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18040778 ( ) |
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| Title | Microglia as a pharmacological target in infectious and inflammatory diseases of the brain. |
| Abstract | Following an eclipse of scientific inquiry regarding the biology of microglia that lasted 50 years, recognition toward the end of the 20th century of their neuropathogenic role in HIV-associated dementia and in neuroinflammatory/neurodegenerative diseases fueled a renaissance of interest in these resident macrophages of the brain parenchyma. Results of a large number of in vitro studies, using isolated microglial cells or glial/neuronal cell cultures, and parallel findings emerging from animal models and clinical studies have demonstrated that activated microglia produce a myriad of inflammatory mediators that both serve important defense functions against invading neurotropic pathogens and have been implicated in brain damage in infectious as well as neuroinflammatory/neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review provides a brief background regarding the physiological and pathophysiological roles of microglia and highlights current pharmacological approaches that target activated microglia with the goal of ameliorating infectious and neuroinflammatory/neurodegenerative diseases of the brain. Although this aspect of the field of neuroimmunopharmacology is in its infancy, it holds great promise for developing new treatments and prevention of diseases that are, in many cases, epidemic throughout the world. and the Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA. on NeuroImmune Pharmacology |
NOTE: Color highlight is limited to the abstract and SciMiner text-mining mode. If you see much more identified targets below from "Targets by SciMiner Summary" and "Targets by SciMiner Full list", they may have been identified from the full text.
Targets by SciMiner Summary
| HUGO ID | Symbol | Target Name | #Occur | ActualStr |
|---|---|---|---|---|
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | 12 | COX | COX-2 | cox 2 | |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | 8 | tumor necrosis factor | TNF-A | |
| 5992 | IL1B | interleukin 1, beta | 5 | IL-1 | il 1 | il 1b | IL-1B | |
| 10618 | CCL2 | chemokine (C-C motif) ligand 2 | 2 | CCL2 | |
| 6018 | IL6 | interleukin 6 (interferon, beta 2) | 2 | IL-6 | il 6 | |
| 5962 | IL10 | interleukin 10 | 2 | IL-10 | il 10 | |
| 10632 | CCL5 | chemokine (C-C motif) ligand 5 | 2 | CCL5 | |
| 6025 | IL8 | interleukin 8 | 2 | CXCL8 | |
| 10637 | CXCL10 | chemokine (C-X-C motif) ligand 10 | 1 | CXCL10 | |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | 1 | amyloid | |
| 7685 | NDUFA2 | NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 2, 8kDa | 1 | CD14 | |
| 10627 | CCL3 | chemokine (C-C motif) ligand 3 | 1 | CCL3 | |
| 7176 | MMP9 | matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase) | 1 | mmp 9 | |
| 11765 | TGFA | transforming growth factor, alpha | 1 | transforming growth factor | |
| 24692 | FCAMR | Fc receptor, IgA, IgM, high affinity | 1 | fc receptor | |
| 10630 | CCL4 | chemokine (C-C motif) ligand 4 | 1 | CCL4 | |
| 6014 | IL4 | interleukin 4 | 1 | interleukin 4 | |
| 4571 | GRIA1 | glutamate receptor, ionotropic, AMPA 1 | 1 | glutamate receptor | |
| 1678 | CD4 | CD4 molecule | 1 | CD4 | |
| 9604 | PTGS1 | prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase) | 1 | COX-1 | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | TNF | 1.2 | actively secrete both neurotoxins such as tumor necrosis factor (TNF)-A, TNF -A interleukin (IL)-1B, IL -1B CXCL8 glutamate quinolinic acid platelet |
| 6025 | IL8 | interleukin 8 | CXCL8 | 1.3 | tumor necrosis factor (TNF)-A, TNF -A interleukin (IL)-1B, IL -1B CXCL8 glutamate quinolinic acid platelet activating factor eicosanoids and nitric oxide |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | TNF-A | 1.2 | benzodiazepines which cross the CNS bind to microglia inhibit LPS-induced TNF-A production suppress HIV-1 Tat protein-induced chemotaxis and also inhibit HIV-1 |
| 7685 | NDUFA2 | NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 2, 8kDa | CD14 | 1.0 | nonopsonized M tuberculosis by human microglia is facilitated by the CD14 receptor (Rock Rock et al. 2004 |
| 5992 | IL1B | interleukin 1, beta | IL-1 | 1.8 | that following infection there is a lasting inhibition of both IL-1 and IL-10 production (Curto Curto et al. 2004 |
