	cox 2	cox 2	1.0	when the number of neurons with cox 2 ir was counted the percentage of cox 2 positive motor neurons and interneurons was found to be significantly increased in sals patients compared to controls despite an overall reduction in the number of neurons 13.31 _amp_plusmn; 5 vs 37.
14511332	cox 2	cox 2	1.0	furthermore expression of cox 2 was found to be enhanced in sals cases compared to controls in cells that showed no neuronal morphology i.e. cells of presumed glial origin fig 2f and g .
14511332	cox 2	cox 2	1.0	as demonstrated by the coexpression with gfap glial cox 2 expression was predominantly found in astrocytes fig 2h .
14511332	cox 2	cox 2	1.0	however cox 2 ir was occasionally detected in smaller cells with the morphological characteristics of microglia as shown by its coexpression with the microglia marker mac 1 fig 2i .
14511332	cox 2	cox 2	1.0	overall the glial expression of cox 2 was significantly increased in sals cases 0.71 _amp_plusmn; 0.5 vs 2.3 _amp_plusmn; 0.5; wilcoxon signed ranked test p _lt_ 0.05; fig 5 .
14511332	cox 2	cox 2	1.0	firstly despite a significant reduction of neurons in the spinal cord the percentage of cox 2 expressing motor neurons and interneurons was increased in sals.
14511332	cox 2	cox 2	1.0	secondly glial expression of cox 2 was enhanced in sals.
14511332	cox 2	cox 2	1.0	cox 2 overexpression in sals
14511332	cox 2	cox 2	1.0	expression of cox 2 in human diseases is a topic of considerable interest with regard to the recent development of cox 2 selective inhibitors hawkey 1999 .
14511332	cox 2	cox 2	1.0	regarding als drachman and rothstein drachman _amp_ rothstein 2000 demonstrated a beneficial effect of cox 2 inhibition in an in vitro model while almer et al .
14511332	cox 2	cox 2	1.0	2001 demonstrated a role for cox 2 in mutant sod1 mice and yasojima et al .
14511332	cox 2	cox 2	1.0	2001 showed up regulation of cox 2 mrna in spinal cord specimens of sals cases.
14511332	cox 2	cox 2	1.0	recently two animal studies demonstrated a beneficial effect of selective cox 2 inhibition in mouse models of als drachman et al . 2002 ; pompl et al . 2003 .
14511332	cox 2	cox 2	1.0	however the cellular origin of cox 2 up regulation in human sals has so far not been delineated.
14511332	cox 2	cox 2	1.0	here we provide immunohistochemical evidence for a dramatic increase in spinal cox 2 expression in motor neurons interneurons and glial cells in sals despite an overall reduction in the number of neurons compared to controls.
14511332	cox 2	cox 2	1.0	cox 2 was also observed in motor neurons of control specimens the staining was accentuated in the perinuclear region.
14511332	cox 2	cox 2	1.0	this agrees with reports on the constitutive expression of cox 2 in the spinal cord of rodents and the localization of cox 2 protein determined electron microscopically maihofner et al . 2000b ; maihofner et al . 2001 .
14511332	cox 2	cox 2	1.0	in normal conditions cox 2 derived pgs are assumed to play homeostatic functions beiche et al . 1996 ; vane et al . 1998 ; maihofner et al . 2000b .
14511332	cox 2	cox 2	1.0	nevertheless the reason for the dramatic cox 2 overexpression in sals is unknown.
14511332	cox 2	cox 2	1.0	one potential explanation could be cox 2's interplay with glutamate levels of which are elevated in the csf of sals patients plaitakis et al . 1988 .
14511332	cox 2	cox 2	1.0	in pain models cox 2 protein was induced following glutamatergic stimulation maihofner et al . 2000b .
14511332	cox 2	cox 2	1.0	nf kappa b. nf kappa b in particular is crucial for cox 2 induction in several cell types vane et al . 1998 and its activation has also been linked to neurodegeneration grilli _amp_ memo 1999 .
14511332	cox 2	cox 2	1.0	cytokines could also contribute to high expression of cox 2 in sals particularly il 1beta and il 6.
14511332	cox 2	cox 2	1.0	both are known inducers of cox 2 expression and their concentrations are elevated in the csf of als cases sekizawa et al . 1998 ; vane et al . 1998 ; li et al . 2000 .
14511332	cox 2	cox 2	1.0	consistently we demonstrated a significantly higher expression of cox 2 in glial cells.
14511332	cox 2	cox 2	1.0	in agreement with a study in transgenic msod1 mice almer et al . 2001 cox 2 was found to be predominantly expressed in astrocytes and not microglia.
14511332	cox 2	cox 2	1.0	this might be explained by the capability of il 1beta to induce cox 2 in astrocytes but not in microglia cells vane et al . 1998 .
14511332	cox 2	cox 2	1.0	cox 2 expression in the astroglia of rodents has been shown previously beiche et al . 1996 ; maihofner et al . 2000b .
14511332	cox 2	cox 2	1.0	furthermore despite a significant reduction in the number of interneurons in our sals cases cox 2 expression was also found to be increased in this cell type.
14511332	cox 2	cox 2	1.0	2001 also found that cox 2 was present in motor neurons and predominantly in astroglia although no apparent differences in cox 1 expression were seen between msod1 mice and controls.
14511332	cox 2	cox 2	1.0	therefore we do not think that misclassification of neurons led to the high expression of cox 2 protein in sals presented here.
14511332	cox 2	cox 2	1.0	been used in previous studies maihofner et al . 2000b ; damm et al . 2001 ; maihofner et al . 2001 ; charalambous et al . 2003 ; maihofner et al . 2003 and were shown to be specific for the cox 1 and cox 2 protein respectively.
14511332	cox 2	cox 2	1.0	we have intentionally focused on the in situ expression of both cox 1 and cox 2 proteins in human als spinal cords.
14511332	cox 2	cox 2	1.0	increased pg e 2 levels are also in agreement with the results of two recent animal studies where selective cox 2 inhibition was found to be protective against motor neuron death drachman et al . 2002 ; pompl et al . 2003 .
14511332	cox 2	cox 2	1.0	a role for cox 2 in the pathogenesis of sals?
14511332	cox 2	cox 2	1.0	what is the significance of cox 2 overexpression in als?
14511332	cox 2	cox 2	1.0	there are several lines of evidence that cox 2 might play a role in the pathogenesis of als.
14511332	cox 2	cox 2	1.0	firstly application of a selective cox 2 inhibitor in an in vitro organotypic model of als protected against the loss of motor neurons in this system drachman _amp_ rothstein 2000 .
14511332	cox 2	cox 2	1.0	secondly this finding was corroborated in two in vivo studies where application of a selective cox 2 inhibitor protected against motor neuron degeneration and prolonged survival in transgenic mouse models of als drachman et al . 2002 ; pompl et al . 2003 .
14511332	cox 2	cox 2	1.0	thirdly based on the action of pgs cox 2 could promote inflammatory processes in als.
14511332	cox 2	cox 2	1.0	therefore cox 2 derived pgs could play a role in glutamate excitotoxicity which is postulated to occur in als rowland _amp_ shneider 2001 .
14511332	cox 2	cox 2	1.0	this is also in line with the study of kelley and colleagues kelley et al . 1999 demonstrating a potentiation of kainic acid induced excitotoxicity in transgenic mice overexpressing cox 2 protein.
14511332	cox 2	cox 2	1.0	fourthly cox 2 may also be involved in the production of reactive oxygen species and oxidative stress vane et al . 1998 .
14511332	cox 2	cox 2	1.0	finally cox 2 appears to be involved in neuronal cell cycle regulation.
14511332	cox 2	cox 2	1.0	2002 showed that the expression of the endogenous cell cycle dependent kinase cdk inhibitor inhibitor kinase ink p18ink4 is a downstream target of neuronal cox 2 expression. p18ink4 inhibits cdk 4 6 which is in turn a key player in the regulation of g1 progression zindy et al . 1997 .
14511332	cox 2	cox 2	1.0	therefore cox 2 inhibition might attenuate apoptotic damage in neurodegenerative diseases.
14511332	cox 2	cox 2	1.0	however the specifity of cox 2 expression for als has to be questioned.
14511332	cox 2	cox 2	1.0	increased cox 2 levels were also shown for alzheimer's disease parkinson's disease epilepsy and even cerebral infarction pasinetti _amp_ aisen 1998 ; vane et al . 1998 ; scali et al . 2000 ; kunz _amp_ oliw 2001 .
14511332	cox 2	cox 2	1.0	therefore we would explicitly like to state that cox 2 expression seems to be a common endpoint in neurodegeneration rather than the actual cause of als.
14511332	cox 2	cox 2	1.0	furthermore there is the possibility that cox 2 expression might be protective and antiapoptotic.
14511332	cox 2	cox 2	1.0	recently one of us was able to show that the expression of cox 2 in crc parallels the expression of il 1 beta and il 6 in crc maihofner et al . 2003 .
14511332	cox 2	cox 2	1.0	in this context cox 2 is thought to be actively involved in carcinogenesis and antiapoptosis.
14511332	cox 2	cox 2	1.0	therefore although the animal findings are corroborated by the immunohistochemical results presented here the exact role of cox 2 in the pathogenesis of human als still remains to be elucidated.
14511332	cox 2	cox 2	1.0	clinical trials are underway in the united states north east als consortium to test a potential benefit of selective cox 2 inhibition in human als.
14511332	cox 2	cox 2	1.0	in contrast to the cox 2 protein cox 1 expression was predominantly found in microglia cells and showed no significant difference between sals and controls.
14511332	cox 2	cox 2	1.0	alzheimer disease pasinetti _amp_ aisen 1998 where cox 2 was found to be the pivotal isoform involved in the pathology.
14511332	cox 2	cox 2	1.0	expression of cox 2 protein was markedly increased in the motoneurons interneurons and glial cells of sals cases compared to controls.
14511332	cox 2	cox 2	1.0	based on the beneficial effects of selective cox 2 inhibition in models of als the results of this and other studies might give a rationale for clinical investigations on potential positive effects of selective cox 2 inhibitors in human sals.
14511332	cox 2	cox 2	1.0	inhibition in models of als the results of this and other studies might give a rationale for clinical investigations on potential positive effects of selective cox 2 inhibitors in human sals.
14720207	cox 2	cox 2	1.0	we investigated the therapeutic effects of cyclooxygenase 2 cox 2 inhibitors both alone and in combination with creatine in the g93a transgenic mouse model of als.
14720207	cox 2	cox 2	1.0	the administration of cox 2 inhibitors significantly reduced prostaglandin e2 levels at 110 days of age.
14720207	cox 2	cox 2	1.0	the combination of creatine with cox 2 inhibitors produced additive neuroprotective effects and extended survival by approximately 30%.
14720207	cox 2	cox 2	1.0	the cox 2 inhibitors significantly protected against depletion of anterior horn motor neurons and creatine with cox 2 inhibitors showed greater protection than cox 2 inhibitors alone.
15081582	cox 2	cox 2	1.0	there are two distinct cox isoenzymes known as cox 1 and cox 2 that are 65% homologous.
15081582	cox 2	cox 2	1.0	conversely cox 2 was initially characterized as an inducible enzyme that is expressed in response to inflammatory stimuli cytokines and mitogens o'banion 1999 .
15081582	cox 2	cox 2	1.0	cox 2 is now known to be constitutively expressed in the kidney stomach and central nervous system hoffmann 2000 .
15081582	cox 2	cox 2	1.0	many cellular factors induce cox 2 expression including multiple growth factors cytokines interleukin il 1_amp_#x3b2; tumor necrosis factor tnf lipopolysaccharide lps phorbol ester and elevated intracellular calcium concentration.
15081582	cox 2	cox 2	1.0	one transcription factor that influences cox 2 expression following exposure to these cellular factors is nf _amp_#x3ba;b.
15081582	cox 2	cox 2	1.0	cox 2 has an nf _amp_#x3ba;b binding site in its promoter region that is shared with other inflammatory mediators including icam 1 il 2 il 8 and complement baldwin 1996 and schmedtje et al. 1997 .
15081582	cox 2	cox 2	1.0	specific inhibition of cox 2 upregulation can be achieved by factors that inhibit nf _amp_#x3ba;b activity such as il 4 il 10 and il 13 and glucocorticoids o'banion 1999 see table 1 .
15081582	cox 2	cox 2	1.0	the cox enzymes cox 1 and cox 2 are more completely termed prostaglandin g/h synthases 1 and 2 .
15081582	cox 2	cox 2	1.0	the second peroxidase step of the cox 2 reaction produces the free radical superoxide which may cause damage to cells in als and other neurodegenerative diseases kaufmann et al. 1996 .
15081582	cox 2	cox 2	1.0	although it is unlikely that upregulation of cox 2 activity alone produces enough free radicals to account for the degree of oxidative damage associated with neurodegenerative diseases it may be one of several sources that together cause significant
15081582	cox 2	cox 2	1.0	immunoreactivity for cox 2 is present in the dendritic spines of cortical neurons and thus may be involved in synaptic signaling kaufmann et al. 1996 .
15081582	cox 2	cox 2	1.0	these rats display a distinct alteration in the laminar pattern of cortical cox 2 immunoreactivity kaufmann et al. 1996 .
15081582	cox 2	cox 2	1.0	cox 2 immunoreactivity also is observed in the soma and throughout the dendritic extent of many neurons kaufmann et al. 1996 .
