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| 16014720 | MPO | MPO | 7.1 | Here we show that myeloperoxidase (MPO), MPO a key oxidant-producing enzyme during inflammation is upregulated in the | |  |
| 16014720 | MPO | MPO | 7.1 | that ventral midbrain dopaminergic neurons of mutant mice deficient in MPO are more resistant to MPTP-induced cytotoxicity than their wild-type littermates | | |
| 16014720 | MPO | MPO | 7.1 | Supporting the oxidative damaging role of MPO in this PD model are the demonstrations that MPO-specific biomarkers | | |
| 16014720 | MPO | MPO-specific | 1.0 | of MPO in this PD model are the demonstrations that MPO-specific biomarkers 3-chlorotyrosine and hypochlorous acid-modified proteins increase in the brains | | |
| 16014720 | MPO | MPO | 7.1 | This study demonstrates that MPO participates in the MPTP neurotoxic process and suggests that inhibitors | | |
| 16014720 | MPO | MPO | 7.1 | in the MPTP neurotoxic process and suggests that inhibitors of MPO may provide a protective benefit in PD | | |
| 16014720 | MPO | MPO | 7.1 | Conversely myeloperoxidase (MPO), MPO and not ONOO seems to promote O O '-dityrosine formation | | |
| 16014720 | MPO | MPO | 7.1 | Moreover MPO can use the NO degradation product NO 2 to generate | | |
| 16014720 | MPO | MPO | 7.1 | Vliet et al. 1997 and studies of mice deficient in MPO demonstrate that this enzyme is one of the major sources | | |
| 16014720 | MPO | MPO | 7.1 | Thus these results raise the unanticipated possibility that MPO a heme enzyme expressed in abundance in a variety of | | |
| 16014720 | MPO | MPO | 7.1 | Consistent with this hypothesis we show here not only that MPO is detected in affected brain areas of MPTP-injected mice and | | |
| 16014720 | MPO | MPO | 7.1 | in glial cells but also that mutant mice deficient in MPO are more resistant to MPTP-induced dopaminergic neurotoxicity | | |
| 16014720 | MPO | MPO | 7.1 | These findings indicate that MPO does participate in the MPTP neurotoxic process and suggest that | | |
| 16014720 | MPO | MPO | 7.1 | in the MPTP neurotoxic process and suggest that inhibitors of MPO may provide protective benefit in PD | | |
| 16014720 | MPO | MPO-deficient | 1.0 | C57BL 6J mice ( Charles River Laboratories Wilmington MA and MPO-deficient mice that had been backcrossed >10 times into the C57BL/6J | | |
| 16014720 | MPO | MPO | 7.1 | previously (Wu Wu et al. 2003 beta-actin were as follows MPO 5'-AGGATAGGACTGGATTGCCTG-3' (forward) forward and 5'-GTGGTGATGCCAGTGTTGTCA-3' (reverse); reverse beta-actin 5'-CTTTGATGTCACGCACGATTTC-3' (forward) | | |
| 16014720 | MPO | MPO | 7.1 | MPO isolation and activity | | |
| 16014720 | MPO | MPO | 7.1 | The methods used to prepare brain samples and to measure MPO activity are slight modifications of those described previously by Daugherty | | |
| 16014720 | MPO | MPO | 7.1 | centrifugation final supernatants were collected and used immediately to assess MPO activity by monitoring the oxidation of tetramethylbenzidine as described previously | | |
| 16014720 | MPO | MPO | 7.1 | Mouse MPO glial fibrillary acidic protein beta 2 integrin MAC-1 (CD116/CD18), CD116 | | |
| 16014720 | MPO | MPO | 7.1 | mouse tissues the primary anti-MPO antibody was a rabbit anti-human MPO antibody (DakoCytomation, DakoCytomation Carpinteria CA used at 1 1000 for | | |
| 16014720 | MPO | MPO-deficient | 1.0 | with UV detection ( = 295 nm in WT and MPO-deficient mice at 90 min after the last injection of 20 | | |