| 5962 | IL10 | interleukin 10 | IL-10 | 1.3 | infection there is a lasting inhibition of both IL-1 and IL-10 production (Curto Curto et al. 2004 |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | TNF-A | 1.2 | microglia elicited robust amounts of several cytokines/chemokines, cytokines chemokines including TNF-A IL-6 IL-1B CCL2 CCL5 and CXCL10 |
| 6018 | IL6 | interleukin 6 (interferon, beta 2) | IL-6 | 1.6 | elicited robust amounts of several cytokines/chemokines, cytokines chemokines including TNF-A IL-6 IL-1B CCL2 CCL5 and CXCL10 |
| 5992 | IL1B | interleukin 1, beta | IL-1B | 1.8 | robust amounts of several cytokines/chemokines, cytokines chemokines including TNF-A IL-6 IL-1B CCL2 CCL5 and CXCL10 |
| 10618 | CCL2 | chemokine (C-C motif) ligand 2 | CCL2 | 0.3 | amounts of several cytokines/chemokines, cytokines chemokines including TNF-A IL-6 IL-1B CCL2 CCL5 and CXCL10 |
| 10632 | CCL5 | chemokine (C-C motif) ligand 5 | CCL5 | 0.1 | of several cytokines/chemokines, cytokines chemokines including TNF-A IL-6 IL-1B CCL2 CCL5 and CXCL10 |
| 10637 | CXCL10 | chemokine (C-X-C motif) ligand 10 | CXCL10 | 0.0 | cytokines/chemokines, cytokines chemokines including TNF-A IL-6 IL-1B CCL2 CCL5 and CXCL10 |
| 10630 | CCL4 | chemokine (C-C motif) ligand 4 | CCL4 | 1.0 | in the presence of specific antibody human microglia produce CCL3 CCL4 CCL2 CXCL8 and low levels of CCL5 via Fc-receptor activation |
| 6025 | IL8 | interleukin 8 | CXCL8 | 1.3 | presence of specific antibody human microglia produce CCL3 CCL4 CCL2 CXCL8 and low levels of CCL5 via Fc-receptor activation (Goldman Goldman |
| 10627 | CCL3 | chemokine (C-C motif) ligand 3 | CCL3 | 0.2 | Also in the presence of specific antibody human microglia produce CCL3 CCL4 CCL2 CXCL8 and low levels of CCL5 via Fc-receptor |
| 10618 | CCL2 | chemokine (C-C motif) ligand 2 | CCL2 | 0.4 | the presence of specific antibody human microglia produce CCL3 CCL4 CCL2 CXCL8 and low levels of CCL5 via Fc-receptor activation (Goldman |
| 10632 | CCL5 | chemokine (C-C motif) ligand 5 | CCL5 | 0.0 | microglia produce CCL3 CCL4 CCL2 CXCL8 and low levels of CCL5 via Fc-receptor activation (Goldman Goldman et al. 2001 |
| 620 | APP | amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) | amyloid | 1.0 | or endogenous proteins that have taken on pathological properties e.g. amyloid B peptide (AB) AB in AD and A-synuclein in PD |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | TNF | 1.2 | Lipopolysaccharide (LPS), LPS tumor necrosis factor (TNF)-A, TNF -A reactive oxygen intermediates (ROI), ROI reactive nitrogen intermediates (RNI), |
| 1678 | CD4 | CD4 molecule | CD4 | 0.3 | block neurogenesis microglia activated by interleukin-4 or interferon-G associated with CD4 lymphocyte infiltration induces neurogenesis |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | COX-2 | 1.0 | Cyclooxygenase-2 (COX-2) COX-2 is an enzyme central to the production of prostaglandins a |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | COX-2 | 1.0 | COX-2 and prostaglandin E 2 are elevated in the CNS of |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | COX-2 | 1.0 | implicated in other neuroinflammatory/neurodegenerative neuroinflammatory neurodegenerative diseases and not surprisingly COX-2 has been considered a major therapeutic target |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | 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 |
| 9604 | PTGS1 | prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase) | COX-1 | 0.1 | Hypothetically by inhibiting microglial cell cyclooxygenases (COX-1 COX-1 or COX-2 the metabolism of arachadonic acid is curtailed and |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | COX | 0.0 | In addition to the suppression of prostaglandin production COX inhibitors may also decrease the formation of AB peptide (Hirohata |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | COX-2 | 1.0 | Although preclinical and early clinical data suggested that COX-2 inhibitors may have a beneficial role in AD results of |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | 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 |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | TNF-A | 1.2 | NO production as well as to suppress the production of TNF-A by LPS and AB peptide-stimulated microglia (Dheen Dheen et al. |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | TNF-A | 1.2 | Although early studies have shown that microglia-derived TNF-A induces apoptosis of hippocampal progenitor cells (Cacci Cacci et al. |