15081582	cox 2	cox 2	1.0	constitutive cox 2 is in the spinal dorsal and ventral horns as well as in dorsal root ganglia yaksh et al. 2001 .
15081582	cox 2	cox 2	1.0	indeed the antihyperalgesic activity of cox inhibitors is associated with regulation of constitutive cox 2 in the spinal cord svensson and yaksh 2002 .
15081582	cox 2	cox 2	1.0	although a role for cox 2 in healthy cells is not clear under pathological conditions the induction of cox 2 in neurons has been well demonstrated.
15081582	cox 2	cox 2	1.0	cox 2 was originally localized in neurons using in situ hybridization.
15081582	cox 2	cox 2	1.0	following a single maximal electroconvulsive seizure cox 2 is rapidly induced in hippocampal and cortical neurons peaking between 1 and 2 h and falling to baseline by 24 h.
15081582	cox 2	cox 2	1.0	administration of mk 801 an antagonist of the n methyl aspartic acid nmda receptor completely inhibits the cox 2 induction implying that nmda receptor activation is involved in the upregulation of cox 2 in these neurons.
15081582	cox 2	cox 2	1.0	in addition administration of the glucocorticoid dexamethasone markedly decreases cox 2 induction but only in the neocortex yamagata et al. 1993 .
15081582	cox 2	cox 2	1.0	this study suggests that cox 2 upregulation in neurons is dependent upon glutamatergic activity at the synapse.
15081582	cox 2	cox 2	1.0	intraperitoneal administration of kainic acid and also its local injection into the nuclear basalis can induce seizures in a rat and subsequently upregulate cox 2.
15081582	cox 2	cox 2	1.0	1997 showed that cox 2 induction overlaps with the development of neuronal apoptosis 8 h following seizure induction.
15081582	cox 2	cox 2	1.0	furthermore exposure of mixed cortical cells in vitro to nmda elicits a time dependent accumulation of prostaglandins that precede neuronal death and correlates with the induction of cox 2 mrna.
15081582	cox 2	cox 2	1.0	this nmda stimulated prostaglandin production and subsequent cell death is attenuated by a cox 2 inhibitor but not with a cox 1 selective inhibitor hewett et al. 2000 .
15081582	cox 2	cox 2	1.0	in addition genetic studies show that transgenic mice overexpressing cox 2 specifically in neurons are more susceptible to excitotoxicity kelley et al. 1999 .
15081582	cox 2	cox 2	1.0	in contrast cox 2 knockout mice experience reduced neuronal death compared to wild type mice when exposed to nmda or ischemia iadecola et al. 2001 .
15081582	cox 2	cox 2	1.0	cox 2 is induced in models of cerebral ischemia.
15081582	cox 2	cox 2	1.0	both regions but especially the penumbra region show a significant increase in cox 2 mrna in the ischemic area ipsilateral to the occlusion 4 and 24 h following the occlusion.
15081582	cox 2	cox 2	1.0	there is a direct correlation between the extent of cox 2 mrna induction at 4 h and the severity of subsequent tissue damage.
15081582	cox 2	cox 2	1.0	also the glutamate antagonist agent mk 801 significantly prevents the induction of cox 2 in the penumbra region collaco moraes et al. 1996 .
15081582	cox 2	cox 2	1.0	these studies provide evidence of a linkage between glutamate activity subsequent cox 2 induction and finally apoptotic death in neurons.
15081582	cox 2	cox 2	1.0	although increased extracellular glutamate regardless of its source can induce cox 2 in neurons the full consequences of this induction in neurons are still unclear.
15081582	cox 2	cox 2	1.0	cox 2 activity correlates with apoptosis in certain models; however from studies conducted thus far it is not clear which products of cox 2 induction are contributing to neuronal death which are helping neurons to escape death or which are unrelated to cell death.
15081582	cox 2	cox 2	1.0	in the nervous system cox 2 induction following cell activation or injury is not restricted to neurons since astrocytes also upregulate cox 2.
15081582	cox 2	cox 2	1.0	il 1_amp_#x3b2; causes a rapid induction of cox 2 peaking at 2 h and returning to baseline by 24 h.
15081582	cox 2	cox 2	1.0	dexamethasone can attenuate il 1_amp_#x3b2; mediated pge 2 secretion and cox 2 expression o'banion et al. 1996 .
15081582	cox 2	cox 2	1.0	astrocytic cox 2 is also induced by lps tnf basic fibroblast growth factor bfgf and phorbol ester o'banion 1999 .
15081582	cox 2	cox 2	1.0	although there is strong evidence for the induction of cox 2 in astrocytes in vitro there are few studies that confirm this finding in vivo.
15081582	cox 2	cox 2	1.0	cox 2 immunoreactive astrocytes have been observed in the hippocampus at 1_amp_#x2013;11 weeks but not 3 days following kainic acid seizure induction in rats sandhya et al. 1998 .
15081582	cox 2	cox 2	1.0	in the cortex in alzheimer's disease in situ hybridization with a cox 2 riboprobe revealed signal in a small proportion of gfap positive astrocytes chang et al. 1996 .
15081582	cox 2	cox 2	1.0	in addition cox 2 colocalizes with gfap in infarcted human brains sairanen et al. 1998 .
15081582	cox 2	cox 2	1.0	most in vitro studies are short term and demonstrate cox 2 induction in the order of hours after the insult.
15081582	cox 2	cox 2	1.0	thus the in vitro models may skew attempts to ascertain the significance of cox 2 activity in neurodegenerative disease.
15081582	cox 2	cox 2	1.0	in the context of neurodegenerative diseases the chronic induction of cox 2 will be more pathophysiologically relevant.
15081582	cox 2	cox 2	1.0	microglia have different regulatory mechanisms than macrophages fibroblasts and synovial cells that can induce cox 2 via the cytokines tnf il 1_amp_#x3b2; and il 6.
15081582	cox 2	cox 2	1.0	none of these agents induce cox 2 or nf _amp_#x3ba;b expression in na_amp_#xef;ve microglial cells.
15081582	cox 2	cox 2	1.0	in cultured rat brain microglia lps induces cox 2 expression that is prevented in the presence of inhibitors of nf kappab dexamethasone the antioxidant pyrrolidine dithiocarbamate and the protein c inhibitor go6976 .
15081582	cox 2	cox 2	1.0	thus nf _amp_#x3ba;b is involved in lps stimulated microglial cox 2 expression bauer et al. 1997 .
15081582	cox 2	cox 2	1.0	although increased cox 1 in microglia is observed injury paradigms there are little data indicating the expression of cox 2 in microglia in vivo.
15081582	cox 2	cox 2	1.0	1998 showed cox 2 immunostaining of cells with a microglial like morphology in infarcted human brain but did not show colocalization with microglial markers.
15081582	cox 2	cox 2	1.0	in a carrageenin induced pleurisy model in rats cox 2 induction peaks at 2 h with maximal pge 2 production and an increasing inflammatory response.
15081582	cox 2	cox 2	1.0	at a later time cox 2 increases again but this time with increased levels of pgd 2 and pgj 2 and decreased inflammation.
15081582	cox 2	cox 2	1.0	these temporally different inflammatory responses are modulated by the addition of a cox 2 inhibitor that causes inhibition of the early inflammatory response but increased inflammation later gilroy et al. 1999 .
15081582	cox 2	cox 2	1.0	there also appears to be a dual role for the products of the cox 2 enzyme in the nervous system.
15081582	cox 2	cox 2	1.0	in these models inhibition of cox 2 can delay disease onset and progression.
15081582	cox 2	cox 2	1.0	thus prostaglandin products of cox 2 appear to play a critical role in the development of motor neuron degeneration almer et al. 2002 .
15081582	cox 2	cox 2	1.0	addition of cox 2 inhibitors prevents both pge 2 production and kainic acid induced neuronal death in these cells kim et al. 2002 .
15081582	cox 2	cox 2	1.0	the pge 2 stimulated glutamate release produces a feed forward cycle whereby pge 2 induced glutamate may lead to further excitatory cell activation and cox 2 induction.
15081582	cox 2	cox 2	1.0	this mechanism is highlighted in a model of cox 2 overexpression that displays acceleration of glutamate mediated neuronal apoptosis mirjany et al. 2002 .
15081582	cox 2	cox 2	1.0	independently these cells are protected from death by the cox 2 inhibitor aphs.
15081582	cox 2	cox 2	1.0	one possible reason why there are differential effects on cell survival in the presence or absence of a cox 2 inhibitor may be because cox 2 activity results in the generation of multiple prostaglandins with potentially different effects.
15081582	cox 2	cox 2	1.0	when cox 2 is inhibited both the pro and anti apoptotic products are lost so cellular responses are directly produced by any single prostaglandin added to culture media.
15081582	cox 2	cox 2	1.0	however when cox 2 is not inhibited multiple prostaglandins are present that can act in a synergistic or antagonistic manner.
15081582	cox 2	cox 2	1.0	prostaglandins pga 1 pga 2 and pgj 2 all can suppress nf _amp_#x3ba;b activation and thus suppress cox 2 induction as well as other inflammatory mediators including inducible nitric oxide synthase and certain cytokines.
15081582	cox 2	cox 2	1.0	interestingly this is one area in which the significance of the differential expression of the cox 1 and cox 2 isoforms may arise.
15081582	cox 2	cox 2	1.0	since cox 1 increases in activated microglia and is not regulated by nf _amp_#x3ba;b then prostaglandins of microglial origin can regulate the activity of nf _amp_#x3ba;b and cox 2 in adjacent neurons without the same feedback regulation affecting the microglia.
15081582	cox 2	cox 2	1.0	cox 2 activity appears to play an important role in als.
15081582	cox 2	cox 2	1.0	in many different models cox 2 upregulation occurs concurrently with als disease events.
15081582	cox 2	cox 2	1.0	cox 2 and pge 2 are significantly elevated upwards of sevenfold in postmortem spinal cords of patients with sporadic als almer et al. 2001 and yasojima et al. 2001 .
15081582	cox 2	cox 2	1.0	in the spinal cords of transgenic mutant human sod1 expressing msod1 mice there is increased expression of cox 2 but not cox 1 mrna.
15081582	cox 2	cox 2	1.0	cox 2 mrna and protein levels cox catalytic activity and pge 2 levels are all increased in the spinal cord but not the cerebellum of msod1 mice.
15081582	cox 2	cox 2	1.0	cox 2 levels in msod1 mice are increased in both early symptomatic and end stage disease in neurons and to a lesser extent in astrocytes in the anterior horn of the spinal cord.
15081582	cox 2	cox 2	1.0	selective inhibition of cox 2 with sc236 protects motor neurons in an organotypic cell culture model of als drachman and rothstein 2000 .
15081582	cox 2	cox 2	1.0	this delayed onset is recapitulated when the selective cox 2 inhibitor nimesulide is administered prophylactically in these mice pompl et al. 2003 .
15081582	cox 2	cox 2	1.0	treatment with celecoxib a different selective cox 2 inhibitor also prolongs survival in the msod1 mouse model of als drachman et al. 2002 .
15081582	cox 2	cox 2	1.0	it seems that neuroinflammation proceeds albeit more slowly in cox 2 inhibitor treated animals possibly through the slower microglial cox 1 upregulation and likely through multiple additional regulatory mechanisms.
15081582	cox 2	cox 2	1.0	experiments that demonstrate protective abilities of cox 2 inhibition imply that cox 2 activation contributes to neuronal vulnerability and apoptosis by an undefined mechanism or mechanisms.
15081582	cox 2	cox 2	1.0	in addition some of the prostaglandin products of the cox 2 enzyme cause direct damage to neurons as well as act in both an autocrine and paracrine manner to propagate inflammation.
15081582	cox 2	cox 2	1.0	it is clear that neuroinflammation particularly cox 2 upregulation and prostaglandin production plays a significant role in neurodegenerative disorders such as als.
15081582	cox 2	cox 2	1.0	it seems likely that cox 2 inhibitors can delay the progression of symptoms and clinical studies addressing this issue are both warranted and currently underway.
15081582	cox 2	cox 2	1.0	although treatment of neurodegenerative diseases such as als with cox 2 inhibitors is likely to produce some symptomatic benefit it is very unlikely that these drugs will revolutionize the treatment of neurodegenerative disease.
15081582	cox 2	cox 2	1.0	in fact it is reported that high doses of certain nsaids can activate nf _amp_#x3ba;b leading to a paradoxical activation of the cox 2 enzyme that is clearly a problem for this therapeutic approach niederberger et al. 2001 .
15081582	cox 2	cox 2	1.0	this finding is not surprising given that it is the level of prostaglandins that feedback on nf _amp_#x3ba;b to regulate transcription of cox 2.
15081582	cox 2	cox 2	1.0	certain downstream products of the cox 2 enzyme are pro apoptotic while others are neuroprotective.
15081582	cox 2	cox 2	1.0	inhibiting cox 2 will block both the neurodegenerative and neuroprotective products of this enzyme.
15081582	cox 2	cox 2	1.0	it may be more appropriate in the development of future therapies rather than broadly targeting cox 2 or even further upstream at the level of nf _amp_#x3ba;b to target specific prostaglandin synthases downstream of cox 2.
15081582	cox 2	cox 2	1.0	or even further upstream at the level of nf _amp_#x3ba;b to target specific prostaglandin synthases downstream of cox 2.