| 16014720 | MPO | MPO | 7.1 | MPO is induced in the mouse ventral midbrain during MPTP-induced dopaminergic | | |
| 16014720 | MPO | MPO | 7.1 | To examine the possibility that MPO is a component of the inflammatory response seen in the | | |
| 16014720 | MPO | MPO | 7.1 | et al. 1999 Wu et al. 2002 we first assessed MPO mRNA and protein content in the ventral midbrain (i.e., i.e. | | |
| 16014720 | MPO | MPO | 7.1 | saline-injected control mice the ventral midbrain contained low levels of MPO mRNA and protein ( Fig 1 A-C | | |
| 16014720 | MPO | MPO | 7.1 | In contrast in MPTP-injected mice ventral midbrain levels of both MPO mRNA and protein increased in a time-dependent manner ( Fig | | |
| 16014720 | MPO | MPO | 7.1 | Ventral midbrain MPO mRNA and protein expression levels peaked at 1 and 2 | | |
| 16014720 | MPO | MPO | 7.1 | We next asked whether the observed changes in MPO ventral midbrain content in MPTP-injected animals paralleled an alteration of | | |
| 16014720 | MPO | MPO | 7.1 | ventral midbrain content in MPTP-injected animals paralleled an alteration of MPO enzymatic activity by monitoring oxidation of tetramethylbenzidine | | |
| 16014720 | MPO | MPO | 7.1 | Consistent with the protein data we found that ventral midbrain MPO activity also rose during MPTP neurotoxicity in a time-dependent manner | | |
| 16014720 | MPO | MPO | 7.1 | In contrast in mutant mice deficient in MPO (MPO MPO n = 2 the ventral midbrain did not | | |
| 16014720 | MPO | MPO | 7.1 | In contrast in mutant mice deficient in MPO (MPO MPO n = 2 the ventral midbrain did not show higher | | |
| 16014720 | MPO | MPO | 7.1 | Unlike in the ventral midbrain levels of MPO mRNA proteins and catalytic activity in the cerebellum (brain brain | | |
| 16014720 | MPO | MPO | 7.1 | However more unexpected was the finding that no MPO alteration could be detected in the striatum (where where dopaminergic | | |
| 16014720 | MPO | MPO | 7.1 | administration as illustrated by the lack of change in striatal MPO activity saline 14.0 _amp_#177 4.1 ( n = 7 versus | | |
| 16014720 | MPO | MPO | 7.1 | Thus both protein levels and activity of MPO increase in the MPTP mouse model of PD specifically in | | |
| 16014720 | MPO | MPO | 7.1 | The present study shows that the level of MPO expression increases markedly in diseased SNpc from both mice exposed | | |
| 16014720 | MPO | MPO | 7.1 | This work also demonstrates that changes of MPO protein content and enzymatic activity in MPTP-intoxicated mice parallel ( | | |
| 16014720 | MPO | MPO | 7.1 | Moreover MPO is found primarily in SNpc-reactive astrocytes (Figs Figs 2 3 | | |
| 16014720 | MPO | MPO | 7.1 | to detect any of the well established cellular sources of MPO (neutrophils, neutrophils monocytes or macrophages (Hampton Hampton et al. 1998 | | |
| 16014720 | MPO | MPO | 7.1 | The presence of MPO in damaged SNpc thus appears to derive essentially from a | | |
| 16014720 | MPO | MPO | 7.1 | other neurodegenerative diseases namely HD and ALS it appears that MPO upregulation in the brain is not pathognomonic of PD | | |
| 16014720 | MPO | MPO | 7.1 | Instead we believe that the occurrence of MPO in diseased brains is likely indicative of a disease process | | |
| 16014720 | MPO | MPO | 7.1 | are generally believed to be the only cellular sources of MPO | | |
| 16014720 | MPO | MPO | 7.1 | However neuronal expression of MPO is also increased in Alzheimer's disease (Green Green et al. | | |
| 16014720 | MPO | MPO | 7.1 | injections are associated with a time-dependent increase in ventral midbrain MPO mRNA ( A C protein expression ( B C and | | |