| 5992 | IL1B | interleukin 1, beta | il 1b | 1.0 | indeed it is now recognized that hiv 1 infected microglia and other brain macrophages actively secrete both neurotoxins such as tumor necrosis factor tnf a interleukin il 1b cxcl8 glutamate quinolinic acid platelet activating factor eicosanoids and nitric oxide no as well as neurotoxic viral proteins such as tat gp120 and gp41. |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | tumor necrosis factor | 1.0 | indeed it is now recognized that hiv 1 infected microglia and other brain macrophages actively secrete both neurotoxins such as tumor necrosis factor tnf a interleukin il 1b cxcl8 glutamate quinolinic acid platelet activating factor eicosanoids and nitric oxide no as well as neurotoxic viral proteins such as tat gp120 and gp41. |
| 7176 | MMP9 | matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase) | mmp 9 | 1.0 | the drugs indinavir and zidovudine have been shown to inhibit lipopolysaccharide lps stimulated microglial production of matrix metalloproteinase mmp 9 thereby demonstrating an effect on microglia that extends beyond pure antiviral activity liuzzi et al. 1999 . |
| 5992 | IL1B | interleukin 1, beta | il 1 | 1.0 | dy demonstrated that human microglia are more efficient at ingesting m. tuberculosis than virulent and avirulent strains of m. avium and that following infection there is a lasting inhibition of both il 1 and il 10 production curto et al. 2004 . |
| 5962 | IL10 | interleukin 10 | il 10 | 1.0 | trated that human microglia are more efficient at ingesting m. tuberculosis than virulent and avirulent strains of m. avium and that following infection there is a lasting inhibition of both il 1 and il 10 production curto et al. 2004 . |
| 5992 | IL1B | interleukin 1, beta | il 1b | 1.0 | in these experiments m. tuberculosis infected microglia elicited robust amounts of several cytokines/chemokines including tnf a il 6 il 1b ccl2 ccl5 and cxcl10. |
| 6018 | IL6 | interleukin 6 (interferon, beta 2) | il 6 | 1.0 | in these experiments m. tuberculosis infected microglia elicited robust amounts of several cytokines/chemokines including tnf a il 6 il 1b ccl2 ccl5 and cxcl10. |
| 24692 | FCAMR | Fc receptor, IgA, IgM, high affinity | fc receptor | 1.0 | also in the presence of specific antibody human microglia produce ccl3 ccl4 ccl2 cxcl8 and low levels of ccl5 via fc receptor activation goldman et al. 2001 . |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | tumor necrosis factor | 1.0 | lipopolysaccharide lps tumor necrosis factor tnf a reactive oxygen intermediates roi reactive nitrogen intermediates rni quinolinic acid qa multiple sclerosis ms alzheimer's disease ad parkinson's disease pd amyotrophic lateral sclerosis als . |
| 11765 | TGFA | transforming growth factor, alpha | transforming growth factor | 1.0 | evidence supporting this neuroprotective role includes the microglial production of transforming growth factor b1 in an acute neuronal injury model lehrmann et al. 1998 in vitro studies demonstrating microglial production of neurotrophic factors nakajima and kohsaka 2002 and evidence that transplanted microgl |
| 6014 | IL4 | interleukin 4 | interleukin 4 | 1.0 | 2006 have advanced the concept of _amp_#8220;protective autoimmunity_amp_#8221; by demonstrating that whereas microglia activated by endotoxin block neurogenesis microglia activated by interleukin 4 or interferon g associated with cd4 lymphocyte infiltration induces neurogenesis. |
| 4571 | GRIA1 | glutamate receptor, ionotropic, AMPA 1 | glutamate receptor | 1.0 | the role of these receptors in neuronal microglial cell communication is not understood; however the production of glutamate and the glutamate receptor ligand quinolinic acid by activated microglia has been implicated in excitotoxicity of neurons in several neurodegenerative diseases matute et al. 2002 . |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | 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 |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | 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 . |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | 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. |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | 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 . |
| 9605 | PTGS2 | prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) | 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. |