15210305	cox 2	cox 2	1.0	cox 2 and cd11b a specific marker of microglia activation have been reported to be up regulated in als spinal cord tissue [ 113 ].
15210305	cox 2	cox 2	1.0	the significant up regulation of cox 2 in als spinal cord compared to control tissues including patients affected by parkinson's disease pd ad cerebrovascular accidents and other non neurological disorders adds further evidence to the obs
15210305	cox 2	cox 2	1.0	cox 2 mrna up regulation was restricted to pathologically affected tissue and this was accompanied by increased cox 2 protein levels.
15453089	cox 2	cox 2	1.0	cox 2 is the inducible isoform rapidly expressed in several cell types in response to growth factors cytokines and pro inflammatory molecules.
15453089	cox 2	cox 2	1.0	since its discovery in the early 1990s cox 2 has emerged as a major player in inflammatory reactions in peripheral tissues.
15453089	cox 2	cox 2	1.0	by extension cox 2 expression in brain has been associated with pro inflammatory activities thought to be instrumental in neurodegenerative processes of several acute and chronic diseases.
15453089	cox 2	cox 2	1.0	first in the central nervous system cox 2 is expressed under normal conditions and contributes to fundamental brain functions such as synaptic activity memory consolidation and functional hyperemia.
15453089	cox 2	cox 2	1.0	in spite of the intense research of the last decade the evidence of a direct role of cox 2 in neurodegenerative events is still controversial.
15453089	cox 2	cox 2	1.0	furthermore the emerging role of cox 2 in behavioral and cognitive functions will be discussed.
15453089	cox 2	cox 2	1.0	besides a constitutive isoform cox 1 which is widely distributed in virtually all cell types and is thought to mediate physiological responses a second and inducible isoform termed cox 2 was identified in the early 1990s 4 .
15453089	cox 2	cox 2	1.0	cox 2 is rapidly expressed in several cell types in response to growth factors cytokines and pro inflammatory molecules and has emerged as the isoform primarily responsible for prostanoid production in acu
15453089	cox 2	cox 2	1.0	cox 1 and cox 2 are coded by 2 distinct genes located on human chromosome 9 and 1 respectively.
15453089	cox 2	cox 2	1.0	the cox 2 gene is characterized by the presence of a tata box and a multitude of binding sites for transcription factors in its promoter region which account for the complex regulation of cox 2 expression.
15453089	cox 2	cox 2	1.0	n a long 3' untranslated region which has been found in many immediate early genes acts as mrna instability determinant or as translation inhibitory element suggesting post transcriptional control of cox 2 expression.
15453089	cox 2	cox 2	1.0	ites are conserved a few crucial substitutions cause important conformational variations in the active site pocket of the 2 isoenzymes which could account for the different sensitivities of cox 1 and cox 2 to specific inhibitors 5 .
15453089	cox 2	cox 2	1.0	one important difference between the 2 isoforms is the 18 amino acid insert near the cox 2 c terminus which is not present in cox 1 and has allowed the production of specific antibodies.
15453089	cox 2	cox 2	1.0	however in brain testes and kidney macula densa cells both cox 1 and cox 2 are expressed under physiological conditions 2 .
15453089	cox 2	cox 2	1.0	in rat brain cox 1 and cox 2 immunoreactivities are present in discrete neuronal populations distributed in distinct areas of cerebral cortex and hippocampus.
15453089	cox 2	cox 2	1.0	similarly mrnas for both cox 1 and cox 2 are present in several regions of human brain although cox 2 is the prominent isoform particularly in the hippocampus 8 9 .
15453089	cox 2	cox 2	1.0	the relative contribution of cox 1 and cox 2 activity to brain pathology and physiology has been recently questioned 10 11 .
15453089	cox 2	cox 2	1.0	on one side it has been argued that cox 1 activity in brain diseases has been overlooked; on the other side mandatory evidence suggests that cox 2 plays a special role in normal neuronal function and in neurotoxicity.
15453089	cox 2	cox 2	1.0	although this debate will be solved only by further clinical and experimental studies it is clear that the popular paradigm by which cox 1 serves physiological functions and cox 2 is responsible for _amp_#147;pathological_amp_#148; pgs cannot explain an increasing number of findings.
15453089	cox 2	cox 2	1.0	over expression of cox 2 has been associated with neurotoxicity in acute conditions such as hypoxia/ ischemia and seizures.
15453089	cox 2	cox 2	1.0	however the beneficial or detrimental role played by cox 2 in inflammatory and neurodegenerative brain pathologies is still controversial.
15453089	cox 2	cox 2	1.0	first the emerging role of cox 2 in cognitive functions will be discussed since understanding the role of cox 2 in brain function is an important prerequisite to fully understanding how to exploit the potential benefits of cox 2 inhibition in disabling neurological diseases.
15453089	cox 2	cox 2	1.0	in brain function is an important prerequisite to fully understanding how to exploit the potential benefits of cox 2 inhibition in disabling neurological diseases.
15453089	cox 2	cox 2	1.0	in mammalian brain cox 2 is constitutively expressed in specific neuronal populations under normal physiological conditions.
15453089	cox 2	cox 2	1.0	in rat brain cox 2 mrna and immunoreactivity were detected in dentate gyrus granule cells pyramidal cell neurons in the hippocampus the piriform cortex superficial cell layers of neocortex the amygdala and at low level
15453089	cox 2	cox 2	1.0	this _amp_#147;constitutive_amp_#148; neuronal cox 2 expression should be more correctly regarded as _amp_#147;dynamically_amp_#148; regulated since it is dependent on normal synaptic activity is rapidly increased during seizures or ischemia and is dow
15453089	cox 2	cox 2	1.0	the dependence of cox 2 expression on natural excitatory synaptic activity is supported by the presence of cox 2 immunoreactivity in distal dendrites and dendritic spines which are involved in synaptic signaling and by its exclusive localization to excitatory glutamatergic neurons.
15453089	cox 2	cox 2	1.0	furthermore the heterogeneous distribution within a neuronal population is compatible with induction of cox 2 in subsets of neurons in response to natural excitatory synaptic stimulation as shown for other immediate early genes activated by excitatory stimulation 14 .
15453089	cox 2	cox 2	1.0	the involvement of cox 2 in synaptic activity is further supported by the developmental profile of cox 2 expression.
15453089	cox 2	cox 2	1.0	in rat brain cox 2 expression follows developmental gradients and coincides with the critical period of activity dependent cortical development 17 .
15453089	cox 2	cox 2	1.0	yndrome_amp_#151;a neurological disorder associated with mental retardation defective development of cortical neurons and abnormalities of dendritic branching_amp_#151;the laminar pattern of cortical cox 2 immunoreactivity is disrupted in that cox 2 positive neurons are decreased in number and randomly distributed 18 .
15453089	cox 2	cox 2	1.0	immunoreactivity is disrupted in that cox 2 positive neurons are decreased in number and randomly distributed 18 .
15453089	cox 2	cox 2	1.0	rats subjected to selective destruction of basal forebrain cholinergic neurons during the first post natal week showed decreased levels of cox 2 but not cox 1 in the hippocampus at adulthood.
15453089	cox 2	cox 2	1.0	this effect was accompanied by impairment in social memory suggesting that the early loss of hippocampal cholinergic input may impact on the expression of cox 2 in hippocampal neurons and on the functional role of pgs in synaptic activity 19 .
15453089	cox 2	cox 2	1.0	indirect evidence of cox 2 involvement in synaptic plasticity has been obtained in the recent years by using cox inhibitors in in vivo and in vitro models of synaptic plasticity.
15453089	cox 2	cox 2	1.0	cox 2 inhibitors but not cox 1 selective inhibitors administered systemically shortly after training in the morris water maze a hippocampal dependent learning task have been shown to impair spatial memory
15453089	cox 2	cox 2	1.0	in addition pre training infusion of a cox 2 specific inhibitor celecoxib in the hippocampus of adult rats impaired acquisition of the morris water maze suggesting that in rats cox 2 activity in the hippocampus is necessary for both memory and learning of a spatial task 22 .
15453089	cox 2	cox 2	1.0	in agreement with this hypothesis pge 2 but not pgd 2 reversed the suppression of ltp induced by cox 2 inhibitor in hippocampal dentate granule neurons in vitro 24 .
15453089	cox 2	cox 2	1.0	pge 2 which is preferentially formed during the enzymatic activity of cox 2 rather than of cox 1 could participate to synaptic plasticity through several mechanisms including modulation of adrenergic noradrenergic and glutamatergic neurotransmission remodeling of actin in th
15453089	cox 2	cox 2	1.0	moreover cox 2 derived pgs are involved in the coupling of synaptic plasticity with cerebral blood flow as suggested by the attenuation of the increase in neocortical blood flow in response to vibrissal stimulation
15453089	cox 2	cox 2	1.0	pgs are involved in the coupling of synaptic plasticity with cerebral blood flow as suggested by the attenuation of the increase in neocortical blood flow in response to vibrissal stimulation by the cox 2 inhibitor ns398.
15453089	cox 2	cox 2	1.0	the hyperemic response was also impaired in mutant mice lacking of cox 2 26 .
15453089	cox 2	cox 2	1.0	in spite of the emerging evidence of a physiological role for cox 2 in brain development and function cox 2 knockout mice show no gross abnormalities of brain anatomy.
15453089	cox 2	cox 2	1.0	in this light the expression of cox 2 and its contribution to the pathogenic events in ms have been explored in several animal models and in ms patients.
15453089	cox 2	cox 2	1.0	cox 2 immunoreactivity has been found in experimental autoimmune encephalomyelitis eae an extensively used animal model.
15453089	cox 2	cox 2	1.0	analysis of spinal cord of sjl mice immunized with a peptide of the myelin constituent proteolipid protein revealed that during the acute phase of eae cox 2 expression is confined within infiltrating macrophages and ramified microglia close to the inflammatory infiltrates.
15453089	cox 2	cox 2	1.0	very rare reactive astrocytes expressed cox 2 in this phase but their number significantly increased during relapse phase suggesting that cox 2 induction in astrocytes could be due to soluble factors i.e. cytokines produced during the protracted inflammatory insults 30 .
15453089	cox 2	cox 2	1.0	in a different eae model in which lewis rats were immunized with a peptide of another myelin protein the myelin basic protein cox 2 immunoreactivity was exclusively found associated with neurons and endothelial cells 31 .
15453089	cox 2	cox 2	1.0	the number of cox 2 positive endothelial cells increased with the progression of the disease most prominently in areas of cellular infiltration.
15453089	cox 2	cox 2	1.0	in eae the number of cox 1 positive macrophages increased along with that of cox 2 positive cells.
15453089	cox 2	cox 2	1.0	sensitivity response to heat killed bacillus calmette gu_amp_#233;rin which results in t cell and macrophage recruitment to the brain parenchyma breakdown of bbb primary demyelination and axon damage cox 2 expression was restricted to major infiltrating hematogenous cell populations such as neutrophils and mononuclear phagocytes and to perivascular cells of the blood vessels in the vicinity of the lesi
15453089	cox 2	cox 2	1.0	these perivascular cells were identified as macrophages but the possibility that some endothelial cells also expressed cox 2 could not be ruled out.
15453089	cox 2	cox 2	1.0	neuronal cox 2 was not affected by the ongoing inflammation.
15453089	cox 2	cox 2	1.0	in spite of the extensive astrocyte and microglial reaction occurring over a broad area surrounding the inflammatory lesions there was no obvious cox 2 staining in these cells indicating that the upregulation of cox 2 expression in this model of chronic immune mediated lesions is remarkably restricted to the lesion sites 32 .
15453089	cox 2	cox 2	1.0	staining in these cells indicating that the upregulation of cox 2 expression in this model of chronic immune mediated lesions is remarkably restricted to the lesion sites 32 .
15453089	cox 2	cox 2	1.0	a similar restricted cox 2 expression has been described in brain tissues from 7 ms patients 33 .
15453089	cox 2	cox 2	1.0	in these specimens characterized by the presence of chronic active lesions cox 2 expression was studied by sophisticated confocal microscopy analysis.
15453089	cox 2	cox 2	1.0	cox 2 positive cells were present in all chronic active lesions examined and generally located on the border of myelinated regions.
15453089	cox 2	cox 2	1.0	cox 2 immunoreactivity was largely but not exclusively associated with cells expressing the macrophage/microglial marker cd64 the fc receptor typically associated with activated macrophages.
15453089	cox 2	cox 2	1.0	however not all cd64 positive cells expressed cox 2.
15453089	cox 2	cox 2	1.0	expression of cox 2 was frequently associated with that of inducible no synthase inos suggesting that both enzymes could contribute to the progression of ms through their ability to produce free radicals such as superox
15453089	cox 2	cox 2	1.0	the authors also propose that the colocalization of cox 2 and inos may be functionally linked to oligodendroglial excitotoxic death in ms. indeed both pge 2 and peroxinitrite could increase the local concentration of glutamate to toxic levels by inducing ca
15453089	cox 2	cox 2	1.0	nonetheless a protective role of cox 2 in ms cannot be excluded.
15453089	cox 2	cox 2	1.0	the well established role of cox 2 in inflammation and in glutamate dependent neurotoxicity has set the basis for the hypothesis of cox 2 involvement in als pathogenesis.
15453089	cox 2	cox 2	1.0	cox 2 mrna and protein were increased in postmortem spinal cords of als patients 42 and transgenic mutated sod1 mice 43 .