| 16014720 | MPO | MPO | 7.1 | A C Immunochemical studies revealed no specific MPO immunoreactivity in the ventral midbrain of saline-injected control mice | | |
| 16014720 | MPO | MPO | 7.1 | dense network of fibers and scattered cell bodies positive for MPO are seen at the level of the SNpc after MPTP | | |
| 16014720 | MPO | MPO-positive | 1.0 | Black arrows in D show the MPO-positive cellular elements | | |
| 16014720 | MPO | MPO-positive | 1.0 | E-H Confocal microscopy demonstrates that ventral midbrain MPO-positive structures ( E red are also GFAP positive ( F | | |
| 16014720 | MPO | MPO-positive | 1.0 | J-L In contrast ventral midbrain MPO-positive structures ( I red are not MAC-1 positive ( J | | |
| 16014720 | MPO | MPO | 7.1 | A B Ventral midbrain MPO tissue content is increased in postmortem tissue from PD patients | | |
| 16014720 | MPO | MPO | 7.1 | C Positive control (purified purified MPO | | |
| 16014720 | MPO | MPO | 7.1 | C Inventral midbrain sections MPO (blue) blue is not detected in control tissues neither in | | |
| 16014720 | MPO | MPO | 7.1 | D Conversely MPO immunoreactivity (blue, blue small black arrow is found in GFAP-positive | | |
| 16014720 | MPO | MPO | 7.1 | A-D Ablation of MPO in mutant mice attenuates MPTP-induced striatal TH fibers and SNpc | | |
| 16014720 | MPO | MPO | 7.1 | saline-injected animals p _lt_ 0.05 compared with saline- and MPTP-injected MPO mice | | |
| 16014720 | MPO | MPO-deficient | 1.0 | Striatal MPTP metabolism in MPO-deficient mice | | |
| 16014720 | MPO | MPO | 7.1 | MPO is expressed in reactive astrocytes after MPTP injection | | |
| 16014720 | MPO | MPO | 7.1 | To elucidate the cellular origin of MPO in the ventral midbrain of MPTP-treated mice immunohistochemical studies were | | |
| 16014720 | MPO | MPO | 7.1 | In saline controls diffuse MPO immunoreactivity was seen in the neuropil ( Fig 2 A | | |
| 16014720 | MPO | MPO | 7.1 | MPTP-treated mice 2 d after the last injection ventral midbrain MPO immunostaining was stronger especially at the level of the substantia | | |
| 16014720 | MPO | MPO | 7.1 | This analysis confirmed that MPO colocalized with the astrocytic marker GFAP as shown by the | | |
| 16014720 | MPO | MPO | 7.1 | Conversely no evidence of MPO expression in microglial cells could be documented by using the | | |
| 16014720 | MPO | MPO | 7.1 | No noticeable cellular MPO immunoreactivity was observed in the striatum or cerebellum of either | | |
| 16014720 | MPO | MPO | 7.1 | These results demonstrate that MPO is primarily expressed in ventral midbrain astrocytes during the demise | | |
| 16014720 | MPO | MPO | 7.1 | Expression of MPO is increased in PD midbrain | | |
| 16014720 | MPO | MPO | 7.1 | To determine whether the changes in MPO observed in the MPTP mouse model of PD were present | | |
| 16014720 | MPO | MPO | 7.1 | of PD were present in the human condition we assessed MPO protein levels in postmortem ventral midbrain samples from sporadic PD | | |
| 16014720 | MPO | MPO | 7.1 | Consistent with the mouse data PD samples had significantly higher MPO protein contents compared with controls ( Fig 3 A B | | |
| 16014720 | MPO | MPO | 7.1 | Like in mice there was no significant difference in MPO to beta-actin ratios in the striatum (PD, PD 1.1 _amp_#177 | | |
| 16014720 | MPO | MPO | 7.1 | Histologically cellular MPO immunoreactivity was not detected in the control ventral midbrain parenchyma | | |
| 16014720 | MPO | MPO | 7.1 | However MPO immunoreactivity was seen in ventral midbrain sections from PD patients | | |
| 16014720 | MPO | MPO | 7.1 | The similarity of the MPO alterations between the MPTP mice and the PD postmortem specimens | | |
| 16014720 | MPO | MPO | 7.1 | of using this experimental model to study the role of MPO in the PD neurodegenerative process | | |
| 16014720 | MPO | MPO | 7.1 | neurodegenerative diseases we wondered whether increases in the expression of MPO within areas of neurodegeneration can be found in neurodegenerative disorders | | |
| 16014720 | MPO | MPO | 7.1 | cortex from ALS patients did not exhibit higher GFAP or MPO values (data data not shown | | |
| 16014720 | MPO | MPO | 7.1 | 0.1 p _lt_ 0.01 n = 3-4 as well as MPO to beta-actin ratios (HD, HD 0.8 _amp_#177 0.2 vs controls | | |
| 16014720 | MPO | MPO | 7.1 | This suggests that brain MPO expression is not specific to PD but rather generic to | | |
| 16014720 | MPO | MPO | 7.1 | MPO deficiency protects against MPTP-induced neurodegeneration | | |
| 16014720 | MPO | MPO | 7.1 | MPTP on the nigrostriatal pathway of mutant mice deficient in MPO (MPO MPO and their WT littermates (MPO MPO | | |
| 16014720 | MPO | MPO | 7.1 | the nigrostriatal pathway of mutant mice deficient in MPO (MPO MPO and their WT littermates (MPO MPO | | |
| 16014720 | MPO | MPO | 7.1 | deficient in MPO (MPO MPO and their WT littermates (MPO MPO | | |
| 16014720 | MPO | MPO | 7.1 | In saline-injected MPO and MPO mice stereological counts of SNpc dopaminergic neurons and | | |
| 16014720 | MPO | MPO | 7.1 | In saline-injected MPO and MPO mice stereological counts of SNpc dopaminergic neurons and striatal TH-positive | | |
| 16014720 | MPO | MPO | 7.1 | In MPTP-injected MPO mice there was a ~70% loss of SNpc TH-positive neurons | | |
| 16014720 | MPO | MPO | 7.1 | In contrast in MPTP-injected MPO mice there was only ~50% loss of SNpc TH-positive neurons | | |
| 16014720 | MPO | MPO | 7.1 | To examine whether MPO ablation protects not only against structural damage but also against | | |
| 16014720 | MPO | MPO | 7.1 | acid in the striatum as well as locomotor activity between MPO and MPO mice after MPTP injections | | |
| 16014720 | MPO | MPO | 7.1 | the striatum as well as locomotor activity between MPO and MPO mice after MPTP injections | | |
| 16014720 | MPO | MPO | 7.1 | Contrasting with the protection afforded by the lack of MPO on the nigrostriatal dopaminergic neurons the loss of striatal dopamine | | |
| 16014720 | MPO | MPO | 7.1 | in motor performance caused by MPTP were as severe in MPO as in MPO mice ( supplemental material available at www.jneurosci.org | | |
| 16014720 | MPO | MPO | 7.1 | caused by MPTP were as severe in MPO as in MPO mice ( supplemental material available at www.jneurosci.org | | |
| 16014720 | MPO | MPO | 7.1 | To ascertain that the resistance of MPO mice was not attributable to alterations in MPTP toxicokinetics we | | |
| 16014720 | MPO | MPO | 7.1 | (a a measure of mitochondrial function did not differ between MPO mice and their WT littermates ( Table 1 | | |
| 16014720 | MPO | MPO | 7.1 | MPO damages ventral midbrain proteins | | |
| 16014720 | MPO | MPO | 7.1 | MPO is the only known mammalian source of HOCl at plasma | | |
| 16014720 | MPO | MPO | 7.1 | 3-chlorotyrosine a specific and stable biomarker of protein damage by MPO (Heinecke Heinecke et al. 1999 | | |
| 16014720 | MPO | MPO | 7.1 | In contrast in MPTP-treated MPO mice ( n = 3 ventral midbrain 3-chlorotyrosine was undetectable | | |