15453089	cox 2	cox 2	1.0	elevation of pge 2 tissue levels paralleled the increased expression of cox 2 43 .
15453089	cox 2	cox 2	1.0	the cell types expressing cox 2 have been identified in both animal and human specimens.
15453089	cox 2	cox 2	1.0	under normal conditions cox 2 is expressed in neurons in the spinal cord dorsal and ventral horns as well as in dorsal root ganglia.
15453089	cox 2	cox 2	1.0	in postmortem spinal cord of als patients cox 2 expression was markedly increased and localized to both neurons and glial cells.
15453089	cox 2	cox 2	1.0	the number of cox 2 positive motor neurons and interneurons was significantly increased in spite of the expected overall reduction in the total number of neurons.
15453089	cox 2	cox 2	1.0	in addition cox 2 was associated with astrocytes and and to a much lesser extent with microglial cells.
15453089	cox 2	cox 2	1.0	a similar pattern of cox 2 expression was reported for the mutated sod1 transgenic mice 43 .
15453089	cox 2	cox 2	1.0	the role of cox 2 activity in als was examined by using selective cox 2 inhibitors.
15453089	cox 2	cox 2	1.0	in the first study the cox 2 inhibitor sc236 significantly protected motor neurons in an organotypic spinal cord culture model in which neuronal death is induced by treo hydroaspartate an inhibitor of astrocytic glutamate re upt
15453089	cox 2	cox 2	1.0	these findings suggested that cox 2 could take part in the excitotoxic damage caused by elevated glutamate levels.
15453089	cox 2	cox 2	1.0	subsequently the same group showed that treatment of sod1 transgenic mice with cox 2 inhibitor celecoxib significantly delayed the onset of disease prolonged the survival and reduced the spinal neurodegeneration and glial activation 47 .
15453089	cox 2	cox 2	1.0	these studies suggest that inhibition of cox 2 could have therapeutic benefits by altering the cascade of events leading to the progressive neuronal death in als patients.
15453089	cox 2	cox 2	1.0	however in these studies mice received the cox 2 inhibitor treatment beginning several weeks before the onset of disease defined as a 30_amp_#37; decrease in motor performance.
15453089	cox 2	cox 2	1.0	thus the efficacy of cox 2 inhibition in the presence of overt clinical signs of disease remains to be investigated.
15453089	cox 2	cox 2	1.0	several mechanisms could be triggered by cox 2 overexpression.
15453089	cox 2	cox 2	1.0	in addition to the enhancing effect of pge 2 on glutamate release cox 2 could contribute to oxidative stress mediated damage by producing oxidizing reactive species during the peroxidase activity fig 1 .
15453089	cox 2	cox 2	1.0	in transgenic mutated sod1 mice cox 2 and inos are induced with a similar temporal pattern and co expression of the 2 enzymes as discussed in the previous section could lead to the formation of more reactive free radical species such as
15453089	cox 2	cox 2	1.0	cox 2 could also contribute to als by promoting inflammatory processes.
15453089	cox 2	cox 2	1.0	the first study reported an increased expression of cox 2 in ameboid or activated microglial cells in the substantia nigra from 11 idiopathic pd patients whereas neuronal and astroglial cox 2 expression was not different in the control and pd groups.
15453089	cox 2	cox 2	1.0	moderate cox 1 immunoreactivity was observed in some neuronal somata and processes and in few glial cells in both groups suggesting that the greater potential for pg synthesis is associated to cox 2 and microglial cells 53 .
15453089	cox 2	cox 2	1.0	by contrast the second and more recent study 52 showed that cox 2 is specifically induced in substantia nigra dopaminergic neurons in postmortem pd specimens and in the 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine mptp mouse model.
15453089	cox 2	cox 2	1.0	the involvement of cox 2 in pd neurodegeneration was further suggested by the observation that mptp neurodegeneration was mitigated in cox 2 but not in cox 1 knock out mice.
15453089	cox 2	cox 2	1.0	the increase in hippocampal pge 2 levels was associated with a strong induction of cox 2 expression which increased with the progression of disease and was specifically localized to microglial cells 56 .
15453089	cox 2	cox 2	1.0	were then confirmed in a second murine model in which ch3 mice were infected with homogenates from 2 cases of genetic cjd and 3 cases of sporadic cjd 57 suggesting that the selective upregulation of cox 2 in microglial cells is not characteristic of a specific prion agent or mouse strain.
15453089	cox 2	cox 2	1.0	different results were reported in a recent study in which both cox 1 and cox 2 were increased in sporadic cjd cortex 58 .
15453089	cox 2	cox 2	1.0	cox 1 immunoreactivity was present in macrophages/microglial cells whereas cox 2 was predominantly in neurons. mrnas and proteins of both isoforms were higher in tissue from temporal lobe of 1 cjd patient when compared to 1 neuropathologically unaltered control case.
15453089	cox 2	cox 2	1.0	the increased levels of pge 2 in the csf of cjd patients and the high expression of cox 2 in microglial cells in experimental prion diseases suggest that pge 2 synthesis may be associated with the clearance of apoptotic neurons.
15453089	cox 2	cox 2	1.0	in cjd abundance of apoptotic neurons correlated well with microglial activation 60 and recently interaction of microglial cells with apoptotic neurons has been reported to selectively promote cox 2 expression and pge 2 synthesis 61 .
15453089	cox 2	cox 2	1.0	over the last 10 years several analyses of cox 1 and cox 2 expressions have been carried out in animal models and postmortem ad brain tissues providing a substantial but still controversial body of evidence pointing to the involvement of cox 2 in the cascade
15453089	cox 2	cox 2	1.0	expressions have been carried out in animal models and postmortem ad brain tissues providing a substantial but still controversial body of evidence pointing to the involvement of cox 2 in the cascade of events leading to neurodegeneration in ad.
15453089	cox 2	cox 2	1.0	cox 2 mrna levels in ad brains were reported as either decreased or increased 9 65 66 possibly because of the short half life of cox 2 transcripts or individual variability of inflammatory related processes 67 .
15453089	cox 2	cox 2	1.0	several studies reported increased neuronal cox 2 immunoreactivity compared to control brain tissues 9 68 .
15453089	cox 2	cox 2	1.0	however in other studies in which cox 2 expression was related to specific hallmarks of the disease such as clinical dementia rating and braak stage of disease the number of cox 2 positive neurons decreased with the severity of dementia.
15453089	cox 2	cox 2	1.0	in end stage ad cox 2 positive neurons were significantly fewer than in non demented controls 68 69 .
15453089	cox 2	cox 2	1.0	in a more recent study 70 the number of neurons expressing cox 2 negatively correlated with the braak score for amyloid deposits although a moderate albeit non significant cox 2 increase was found at braak stage a corresponding to the mildest stage of disease when compared to non demented control cases.
15453089	cox 2	cox 2	1.0	cox 2 immunoreactivity did not correlate with braak staging for neurofibrillary changes.
15453089	cox 2	cox 2	1.0	these recent studies suggest that cox 2 expression varies with the disease stage and this may explain the controversial findings reported in the literature.
15453089	cox 2	cox 2	1.0	hoozemans et al also reported a colocalization and a significant correlation of neuronal cox 2 expression with cell cycle regulators involved in controlling the g 0 / g 1 phase such as cyclin d1 and e and the retinoblastoma protein 69 70 .
15453089	cox 2	cox 2	1.0	although there are some indications that cox 2 might regulate cell cycle progression 70 the functional link between cox 2 and cell cycle alteration remains elusive.
15453089	cox 2	cox 2	1.0	nonetheless it can be suggested that cox 2 and cell cycle proteins are involved in early steps leading to neurodegeneration.
15453089	cox 2	cox 2	1.0	in contrast to cox 2 the levels of cox 1 mrna and protein were not significantly altered in ad brains 9 72 .
15453089	cox 2	cox 2	1.0	this pattern is consistent with the slight increase in the number of cox 2 positive neurons at braak stage a as well as with the reduction in cox 2 positive neurons reported in patients with severe dementia and braak end stage disease as previously reported 68 70 .
15453089	cox 2	cox 2	1.0	the moderate increase in cox 2 expression and activity at very early stages of ad could explain the primary protective of nsaids by preventing early steps leading to neurodegeneration.
15453089	cox 2	cox 2	1.0	upregulation of neuronal cox 2 is associated with ischemia and excitotoxicity suggesting that cox 2 is involved in neurotoxic mechanisms.
15453089	cox 2	cox 2	1.0	increased susceptibility to excitotoxicity in cox 2 over expressing neurons and neuroprotection by cox 2 inhibition has been shown in several experimental models 64 .
15453089	cox 2	cox 2	1.0	nonetheless increased cox 2 expression could be an adaptive reaction to pathological events such as cerebrovascular dysfunction early inflammatory processes or oxidative stress in the attempt to restore lost physiological funct
15453089	cox 2	cox 2	1.0	taking into account the positive and negative effects of increased cox 2 activity and the emerging role of cox 2 derived pgs in brain function it is difficult to predict the final outcome of long term therapeutic cox 2 inhibition.
15453089	cox 2	cox 2	1.0	derived pgs in brain function it is difficult to predict the final outcome of long term therapeutic cox 2 inhibition.
15453089	cox 2	cox 2	1.0	at present clinical trials of selective cox 2 inhibitors have not been as convincing as expected but these failures may be related to drug selection and dose duration of treatment and state of disease of selected patients 64 .
15453089	cox 2	cox 2	1.0	echanisms such as lowering of a[beta] peptide levels reduction in the plaque pathology and activation of the peroxisome proliferator activated receptor [gamma] suggesting that selective inhibition of cox 2 may not be the optimal therapeutic strategy 64 .
15453089	cox 2	cox 2	1.0	since its discovery in early 1990s cox 2 has emerged as a major player in inflammatory reactions in peripheral tissues.
15453089	cox 2	cox 2	1.0	evidence from several laboratories indicates that cox 2 is induced in various inflammatory settings is the main source of pgs responsible for clinical signs of inflammation and its inhibition leads to anti inflammatory effects.
15453089	cox 2	cox 2	1.0	by extension cox 2 expression in brain has been associated with pro inflammatory activities thought to be instrumental in neurodegenerative processes of several acute and chronic diseases.
15453089	cox 2	cox 2	1.0	however 2 major aspects should be borne in mind when considering the significance of cox 2 activity in brain diseases.
15453089	cox 2	cox 2	1.0	first cox 2 is expressed under normal conditions and contributes to fundamental brain functions such as synaptic activity memory consolidation and functional hyperemia.
15453089	cox 2	cox 2	1.0	in spite of the intense research of the last decade the evidence of a direct role of cox 2 in neurodegenerative events is still controversial and further experimental and clinical studies are required to improve our knowledge of how and when cox 2 inhibition may have beneficial effects for
15453089	cox 2	cox 2	1.0	in neurodegenerative events is still controversial and further experimental and clinical studies are required to improve our knowledge of how and when cox 2 inhibition may have beneficial effects for patients suffering from inflammatory and degenerative neuropathologies.
15453089	cox 2	cox 2	1.0	several cell types including resident cells i.e neurons glia endothelial cells and infiltrating blood cells can express cox 2 in brain.
15453089	cox 2	cox 2	1.0	over expression of cox 2 in each of these cells may have different functional consequences and its final outcome is likely to depend on the prevailing product of cox 2 activity including pgs with different functions and free radicals.
15453089	cox 2	cox 2	1.0	neurons are particularly susceptible to damage caused by free radicals generated through cox 2 peroxidase activity whereas glial cells are more resistant.
15453089	cox 2	cox 2	1.0	specific signals seem responsible for cox 2 induction and/or over expression in particular cell types such as glutamate in neurons cytokines in astrocytes and apoptotic neurons in microglia.
15453089	cox 2	cox 2	1.0	the beneficial effects of specific and non specific cox 2 inhibitors in several experimental models and epidemiological studies are an indirect proof of the causative role of cox 2 in neurodegeneration as cox independent mechanisms cannot be excluded.
15572176	cox 2	cox 2	1.0	reactive astrocytes in als contain protein inclusions express inflammatory makers such as the inducible forms of nitric oxide synthase inos and cyclooxygenase cox 2 display nitrotyrosine immunoreactivity and downregulate the glutamate transporter eaat2.
15572176	cox 2	cox 2	1.0	reactive astrocytes in als show increased immunoreactivity for gfap and the calcium binding protein s100_amp_#x3b2; [ 85 ] and express inflammatory makers such as cox 2 [ 81 ] inos and neuronal nos [ 5 and 115 ].
15572176	cox 2	cox 2	1.0	for example reactive astrocytes in als express cox 2 an enzyme that catalyzes the synthesis of the inflammatory prostaglandin e2 which in turn stimulates glutamate release from astrocytes.
15572176	cox 2	cox 2	1.0	treatment of als mice with the cox 2 inhibitor celecoxib delayed the onset of the disease and increased the survival rates [ 30 ] further suggesting a link between inflammation and excitotoxicity. 4.2.
15572176	cox 2	cox 2	1.0	interestingly cytokine signaling can induce inos cox 2 and nmda receptor subunit phosphorylation with different consequences in glial and neuronal cells.