| 16014720 | MPO | MPO | 7.1 | tissues therefore supports the hypothesis that reactive intermediates produced by MPO damage brain proteins in MPTP-intoxicated mice | | |
| 16014720 | MPO | MPO-damaged | 1.5 | To localize MPO-damaged proteins tissue sections were immunostained with HOP-1 a mouse antibody | | |
| 16014720 | MPO | MPO | 7.1 | was detected in the SNpc of saline-injected mice or MPTP-injected MPO mice (data data not shown | | |
| 16014720 | MPO | MPO | 7.1 | and sometimes in PD did not show any alteration in MPO expression or enzymatic activity as illustrated in Figure 3 | | |
| 16014720 | MPO | MPO | 7.1 | After MPTP injections mutant mice deficient in MPO showed more spared SNpc dopaminergic neurons and striatal dopaminergic fibers | | |
| 16014720 | MPO | MPO | 7.1 | We also found that the lack of MPO did not alter key aspects of MPTP toxicokinetics ( Table | | |
| 16014720 | MPO | MPO | 7.1 | Together these findings indicate that MPO contributes to the pathogenic cascade of deleterious events responsible for | | |
| 16014720 | MPO | MPO | 7.1 | Surprisingly although alterations in MPO protein and enzymatic activity were only detected in the ventral | | |
| 16014720 | MPO | MPO | 7.1 | and fibers of nigrostriatal dopaminergic neurons were preserved in MPTP-injected MPO mice ( Fig 4 | | |
| 16014720 | MPO | MPO | 7.1 | The relative resistance of dopaminergic neurons to MPTP-induced neurotoxicity in MPO mice was however not accompanied by a preservation of striatal | | |
| 16014720 | MPO | MPO | 7.1 | It is thus conceivable that although ablation of MPO attenuates the loss of TH protein (as as evidenced by | | |
| 16014720 | MPO | MPO | 7.1 | Targeting MPO alone may thus suffice to provide observable structural but not | | |
| 16014720 | MPO | MPO | 7.1 | combination of strategies capable of providing structural protection such as MPO inhibition with other strategies capable of protecting/stimulating protecting stimulating dopaminergic | | |
| 16014720 | MPO | MPO | 7.1 | Therefore whether MPO inhibition in PD can succeed not only in slowing neuronal | | |
| 16014720 | MPO | MPO | 7.1 | As to how MPO neurotoxic actions on dopaminergic neurons are mediated two distinct and | | |
| 16014720 | MPO | MPO | 7.1 | First and foremost MPO is known for its production of cytotoxic reactive oxygen species | | |
| 16014720 | MPO | MPO-derived | 1.0 | membrane proteins and lipids subjected to the deleterious effects of MPO-derived oxidants such as HOCl | | |
| 16014720 | MPO | MPO | 7.1 | Also supporting the oxidative role of MPO in the MPTP model is our immunohistochemical demonstration of HOCl-modified | | |
| 16014720 | MPO | MPO | 7.1 | Aside from this oxidative effect MPO can be secreted and bind CD11b/CD18 CD11b CD18 integrins to | | |
| 16014720 | MPO | MPO | 7.1 | the case of neutrophils ligation of CD11b/CD18 CD11b CD18 by MPO stimulates signaling pathways implicated in the activation of these cells | | |
| 16014720 | MPO | MPO | 7.1 | the MPTP model and in PD this cytokine-like effect of MPO may represent an additional mechanism by which dopaminergic neurons are | | |
| 16014720 | myeloperoxidase | myeloperoxidase | 1.0 | here we show that myeloperoxidase mpo a key oxidant producing enzyme during inflammation is upregulated in the ventral midbrain of human pd and mptp mice. | | |
| 16014720 | myeloperoxidase | myeloperoxidase | 1.0 | conversely myeloperoxidase mpo and not onoo seems to promote o o ' dityrosine formation in this model of pd pennathur et al. 1999 . | | |