15572176	cox 2	cox 2	1.0	activation of murine astrocytes with tumour necrosis factor alpha tnf _amp_#x3b1; il 1_amp_#x3b2; and ifn_amp_#x3b3; induces il 6 cox 2 and inos and makes the cells vulnerable to undergo apoptosis in response to fas ligand fasl [ 39 ].
15691215	cox 2	cox 2	1.0	gene transfer of vegf or glial cell line derived neurotrophic factor anti inflammatory cox 2 inhibitors and minocycline have had particularly promising results in mice.
15799549	cox 2	cox 2	1.0	macrophages in als spinal cord showed strong expression of cyclooxygenase 2 cox 2 one log greater than control tissues and inducible nitric oxide synthase.
15799549	cox 2	cox 2	1.0	in control cases with corticospinal tract degeneration following hemispheric cerebral infarction macrophage infiltration of the white matter was cox 2 negative and restricted to lateral and anterior corticospinal tracts.
15804265	cox 2	cox 2	1.0	inhibition of a key mediator of inflammation cyclooxygenase 2 cox 2 represents a promising therapeutic approach in als.
15804265	cox 2	cox 2	1.0	here we tested the in vivo effects of a specific cox 2 inhibitor rofecoxib administered by intraperitoneal injection in the sod1 g93a g1h mouse model of the familial form of als fals .
16101543	cox 2	cox 2	1.0	these compounds are converted from arachnoidic acid aa by two isoforms of the cyclooxygenase cox enzyme namely cox 1 and cox 2.
16101543	cox 2	cox 2	1.0	in particular the action of cox 2 and pgs in cns inflammation has gained much attention recently.
16120782	cox 2	cox 2	1.0	feature of als is the loss of motor neurons talbot 2002 which is accompanied by a robust glial response including activation of microglia and astrocytes as well as the expression of cyclooxygenase 2 cox 2 and nitric oxide synthase inos in the spinal cord phul et al. 2000 ; almer et al. 2001 ; yasojima et al. 2001 ; barbeito et al. 2004 .
16120782	cox 2	cox 2	1.0	for the analysis of inos and cox 2 100 microg of protein samples was separated in 10% sds gels transferred onto immobilon p polyvinylidene difluoride membranes and stained with a polyclonal inos antibody at 1:500 dilution rabbit polyc
16120782	cox 2	cox 2	1.0	difluoride membranes and stained with a polyclonal inos antibody at 1:500 dilution rabbit polyclonal antibody to c terminus of murine inos; santa cruz biotechology heidelberg germany or a polyclonal cox 2 antibody at a 1:600 dilution rabbit polyclonal antibody to synthetic peptide from murine cox 2; cayman ann arbor mi .
16120782	cox 2	cox 2	1.0	antibody at a 1:600 dilution rabbit polyclonal antibody to synthetic peptide from murine cox 2; cayman ann arbor mi .
16120782	cox 2	cox 2	1.0	the specificities of the inos and cox 2 antibodies have been confirmed by positive controls containing inos or cox 2 protein data not shown .
16120782	cox 2	cox 2	1.0	coinduction of cox 2 and inos were described in several neurodegenerative disorders including als as well as in the sod1 g93a model used in this study almer et al. 1999 2001 ; sasaki et al. 2001 .
16120782	cox 2	cox 2	1.0	western blot analysis of lumbar spinal cord lysates from 90 d old mice confirmed cox 2 expression in wild type mice n = 4 and revealed that sod1 g93a mice n = 4 showed elevated cox 2 levels fig 3 b .
16120782	cox 2	cox 2	1.0	in both cases pio treatment significantly decreased cox 2 and inos expression in sod1 g93a mice n = 4 .
16120782	cox 2	cox 2	1.0	quantification of microglia at day 90 of life bottom right; n = 4 for wt and wt pio; n = 5 for sod1 and sod1 pio and of cox 2 and inos western blots n = 4 for all groups from spinal cord samples derived from 90 d old mice b are shown. p _lt_ 0.01 and p _lt_ 0.001 compared with the respective nontreated group. c quantificati
16120782	cox 2	cox 2	1.0	we found a marked reduction in the expression of cox 2 and inos two major proinflammatory enzymes after pio treatment.
16120782	cox 2	cox 2	1.0	coinduction of both enzymes by several factors including glutamate release and secretion of proinflammatory cytokines may be caused by similar or identical stimulators o'banion 1999 because the cox 2 and inos promoters share several binding sites for signal transduction factors involved in inflammatory signal cascades xie et al. 1993 ; nathan and xie 1994 .
16120782	cox 2	cox 2	1.0	apart from the detrimental action of either inos derived excess no or cox 2 generated proinflammatory prostanoids the dual inhibition of both enzymes observed in response to pio treatment may be advantageous because both pathways mutually increase their pathogenicity.
16120782	cox 2	cox 2	1.0	thus no may increase the catalytic activity of cox 2 thereby increasing the production of proinflammatory prostanoids nogawa et al. 1998 .
16120782	cox 2	cox 2	1.0	the latter signal transduction pathway is also involved in the inos and cox 2 gene regulation after inflammatory stimulation.
16120782	cox 2	cox 2	1.0	nd socs 3 levels in response to pio treatment reflects one mechanism of the anti inflammatory effect observed and antagonizing the jak stat pathway contributes to the observed suppression of inos and cox 2 expression.
16380619	cox 2	cox 2	1.0	the same observation was made for prostaglandin e 2 pge 2 which is an inflammatory mediator and a major downstream product of cyclooxygenase 2 cox 2 .
16380619	cox 2	cox 2	1.0	increased levels of pge 2 and cox 2 were described in patients with als.
16380619	cox 2	cox 2	1.0	pge 2 and cox 2 presented both angiogenic properties and reciprocal interactions between cox 2/pge 2 and vegf are described.
16380619	cox 2	cox 2	1.0	our findings suggest that increased levels of il 6 tnf alpha pge 2. and cox 2 observed in patients with als parallel motor neuronal loss and could correspond to a natural response to hypoxemia.
16380619	cox 2	cox 2	1.0	we hypothesize that cox 2 inhibitors may even be harmful in patients with als because they can block the natural upregulation loop of vegf during hypoxemia.
16624536	cox 2	cox 2	1.0	an increased expression of pro inflammatory cytokines cox 2 [29] [30] and [31] and of microglia mediated protein oxidative pathology [32] is also observed in als.
16624536	cox 2	cox 2	1.0	this process is associated with an increased level of cox 2 mrna and protein and an increase in pge 2 content limited to the regions associated with motor neuron pathology further confirming a role for microglial activation [31] and [51] .
16624536	cox 2	cox 2	1.0	the latter observation is consistent with in vitro observations that the motor neuron death induced by chronic glutamate excitotoxicity in organotypic spinal cord cultures can be suppressed by cox 2 inhibition [52] .
16624536	cox 2	cox 2	1.0	this stimulation results in increased glutamate uptake and decreased no production as well as decreased mrna expression of inflammatory products including cox 2 inos and i_amp_#x3ba;b an inhibitor of nf _amp_#x3ba;b by microglia compared to lps treated microglia.
16624536	cox 2	cox 2	1.0	like microglia reactive astrocytes express inflammatory markers including inos and cox 2 [114] and can produce proinflammatory mediators including prostaglandins [115] il 6 [116] and tnf [114] .
16624536	cox 2	cox 2	1.0	celecoxib celebrex and rofecoxib are inhibitors of cox 2.
16624536	cox 2	cox 2	1.0	treatment with these cox 2 inhibitors combined with creatine increased survival by up to 30% in sod1 mutant mice [139] [140] and [141] while treatment with a non specific cox inhibitor sulindac extended survival by roughly 10%
16647138	cox 2	cox 2	1.0	three forms of cox enzymes designated as cox 1 cox 2 and cox 3 occur in mammalian tissues.
16647138	cox 2	cox 2	1.0	inflammatory mediators such as cytokines growth factors and bacterial endotoxin rapidly induce cox 2 which is normally undetectable in healthy tissues.
16647138	cox 2	cox 2	1.0	cox 2 is constitutively expressed in the kidney stomach and brain hoffmann 2000 .
16647138	cox 2	cox 2	1.0	cox 1 and cox 2 are homodimers.
16647138	cox 2	cox 2	1.0	cox 1 contains val at the 434 and 523 positions whereas cox 2 has ile at positions 434 and 523.
16647138	cox 2	cox 2	1.0	these differences in amino acid sequences may result in larger and more flexible substrate and inhibitor binding sites in cox 2 than in cox 1 kurumbail et al. 1996 .
16647138	cox 2	cox 2	1.0	the amino acid sequences of cox 1 and cox 2 also differ from each other at the n and c termini.
16647138	cox 2	cox 2	1.0	cox 2 lacks a 17 amino acid sequence at the n terminus but has an extra 18 amino acid sequence at the c terminus.
16647138	cox 2	cox 2	1.0	thus the active site of cox 2 is larger and more accommodating than that of cox 1 and cox 1 displays negative allosterism at low concentrations of aa.
16647138	cox 2	cox 2	1.0	this property may be responsible for greater eicosanoid production by cox 2 when the aa concentration is low smith et al. 2000 .
16647138	cox 2	cox 2	1.0	aa is the preferred substrate for cox 1 and cox 2.
16647138	cox 2	cox 2	1.0	the cox 2 gene is 8.3 kb whereas the cox 1 gene is much larger 22 kb vane et al. 1998 .
16647138	cox 2	cox 2	1.0	cox 1 mrna is approximately 2.8 kb while cox 2 mrna is approximately 4.0 kb.
16647138	cox 2	cox 2	1.0	analysis of the 5_amp_#x2032; flanking untranslated regions of cox 1 and cox 2 indicates that the cox 1 gene is associated with housekeeping activities whereas the cox 2 gene is involved in response related activities.
16647138	cox 2	cox 2	1.0	the 5_amp_#x2032; flanking region of the cox 2 gene has a tata box 30 base pairs upstream from the transcription start site tazawa et al. 1994 whereas the same region in the cox 1 gene has no canonic tata box wu 1995 .
16647138	cox 2	cox 2	1.0	the cox 2 gene also contains a number of putative regulatory sites including the cyclic amp response element il 6 response element ap 2 nuclear factor _amp_#x3ba;b nf _amp_#x3ba;b sp 1 pea 3 gata 1 and glucoco
16647138	cox 2	cox 2	1.0	thus factors that inhibit nf _amp_#x3ba;b activity such as il 4 il 10 and il 13 can specifically inhibit cox 2 upregulation.
16647138	cox 2	cox 2	1.0	the cox 1 gene also has some putative regulatory sites such as sp 1 ap 2 nf il 6 gata 1 and a shear stress response element but the location of these sites differs considerably from those in the cox 2 gene.
16647138	cox 2	cox 2	1.0	cox 1 does not respond to nf _amp_#x3ba;b as intensely as cox 2.
16647138	cox 2	cox 2	1.0	in rat and ovine brain cox 1 and cox 2 immunoreactivities are present in discrete neuronal populations distributed in distinct areas of cerebral cortex midbrain and hippocampus.
16647138	cox 2	cox 2	1.0	cox 1 immunoreactivity is enriched in midbrain pons and medulla breder et al. 1995 whereas cox 2 immunoreactivity prevails in neurons and glial cells of hippocampus hypothalamus and amygdala andreasson et al. 2001 and yamagata et al. 1993 .
16647138	cox 2	cox 2	1.0	in neurons astrocytes and microglial cells cox 2 immunoreactivity is localized to the perinuclear regions tomimoto et al. 2000 .
16647138	cox 2	cox 2	1.0	the expression of cox 2 is markedly increased in microglial cells after intraperitoneal administration of lipopolysaccharide lps whereas neuronal cox 2 remains unchanged elmquist et al. 1997 .
16647138	cox 2	cox 2	1.0	in microglial cells cox 2 expression and ability to release pge 2 txa 2 and txb 2 upon stimulation by lps are several times higher than in astrocytes but lower than in peripheral macrophages giulian et al. 1996 and minghetti
16647138	cox 2	cox 2	1.0	cox 2 induction in microglia by proinflammatory stimuli is apparently similar to peripheral macrophages and plays important roles in inflammatory and immune responses.
16647138	cox 2	cox 2	1.0	although different pharmacological properties have been described for cox 3 compared with cox 1 or cox 2 enzymes many investigators consider it to be a splice variant of cox 1 chandrasekharan et al. 2002 and davies et al. 2004 .
16647138	cox 2	cox 2	1.0	comparison of canine cox 3 activity with murine cox 1 and cox 2 demonstrates that analgesic/antipyretic drugs such as acetaminophen phenacetin antipyrine and dipyrone selectively inhibit cox 3 and some nonsteroidal anti inflammatory drugs potently inhibit cox 3.
16647138	cox 2	cox 2	1.0	ce analysis indicated that the 98 base pair intron 1 of cox 1 gene remains unprocessed in cox 3 inducing a frameshift mutation and a 127 amino acid open reading frame with no sequence similarity with cox 2 snipes et al. 2005 .
16647138	cox 2	cox 2	1.0	in addition adenovirus mediated cyp2c9 gene transfection and epox overexpression in endothelial cells result in endothelial cell tube formation by stimulating cox 2 expression and prostacyclin production michaelis et al. 2005 .
16647138	cox 2	cox 2	1.0	the first phase of arachidonic acid release involves the expression and stimulation of ipla 2 with the generation of pge 2 ltb 4 and paf through cox 2 lox and acetyl coa acetyltransferase reactions respectively.
16647138	cox 2	cox 2	1.0	pla 2 cox 2 and lox inhibitors have been used to treat acute inflammation and pain de gaetano et al. 2003 farooqui et al. in press and yeo et al. 2004 in various animal models of pain mediated by inflammation.
16647138	cox 2	cox 2	1.0	cox 1 and cox 2 play a central role in the induction of nociception produced by injections of complete freund's adjuvant or carrageenan into the paw hay et al. 1997 ichitani et al. 1997 and ito et al. 2001b .
16647138	cox 2	cox 2	1.0	an increase in the expression of cox 2 activity accompanies the induction of nociception svensson and yaksh 2002 .
16647138	cox 2	cox 2	1.0	cox 2 expression and its activity in neuropathic pain are controversial.
16647138	cox 2	cox 2	1.0	cox 2 levels in the dorsal spinal cord increase following a l5/l6 spinal nerve ligation zhao et al. 2000 and intrathecal or local injections of cox 2 inhibitors prevent the development of nociception.
16647138	cox 2	cox 2	1.0	in contrast only a very small change in spinal cord cox 2 mrna and protein expression follows the spared nerve injury model of partial nerve injury in the rat and selective cox 2 inhibition does not alter the nociception.
16647138	cox 2	cox 2	1.0	this indicates that cox 2 does not play a role in the development and maintenance of nociception broom et al. 2004 .
16647138	cox 2	cox 2	1.0	this suggests that nociception is modulated by interactions between central as well as peripheral nociceptive mechanisms and both mechanisms involve cox 2 generated metabolites.
16647138	cox 2	cox 2	1.0	nmda receptor dependent synaptic activity dynamically regulates the expression of the cox 2 gene in brain.
16647138	cox 2	cox 2	1.0	during ltp induction the most abundant prostaglandins generated in the brain through cox 1/cox 2 pathways pge 2 pgf 2a and pgd 2 are modulators of synaptic activity and efficacy by exerting their paracrine effect through pre and postsynaptic receptors and their autocrine effect through intraneur
16647138	cox 2	cox 2	1.0	the observation that cox 2 inhibitors block the induction of ltp in hippocampal dentate granules neurons supports this suggestion chen et al. 2002 .
16647138	cox 2	cox 2	1.0	the addition of pge 2 but not pgd 2 or pgf 2_amp_#x3b1; reverses cox 2 mediated suppression of ltp.
16647138	cox 2	cox 2	1.0	these studies suggest that pge 2 is the effector of cox 2 induced synaptic plasticity.
16647138	cox 2	cox 2	1.0	the translocation of cox 2 to the nuclear envelope during neural cell stimulation generates eicosanoids that are involved in gene expression morita et al. 1995 and vane et al. 1998 .
16647138	cox 2	cox 2	1.0	by 4 hne can result in the depolarization of neuronal membranes leading to the opening of nmda receptor channels and the influx of additional calcium into the cell kadoya et al. 2003 . 4 hne induces cox 2 expression in macrophages.
16647138	cox 2	cox 2	1.0	the expression of cox 2 plays an important role in the intensification of inflammatory responses in brain tissue.
16647138	cox 2	cox 2	1.0	paf also stimulates the inducible isoform of cox 2 bazan et al. 1993 .
16647138	cox 2	cox 2	1.0	an immediate early gene encodes cox 2 which is responsible for prostaglandin synthesis in neuropathological processes.
16647138	cox 2	cox 2	1.0	preincubation of cells with paf antagonist bn 50730 blocks stimulation of the immediate early gene responsible for cox 2 bazan et al. 1997 .
16647138	cox 2	cox 2	1.0	the cox 2 inhibitor ns 398 was ineffective as were two cytochrome p450 antagonists ms ppoh and miconazole suggesting that cox 2 and p450 metabolites do not play a significant role in vasodilation as compared to cox 1 metabolites.
16647138	cox 2	cox 2	1.0	2006 observed dense immunohistochemical staining for cox 1 but not cox 2 in the astrocytic endfeet that ensheath cortical arterioles as well as in small cells with a morphology typical of microglial cells.
16647138	cox 2	cox 2	1.0	cox 2 expression and prostaglandin e2 production are enhanced in the spinal cord after peripheral tissue injury and subsequent inflammation dirig and yaksh 1999 ichitani et al. 1997 nakayama et al. 2002 an
16647138	cox 2	cox 2	1.0	constitutive levels of cox 2 in the spinal cord are low but peripheral inflammation upregulates this enzyme beiche et al. 1996 .
16647138	cox 2	cox 2	1.0	in the brain synaptic activity regulates the basal expression of cox 2.
16647138	cox 2	cox 2	1.0	furthermore cox 2 is localized in neuronal dendritic spines where active synapses are located kaufmann et al. 1996 implying that both constitutive and inducible cox 2 may participate in synaptic plasticity.
16647138	cox 2	cox 2	1.0	selective cox 2 inhibition significantly reduced postsynaptic excitability back propagation of dendritic action potential associated ca 2+ influx and induction of long term potentiation in hippocampal dentate granul
16647138	cox 2	cox 2	1.0	these results are consistent with a likely role of pge 2 generated by cox 2 in the regulation of membrane excitability and long term synaptic plasticity in hippocampal perforant path_amp_#x2013;dentate gyrus synapses.
16647138	cox 2	cox 2	1.0	cox 2 synthesized pge 2 may act on pg receptors within the same neuron or in neighboring neurons.
16647138	cox 2	cox 2	1.0	administration of a selective cox 2 inhibitor to eliminate endogenous pge 2 reduced somatic and dendritic membrane excitability in hippocampal ca1 pyramidal neurons in brain slices.
16647138	cox 2	cox 2	1.0	as reversed by applications of pge 2 which produced significant increases in frequency of firing excitatory postsynaptic potential amplitude and temporal summation in slices previously treated with a cox 2 inhibitor chen and bazan 2005 .
16647138	cox 2	cox 2	1.0	an interesting new finding is that there is a profound difference between nsaids with different selectivities for cox 1 and cox 2 with regard to their effects on the synthesis of endogenous levels of rat brain kynurenic acid kyna schwieler et al. 2005 .
16647138	cox 2	cox 2	1.0	nsaids displaying an inhibitory action on cox 1 increased brain kyna formation whereas cox 2 selective inhibitors had the opposite effect.
16647138	cox 2	cox 2	1.0	the development of cox deficient mice has allowed investigators to study the individual roles of the cox 1 and cox 2 isoforms.
16647138	cox 2	cox 2	1.0	cox 2 deficient mice have poor survival rates reduced resolution of gastrointestinal ulcers progressive renal disease reduced ovulation fertilization implantation and decidualization normal uninduced pg le
16647138	cox 2	cox 2	1.0	it is noteworthy that central nervous system involvement does not appear in these lists and that for the maintenance of normal physiology cox 2 appears to play a more critical role.
16647138	cox 2	cox 2	1.0	at 30 to 40 min after il 1_amp_#x3b2; cox 1 ko mice showed a smaller reduction in milk intake in comparison with wild type mice whereas cox 2 mice responded more like wild type animals.
16647138	cox 2	cox 2	1.0	however at 90 to 120 min after il 1_amp_#x3b2; administration cox 2 ko mice showed only small responses while cox 1 ko mice responded normally.
16647138	cox 2	cox 2	1.0	this result suggests that while cox 1 is primarily involved in the early phase of milk intake cox 2 is more responsible for the later phase swiergiel and dunn 2002 .
16647138	cox 2	cox 2	1.0	iadecola et al. 2001a and iadecola et al. 2001b have demonstrated reduced and increased susceptibility to ischemic brain injury in cox 2 and cox 1 deficient mice respectively.
16647138	cox 2	cox 2	1.0	2004 also observed a decreased level of neuronal injury produced by transient global ischemia in cox 2 deficient mice in comparison with wild type mice.
16647138	cox 2	cox 2	1.0	various lines of evidence implicate cox 2 in fever production.
16647138	cox 2	cox 2	1.0	its expression is enhanced in the brain after peripheral intraperitoneal lipopolysaccharide lps or intravenous and intracerebral il 1_amp_#x3b2; administration whereas cox 2 inhibitors suppress the fever induced by these pyrogens cao et al. 1996 cao et al. 1997 cao et al. 2001 ek et al. 2001 and minghetti et al. 1999 .
16647138	cox 2	cox 2	1.0	1999 assessed the febrile response to injection of intraperitoneal lps in cox 1 and cox 2 deficient mice.
16647138	cox 2	cox 2	1.0	the wild type and cox 1 _amp_#x2212;/_amp_#x2212; mice responded to lps with a 1_amp_#xb0;c rise in temperature whereas the cox 2 _amp_#x2212;/_amp_#x2212; mice displayed no increase in temperature indicating that cox 2 is necessary for lps induced fever production.
16647138	cox 2	cox 2	1.0	_amp_#x2212;/_amp_#x2212; mice displayed no increase in temperature indicating that cox 2 is necessary for lps induced fever production.
16647138	cox 2	cox 2	1.0	endocannabinoids and cox 2
16647138	cox 2	cox 2	1.0	in addition to these hydrolytic pathways endocannabinoids can be selectively oxygenated by a cox 2 pathway kozak and marnett 2002 and yu et al. 1997 .
16647138	cox 2	cox 2	1.0	inhibition of cox 2 can potentiate the action of these endocannabinoids kim and alger 2004 .
16647138	cox 2	cox 2	1.0	furthermore metabolites of aea and 2 ag derived from cox 2 possess biological activity including the activation of protein kinase c as well as having effects on the contractility of smooth muscle preparations nirodi et al. 2004 and ross et al. 2002 .
16647138	cox 2	cox 2	1.0	prostanoids derived from both aea and 2 ag are significantly more stable metabolically than free acid pgs suggesting that cox 2 action on endocannabinoids may provide oxygenated lipids with sufficiently long half lives to act as systemic mediators or pro drugs kozak et al. 2004 and patrignani et al. 2005 .
16647138	cox 2	cox 2	1.0	ns 398 completely inhibited the pge 2 production induced by either aea or maea a selective cox 2 inhibitor indicating induction of cox 2.
16647138	cox 2	cox 2	1.0	aea and maea increased the expression of cox 2 protein an action that am 251 a selective cannabinoid receptor 1 agonist partially inhibited.
16647138	cox 2	cox 2	1.0	additionally aea increased cox 2 promoter activity.
16647138	cox 2	cox 2	1.0	2005 suggested that aea increases cox 2 expression at the transcriptional level through a cannabinoid receptor 1 mediated mechanism in the cerebral microvascular endothelium.
16647138	cox 2	cox 2	1.0	2005 concluded that oxidation of ecb by cox 2 decreases their level in the hippocampus thus enhancing ltp. ecbs which are generated during robust stimulation of hippocampal slices stella et al. 1997 tonically decrease basal excitatory transmissi
16647138	cox 2	cox 2	1.0	conversely inhibition of cox 2 prevented ltp in hippocampal dentate neurons kim and alger 2004 leading to the conclusion that cox 2 regulates the formation of cb1 ligands that negatively regulate ltp.
16647138	cox 2	cox 2	1.0	cox 2 is an important mediator of neuroinflammation feng et al. 1993 .
16647138	cox 2	cox 2	1.0	concussive injury of the rat cerebral cortex caused a bilateral induction of cox 2 mrna in the cortex and dentate gyrus.
16647138	cox 2	cox 2	1.0	cox 2 activity was detectable in these areas and persisted in the ipsilateral cortex for at least 72 h kunz et al. 2002 .
16647138	cox 2	cox 2	1.0	upregulation of cox 2 mrna has also been observed in the rat spinal cord following a traumatic injury adachi et al. 2005 .
16647138	cox 2	cox 2	1.0	cox 2 immunoreactivity in this instance was observed only in endothelial cells of the blood vessels and not in neurons astrocytes monocytes macrophages or microglia at 6 h after injury.
16647138	cox 2	cox 2	1.0	1998 observed trauma induced cox 2 mrna expression in spinal cord neurons and around blood vessels and dash et al.
16647138	cox 2	cox 2	1.0	2000 found cox 2 protein almost exclusively in neurons.
16647138	cox 2	cox 2	1.0	the effects of cox 2 inhibition on recovery following traumatic brain injury tbi in rats have been contradictory.
16647138	cox 2	cox 2	1.0	2000 using celecoxib observed a worsening of motor but not cognitive performance and suggested that cox 2 induction following tbi may play a protective role.
16647138	cox 2	cox 2	1.0	studies on cox 1 and cox 2 gene deletion provided some information on the roles of these enzymes in stroke injury.
16647138	cox 2	cox 2	1.0	cox 2 deficient mice displayed a reduced susceptibility to ischemic brain injury and nmda neurotoxicity iadecola et al. 2001a and sasaki et al. 2004 .
16647138	cox 2	cox 2	1.0	conversely mice with neuronal overexpression of cox 2 had increased levels of pge 2 with significant increases in infarct volume following middle cerebral artery occlusion dore et al. 2003 .
16647138	cox 2	cox 2	1.0	clinical trials have recently revealed that long term therapy with cox 2 inhibitors increases the incidence of myocardial infarction and stroke which has been attributed to blockade of the vasoprotective effects of cox 2 derived pgi 2 fitzgerald 2003 .
16647138	cox 2	cox 2	1.0	inhibitors increases the incidence of myocardial infarction and stroke which has been attributed to blockade of the vasoprotective effects of cox 2 derived pgi 2 fitzgerald 2003 .
16647138	cox 2	cox 2	1.0	recent studies have demonstrated that pge 2 may be responsible for the neurotoxic effects of cox 2 manabe et al. 2004 .
16647138	cox 2	cox 2	1.0	prostaglandin ep1 receptors may be essential for the neurotoxic effects of cox 2 derived pge 2 .
16647138	cox 2	cox 2	1.0	cox 2 mrna is upregulated in the ischemic rat cerebral hemisphere beginning 6 h after ischemia and reaching a maximum after 12 h nogawa et al. 1997 .
16647138	cox 2	cox 2	1.0	neurons at the medial edge of the ischemic area had cox 2 immunoreactivity and the injured brain had elevated pge 2 levels.
16647138	cox 2	cox 2	1.0	these data would appear to implicate cox 2 in the mechanisms of delayed neuronal death.
16647138	cox 2	cox 2	1.0	arachidonic acid released during stroke ischemic or hemorrhagic by pla 2 activation may be converted to prostaglandins by both cox 1 and cox 2 during the immediate response and predominantly by cox 2 during the delayed response murakami et al. 2002 . spla 2 upregulates cox 2 bidgood et al. 2000 and is functionally coupled with cox 2 but not with cox 1 balsinde et al. 1998 .
16647138	cox 2	cox 2	1.0	during the delayed response murakami et al. 2002 . spla 2 upregulates cox 2 bidgood et al. 2000 and is functionally coupled with cox 2 but not with cox 1 balsinde et al. 1998 .
16647138	cox 2	cox 2	1.0	substantial increases in cox 2 mrna and protein levels occur in the peri infarct and focal ischemic areas of permanent middle cerebral artery occlusion mcao at 3 to 12 h and 12 to 24 h respectively.
16647138	cox 2	cox 2	1.0	in the ischemic core significant increases in cox 2 mrna followed 6 h of ischemia.
16647138	cox 2	cox 2	1.0	the ischemic core during ischemic periods did not show increases in cox 2 protein.
16647138	cox 2	cox 2	1.0	in another human study cox 1 expressed intensely in microglia but weakly in neurons in control brains whereas cox 2 was absent in control autopsied brains.
16647138	cox 2	cox 2	1.0	however cox 2 was induced robustly in neurons during the acute phase of focal ischemia and subsided during the subacute phases.
16647138	cox 2	cox 2	1.0	cox 2 was also upregulated in microglia during focal ischemia tomimoto et al. 2002 .
16647138	cox 2	cox 2	1.0	pretreatment with indomethacin an inhibitor of cox 1 and cox 2 reduced infarct size following focal ischemia with reperfusion in rats buccellati et al. 1998 reduced ischemia evoked ca1 hippocampal injury in a gerbil model sasaki et al. 1988 and suppressed hypere
16647138	cox 2	cox 2	1.0	ibuprofen which also inhibits both cox 1 and cox 2 reduced neuronal injury and improved cerebral blood flow and neurological outcome in global ischemia grice et al. 1987 kuhn et al. 1986 park et al. 2005 and patel et al. 1993 with decreased infarct s
16647138	cox 2	cox 2	1.0	the recent development of selective cox 2 inhibitors has stimulated a number of studies of their efficacy as cerebroprotective agents.
16647138	cox 2	cox 2	1.0	the beneficial effects of ns 389 on ischemic brain injury were not apparent in mice with deletion of the inducible nitric oxide synthase nos gene which suggests that cox 2 reaction products may be another mechanism by which inos derived nitric oxide contributes to ischemic brain injury nagayama et al. 1999 .
16647138	cox 2	cox 2	1.0	another cox 2 inhibitor nimesulide effectively limited hippocampal damage following forebrain ischemia in the gerbil candelario jalil et al. 2002b and candelario jalil et al. 2003a and mouse sasaki et al. 2004 .
16647138	cox 2	cox 2	1.0	the degree of hippocampal neuronal injury produced by global ischemia in cox 2 deficient mice was less than that in wild type mice sasaki et al. 2004 further demonstrating involvement of this enzyme in ischemic injury to the brain.
16647138	cox 2	cox 2	1.0	selective inhibition of cox 1 by valerylsalicylate or of cox 2 by rofecoxib was used to assess the relative contributions of the two enzymes to ischemia induced oxidative damage in the gerbil brain candelario jalil et al. 2003b .
16647138	cox 2	cox 2	1.0	the highly selective cox 2 inhibitor dfu was neuroprotective when administered several hours after transient cerebral ischemia in gerbils candelario jalil et al. 2002a .
16647138	cox 2	cox 2	1.0	the selective cox 2 inhibitors sc58125 and sc58326 are neuroprotective in rat global and focal cerebral ischemia models respectively govoni et al. 2001 and nakayama et al. 1998 .
16647138	cox 2	cox 2	1.0	2004 examined whether the selective cox 2 inhibitor celecoxib reduces cerebral inflammation and edema after intracerebral hemorrhage in rats.
16647138	cox 2	cox 2	1.0	s 2474 a novel nsaid suppresses cox 2 at low nanomolar levels but does not affect cox 1.
16647138	cox 2	cox 2	1.0	these enzymes include pla 2 cox 2 lox and epox.
16647138	cox 2	cox 2	1.0	marked increases in cox 2 and 5 lox mrna and protein levels occur following kainate injections in rat brain adams et al. 1996 manev et al. 1998 and sandhya et al. 1998 .
16647138	cox 2	cox 2	1.0	this increase in cox 2 and 5 lox can be prevented by not only glutamate receptor antagonists koistinaho et al. 1999 and pepicelli et al. 2002 but also by cox 2 and 5 lox inhibitors manev et al. 2000a and pepicelli et al. 2002 indicating that generation of prostaglandins thromboxanes and leukotrienes is a receptor mediated process.
16647138	cox 2	cox 2	1.0	the role of cox 2 and 5 lox in excitotoxicity is also supported by microdialysis studies in vivo in hippocampus of freely moving rats pepicelli et al. 2005 .
16647138	cox 2	cox 2	1.0	pge 2 and 8 epi pgf 2_amp_#x3b1; generation can be blocked by the infusion of nmda antagonists as well as cox 1 and cox 2 inhibitors indicating that both cox 1 and cox 2 contribute to the prostaglandin synthesis and oxidative damage in excitotoxicity pepicelli et al. 2005 .
16647138	cox 2	cox 2	1.0	his cross talk refines communication among glutamate prostaglandin leukotriene and thromboxane receptors but under pathological situations it promotes neuronal injury that depends on the magnitude of cox 2 and 5 lox expression iadecola et al. 2001a nakayama et al. 1998 and pepicelli et al. 2005 .
16647138	cox 2	cox 2	1.0	it is likely that increased cox 2 and 5 lox activities and high levels of their reaction products are involved in extending excitotoxicity and oxidative stress during neurodegeneration.
16647138	cox 2	cox 2	1.0	the neurochemical consequences of increased cox 2 and 5 lox activities and high levels of their products include not only the generation of highly reactive oxygen free radical species with their potent damaging effects on neural membrane phospholipi
16647138	cox 2	cox 2	1.0	our emphasis on the interaction between glutamate receptors and cox 2 and 5 lox activities and their reaction products does not rule out the participation of other mechanisms involved in neural cell injury.
16647138	cox 2	cox 2	1.0	however it is timely and appropriate to apply the concept of synergism between glutamate and cox 2 and 5 lox generated products and their receptors to neural cell injury.
16647138	cox 2	cox 2	1.0	the synergistic actions of glutamate and cox 2 and 5 lox generated products may be rapid whereas in neurodegenerative disorders in which oxygen and nutrients are available to the nerve cell and ionic gradients are maintained to a limited extent d
16647138	cox 2	cox 2	1.0	hereas in neurodegenerative disorders in which oxygen and nutrients are available to the nerve cell and ionic gradients are maintained to a limited extent due to the availability of atp glutamate and cox 2 and 5 lox product mediated damage may take a longer time to develop.
16647138	cox 2	cox 2	1.0	these studies suggest that cox 2 and 5 lox generated products along with free radical formation play critical roles in brain damage mediated by the excitotoxicity.
16647138	cox 2	cox 2	1.0	seizures activate cytosolic pla 2 visioli et al. 1994 and induce the expression of cytosolic pla 2 kajiwara et al. 1996 and cox 2 marcheselli and bazan 1996 .
16647138	cox 2	cox 2	1.0	in rat brain cox 2 mrna is preferentially expressed in neurons where it is developmentally regulated tocco et al. 1997 and cox 2 expression is induced by kainic acid induced seizures chen et al. 1995 and tocco et al. 1997 .
16647138	cox 2	cox 2	1.0	glutamate excitotoxicity in primary cultures of rat cortico hippocampal neurons is also associated with increased expression of cox 2 tocco et al. 1997 .
16647138	cox 2	cox 2	1.0	induction of cox 2 but not cox 1 gene expression has been demonstrated to precede apoptosis in the granule cell layer of the dentate gyrus ho et al. 1998 and may contribute to the mechanisms leading to apoptosis.
16647138	cox 2	cox 2	1.0	in another seizure model the genetically epilepsy susceptible e1 mouse expression of cox 2 in the hippocampus was upregulated after an epileptic seizure and indomethacin a cox 2 inhibitor shortened the duration from seizure onset to full recovery okada et al. 2001 .
16647138	cox 2	cox 2	1.0	a rat hippocampal kindling model enabled a study of the role of cox 2 in seizure activity.
16647138	cox 2	cox 2	1.0	cox 2 encoded in an early response gene increased in a synaptic activity dependent manner with induction becoming evident initially in hippocampal neurons and then spreading to cortical neurons.
16647138	cox 2	cox 2	1.0	when rats were rekindled 34 days later this spreading of cox 2 expression persisted.
16647138	cox 2	cox 2	1.0	the cox 2 selective inhibitor nimesulide attenuated kindling development tu and bazan 2003 thus neuronal cox 2 gene induction and cpla 2 activation are key signaling events in epileptogenesis.
16647138	cox 2	cox 2	1.0	2003 examined the effects of cox 2 on the _amp_#x2018;rapid kindling_amp_#x2019; development in cox 2 knockout mice and mice treated with nimesulide.
16647138	cox 2	cox 2	1.0	they also measured cox 2 mrna expression and pge 2 concentrations.
16647138	cox 2	cox 2	1.0	kindling in hippocampal neurons of control mice markedly increased brain cox 2 mrna levels with a significant increase in pge 2 levels.
16647138	cox 2	cox 2	1.0	moreover conditions of cox 2 deficiency significantly decreased the incidence of after discharges total after discharge duration and seizure behavior induction suggesting that inducible cox 2 facilitates the recurrence of hippocampal seizures.
16647138	cox 2	cox 2	1.0	1999 developed a transgenic mouse model with neuronal overexpression of the human cox 2 to further explore its role in excitotoxicity.
16647138	cox 2	cox 2	1.0	overexpression of hcox 2 potentiated the intensity and lethality of kainic acid excitotoxicity thus demonstrating a cause_amp_#x2013;effect relationship between neuronal cox 2 expression and excitotoxicity.
16647138	hcox 2	hcox 2	1.0	overexpression of hcox 2 potentiated the intensity and lethality of kainic acid excitotoxicity thus demonstrating a cause_amp_#x2013;effect relationship between neuronal cox 2 expression and excitotoxicity.
16647138	cox 2	cox 2	1.0	the cox 2 selective inhibitor rofecoxib significantly reduced kainate induced cell death in the rat hippocampus kunz and oliw 2001b .
16647138	cox 2	cox 2	1.0	another selective cox 2 inhibitor celecoxib was effective in reducing electroshock induced convulsions in rats shafiq et al. 2003 whereas nimesulide aggravated kainic acid induced seizures in the rat kunz and oliw 2001a .
16647138	cox 2	cox 2	1.0	with the exception of high temperature febrile induced seizures no reports on the effects of cox 2 inhibitors on epileptic seizures in humans have appeared.
16647138	cox 2	cox 2	1.0	a marked increase of cox 1 and cox 2 expression and immunoreactivity in cerebral cortex and hippocampal regions of ad brains correlates with the number of senile plaques neuronal atrophy and increased levels of pge 2 found in ad pasinet
16647138	cox 2	cox 2	1.0	the neuroprotective effects of cox 1 and cox 2 inhibitors nsaid strongly support the view that upregulation of these enzymes in ad is detrimental to neuronal survival.
16647138	cox 2	cox 2	1.0	the molecular mechanism by which cox 1 and cox 2 promote amyloidogenic accumulation of _amp_#x3b2; amyloid peptide is not fully understood.
16647138	cox 2	cox 2	1.0	cox 1 and cox 2 potentiate _amp_#x3b2; amyloid peptide generation through mechanisms that involve _amp_#x3b3; secretase activity qin et al. 2003 .
16647138	cox 2	cox 2	1.0	furthermore cox 2 expression is also involved in regulation of cell cycle activity and cell cycle abnormalities are associated with the pathogenesis of ad.
16647138	cox 2	cox 2	1.0	re entry into the cell cycle may underlie cox 2 mediated neuronal damage in ad xiang et al. 2002 .
16647138	cox 2	cox 2	1.0	the sporadic form of this disease is characterized by a prominent neuroinflammatory component upregulation of cox 2 mrna and oxidative stress yasojima et al. 2001 .
16647138	cox 2	cox 2	1.0	upregulation of cox 2 mrna also occurs in sod1 transgenic mice at the onset of als almer et al. 2001 .
16647138	cox 2	cox 2	1.0	in an organotypic cell culture model of als the addition of a selective cox 2 inhibitor sc236 blocked the destruction of motor neurons drachman and rothstein 2000 suggesting that cox 2 may play an important role in inflammatory processes in als.
16647138	cox 2	cox 2	1.0	similarly treatment with celecoxib another cox 2 inhibitor prolongs the survival of neurons in the sod1 mouse model of als drachman et al. 2002 .
16647138	cox 2	cox 2	1.0	although upregulation of cox 2 and pge 2 levels may not be the root cause of als alterations in these parameters may be responsible for the induction and maintenance of inflammation during the progression of als.
16647138	cox 2	cox 2	1.0	at present nothing is known about the expression of cox 2 in patients with pd.
16647138	cox 2	cox 2	1.0	however involvement of cox 2 in the pathogenesis of pd has been explored in an animal model treated with n methyl 4 phenyl 1 2 3 6 tetrahydropyridine mptp as well as in cox 2 gene knockout mice feng et al. 2003 and teismann et al. 2003 .
16647138	cox 2	cox 2	1.0	thus a lower mortality rate has been reported after mptp injection in heterozygous cox 2 deficient mice than in the wild type mice and inhibition of cox 2 protein expression decreases the lesions caused by mptp and protects dopaminergic neurons in the substantia nigra.
16647138	cox 2	cox 2	1.0	the molecular mechanism associated with cox 2 mediated neurodegeneration in animal models of pd remains unknown.
16647138	cox 2	cox 2	1.0	however cox 2 inhibition may prevent the formation of the oxidant species of reactive quinones.
16647138	cox 2	cox 2	1.0	using rt pcr and western blotting both cox 1 and cox 2 are significantly increased in brains from cjd patients compared to age matched controls implicating both enzymes in the pathogenesis of cjd deininger et al. 2003 .
16647138	cox 2	cox 2	1.0	in csf from sporadic and familial cjd and in brain homogenates of scrapie infected mice the upregulation of cox 1 and cox 2 is accompanied by a several fold increase in concentrations of pge 2 and f 2 isoprostane 8 epi prostaglandin f 2_amp_#x3b1; 8 epi pgf 2_amp_#x3b1; compared to age matched controls minghetti et al. 20
16647138	cox 2	cox 2	1.0	in contrast indomethacin a cox 1 and cox 2 inhibitor and baicalein a 12 lox inhibitor do not affect prp106_amp_#x2013;126 induced neurotoxicity in cerebellar granule neuronal cultures stewart et al. 2001 .
16647138	cox 2	cox 2	1.0	in astrocytes tgf_amp_#x3b2;1 upregulates cox 1 expression and serum increases cox 2 expression.
16647138	cox 2	cox 2	1.0	neither tgf_amp_#x3b2;1 nor serum affects cox 1 and cox 2 expression in neurons.
16647138	cox 2	cox 2	1.0	furthermore cox 1 compensates for the loss of cox 2 in the cox 2 knockout cox 2 _amp_#x2212;/_amp_#x2212; mouse brain.
16647138	cox 2	cox 2	1.0	thus cox 2 _amp_#x2212;/_amp_#x2212; shows a compensatory increase in brain cox 1 expression and activity with exogenous arachidonic acid in brain tissue bosetti et al. 2004 .
16753239	cox 2	cox 2	1.0	recent studies demonstrated that tzds block the production of inos tnf _amp_#x3b1; il 6 and cox 2 by primary rat microglia and astrocytes and protected cortical neurons in a neuron glia co culture paradigm.
16766086	cox 2	cox 2	1.0	these agents suppressed cytokine as well as cox 2 expression.
16766086	cox 2	cox 2	1.0	expression of inflammatory genes such as inos cyclooxygenase 2 cox 2 proinflammatory cytokines and intercellular adhesion molecule are upregulated following stroke and increasing the level or the activity of these proteins exacerbates injury while antagonism of the ac
16766086	cox 2	cox 2	1.0	there is a reduced inflammatory infiltrate in tzd treated rats that is associated with reduced expression of inflammatory mediators such as inos cox 2 and il 1_amp_#x3b2; fig 5 .
16766086	cox 2	cox 2	1.0	relative to levels in vehicle treated rats mrna was reduced by approximately 25% for inos 30% for cox 2 and 50% for il 1_amp_#x3b2; n = 4 for each group .
17015226	cox 2	cox 2	1.0	cyclooxygenase 2 cox 2 produced in abundance by microglia and other inflammatory cells but also by neurons and astrocytes plays a key role in stimulating production of proinflammatory cytokines and cox 2 expression is induced in spinal cords of als patients yasojima et_amp_#xa0;al. 2001 and yiangou et_amp_#xa0;al. 2006 .
17015226	cox 2	cox 2	1.0	in mice use of a cox 2 inhibitor celecoxib prolonged survival by slowing disease onset drachman et_amp_#xa0;al. 2002 but disappointingly did not alter progression after onset.
17569578	cox 2	cox2	1.0	ppar_amp_#x3b3; activation in microglial cells suppressed inflammatory cytokine expression inos expression and no production and inhibition of cox2 and subsequent generation of immunostimulated prostanoid synthesis [38] .
17569578	cox 2	cox 2	1.0	activated microglia were significantly reduced at sites of neurodegeneration in pioglitazone treated sod1 g93a mice as were the protein levels of cox 2 and inos.
17569578	cox 2	cox2	1.0	the peripheral leukocytes and microglia mount a robust inflammatory response with the induction of cytokine and chemokine expression as well as elevated expression of adhesion molecules inos cox2 and other inflammatory mediators which act to exacerbate the tissue damage [9] [12] and [181] .
17569578	cox 2	cox2	1.0	the salutary actions of the drugs were associated with reduced infiltration of peripheral leukocytes diminished microglial activation and reduction of inos cox2 and cytokine expression.
17574754	cox 2	cox 2	1.0	induction of cyclooxygenase 2 cox 2 with production of prostaglandins occurs in a wide spectrum of acute and chronic neurodegenerative diseases and is associated with neuronal death.
17574754	cox 2	cox 2	1.0	inhibition of the cox 2 pathway and downstream production of prostaglandins protect neurons in rodent models of cerebral ischemia and neurodegeneration.
17574754	cox 2	cox 2	1.0	recent studies investigating the functions of selected prostaglandin receptor pathways in mediating cox 2 neurotoxicity have demonstrated both toxic and paradoxically neuroprotective effects of several receptors in models of excitotoxicity.
17574754	cox 2	cox 2	1.0	the inducible isoform of cyclooxygenase cox 2 is rapidly upregulated in vivo in hippocampal and cerebral cortical neurons following n methyl d aspartate nmda receptor dependent synaptic activity [23] consistent with a physiologic role in modulat
17574754	cox 2	cox 2	1.0	however in pathologic conditions caused by either excitotoxicity or inflammation cox 2 expression and activity are increased in neurons and glial cells and can promote either primary or secondary neuronal injury respectively.
17574754	cox 2	cox 2	1.0	thus increased cox 2 activity and prostaglandin production are hallmarks of a wide range neurological disease models including acute excitotoxic events such as cerebral ischemia traumatic brain or spinal cord injury as w
17574754	cox 2	cox 2	1.0	in humans increased cox 2 and prostaglandin production have been observed in ad als multiple sclerosis and pd [1] [10] [22] and [24] .
17574754	cox 2	cox 2	1.0	thus cox 2 appears to function physiologically in promoting synaptic activity and pathologically in diseases characterized by excitotoxicity or inflammation.
17574754	cox 2	cox 2	1.0	because inhibition of cox 2 either genetically or pharmacologically decreases neuronal injury in rodent models of nmda dependent excitotoxicity there is considerable interest in defining the downstream mechanisms by which cox 2
17574754	cox 2	cox 2	1.0	either genetically or pharmacologically decreases neuronal injury in rodent models of nmda dependent excitotoxicity there is considerable interest in defining the downstream mechanisms by which cox 2 exerts its neurotoxicity.
17574754	cox 2	cox 2	1.0	a primary focus has been the examination of prostaglandin signaling cascades downstream of cox 2 and the identification of neurotoxic prostaglandin receptors [4] .
17574754	cox 2	cox 2	1.0	prostaglandins are lipid signaling molecules derived from the metabolism of arachidonic acid by cox 1 and the inducible cox 2.
17574754	cox 2	cox 2	1.0	cox 2 neurotoxicity is presumed to be mediated by one or more of these prostaglandin receptor signaling cascades.
17574754	cox 2	cox 2	1.0	induction of cox 2 activity and production of downstream prostaglandins is associated in a wide range of neurological disease models with neuronal injury [9] and [18] .
17574754	cox 2	cox 2	1.0	cox 2 inhibition has been shown to be protective in this in vitro model as well as in the transgenic model of familial als [3] [7] and [8] .
17574754	cox 2	cox 2	1.0	this would suggest that the dp fp and ip receptors do not mediate cox 2 toxicity in this in vitro model and from our previous studies [3] the ep2 and ep3 receptors can also be excluded since they too rescue motor neurons.
17574754	cox 2	cox 2	1.0	in models of in vitro and in vivo excitotoxicity cox 2 inhibition is clearly neuroprotective.
17901552	cox 2	cox 2	1.0	function of cox 2 and prostaglandins in neurological disease.
17901552	cox 2	cox 2	1.0	induction of cox 2 expression and enzymatic activity promotes neuronal injury in a number of models of neurological disease.
17901552	cox 2	cox 2	1.0	inhibition of cox 2 activity either genetically or pharmacologically has been shown to be neuroprotective in rodent models of stroke parkinson's disease and amyotrophic lateral sclerosis.
17901552	cox 2	cox 2	1.0	in this proceeding we review recent data demonstrating effects of prostaglandin signaling on neuronal viability that are paradoxically protective when taken in the context that cox 2 induces neuronal injury in the setting of excitotoxicity.
18040778	cox 2	cox 2	1.0	cyclooxygenase 2 cox 2 is an enzyme central to the production of prostaglandins a family of powerful inflammatory mediators produced by activated microglia that can have both deleterious and neuroprotective effects in the
18040778	cox 2	cox 2	1.0	cox 2 and prostaglandin e 2 are elevated in the cns of patients with als and recent studies have implicated activated microglia in this _amp_#8220;neuron only_amp_#8221; disease weydt and moller 2005 .
18040778	cox 2	cox 2	1.0	prostaglandin production by activated microglia has been implicated in other neuroinflammatory/neurodegenerative diseases and not surprisingly cox 2 has been considered a major therapeutic target.
18040778	cox 2	cox 2	1.0	hypothetically by inhibiting microglial cell cyclooxygenases cox 1 or cox 2 the metabolism of arachadonic acid is curtailed and production of deleterious proinflammatory prostaglandins is suppressed hoozemans and o'banion 2005 .
18040778	cox 2	cox 2	1.0	although preclinical and early clinical data suggested that cox 2 inhibitors may have a beneficial role in ad results of subsequent studies and the development of unanticipated side effects of cox 2 inhibitors have dampened enthusiasm for the use of these agents in the management of ad.
18464922	cox 2	cox 2	1.0	; has been identified as a key regulatory factor in the modulation of target genes with ppar response element ppre in their promoters including those encoding for inflammation inos nf _amp_#x003ba; b cox 2 oxidative stress and apoptosis.
18464922	cox 2	cox 2	1.0	they also showed significant reduction in microglial activation as well as reduction in the expression of cox 2 and inos [ 39 ].
18464925	cox 2	cox2	1.0	the two tzd compounds np00111 and np01138 were reported to inhibit the production of nitric oxide no il 6 and tnf _amp_#x003b1; as well as expression of the inducible enzymes inos and cox2 induced in lps stimulated astrocyte and microglial cultures [ 58 ].
18464925	cox 2	cox 2	1.0	in contrast to the above described tzds the natural ligand 15d pgj 2 prevented the il 1 _amp_#x003b2; induced cox 2 mrna accumulation in human astrocytes through a ppar _amp_#x003b3; independent mechanism [ 60 ].
18464925	cox 2	cox 2	1.0	the same authors then demonstrated that 15d pgj 2 decreases the production of tnf _amp_#x003b1; il 1 _amp_#x003b2; and the expression of cox 2 in the same cell system while increasing the expression of the antioxidant enzyme hemeoxygenase 1 and the intracellular levels of glutathione [ 75 ].
18464925	cox 2	cox 2	1.0	in this cell system cox 2 specific inhibitors failed to promote neuronal survival suggesting protective mechanisms independent of cox 2 metabolism.
18464925	cox 2	cox 2	1.0	at concentrations several fold lower than those required for ppar _amp_#x003b3; activation effectively reduced the lps stimulated production of pgj 2 by directly preventing the enzymatic activity of cox 2 rather than its expression as previously described in activated monocytic cell lines [ 80 83 ] and in bv 2 cells [ 75 ].
18464925	cox 2	cox 2	1.0	the reduction of cox 2 enzymatic activity could be achieved through the modifications of key cysteine residues [ 84 ] as suggested by the ability of 15d pgj 2 electrophilic _amp_#x003b1; _amp_#x003b2; unsaturated ketones t