Key points are not available for this paper at this time.
Microglial-related factors have been implicated in the signaling cascades that contribute to neuronal cell death in various neurodegenerative disorders. Thus, strategies that reduce microglial activation and associated neurotoxicity may have therapeutic benefit. Group II and III metabotropic glutamate receptors (mGluRs) are expressed in microglia and can modulate microglial activity in primary cell cultures. We demonstrate that the group I receptor member mGluR5 is highly expressed in primary microglial cultures and the BV2 microglial cell line. Activation of mGluR5 using the selective agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) significantly attenuates microglial activation in response to lipopolysaccharide and interferon-γ, as indicated by a reduction in the expression of inducible nitric-oxide synthase, production of nitric oxide and tumor necrosis factor-α, and intracellular generation of reactive oxygen species. In addition, microglial-induced neurotoxicity is also markedly reduced by CHPG treatment. The anti-inflammatory effects of CHPG are mediated by the mGluR5 receptor, because either a selective mGluR5 antagonist or small interference RNA knockdown attenuated the actions of this drug. CHPG blocked the lipopolysaccharide-induced increase in expression and enzymatic activity of NADPH oxidase. Moreover, the protective effects of CHPG were significantly reduced when the NADPH oxidase subunits p22phox or gp91phox were knocked down by small interference RNA. These data suggest that mGluR5 represents a novel target for modulating microglial-dependent neuroinflammation, and may have therapeutic relevance for neurological disorders that exhibit microglial-mediated neurodegeneration. Microglial-related factors have been implicated in the signaling cascades that contribute to neuronal cell death in various neurodegenerative disorders. Thus, strategies that reduce microglial activation and associated neurotoxicity may have therapeutic benefit. Group II and III metabotropic glutamate receptors (mGluRs) are expressed in microglia and can modulate microglial activity in primary cell cultures. We demonstrate that the group I receptor member mGluR5 is highly expressed in primary microglial cultures and the BV2 microglial cell line. Activation of mGluR5 using the selective agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) significantly attenuates microglial activation in response to lipopolysaccharide and interferon-γ, as indicated by a reduction in the expression of inducible nitric-oxide synthase, production of nitric oxide and tumor necrosis factor-α, and intracellular generation of reactive oxygen species. In addition, microglial-induced neurotoxicity is also markedly reduced by CHPG treatment. The anti-inflammatory effects of CHPG are mediated by the mGluR5 receptor, because either a selective mGluR5 antagonist or small interference RNA knockdown attenuated the actions of this drug. CHPG blocked the lipopolysaccharide-induced increase in expression and enzymatic activity of NADPH oxidase. Moreover, the protective effects of CHPG were significantly reduced when the NADPH oxidase subunits p22phox or gp91phox were knocked down by small interference RNA. These data suggest that mGluR5 represents a novel target for modulating microglial-dependent neuroinflammation, and may have therapeutic relevance for neurological disorders that exhibit microglial-mediated neurodegeneration. A prominent feature of many neurological disorders such as Alzheimer disease, Parkinson disease, multiple sclerosis, AIDS-associated dementia, or brain trauma, is a prolonged localized inflammatory response that contributes to the progressive loss of neurons in discrete areas of the central nervous system (1.Gao H.M. Hong J.S. Trends Immunol. 2008; 29: 357-365Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar). Microglia, the resident immune cells in the brain, are highly responsive to environmental stresses or immunological challenges and have been implicated as the predominant cell type governing inflammation-mediated neuronal damage (2.Hanisch U.K. Kettenmann H. Nat. Neurosci. 2007; 10: 1387-1394Crossref PubMed Scopus (2761) Google Scholar). In particular, activated microglia exert neurotoxic effects by releasing inflammatory mediators such as eicosanoids, cytokines, chemokines, and reactive free radicals (3.Block M.L. Zecca L. Hong J.S. Nat. Rev. Neurosci. 2007; 8: 57-69Crossref PubMed Scopus (3108) Google Scholar). Although these factors are necessary for immunological surveillance of the local brain environment, microglial responses must be tightly regulated so as to avoid over-activation and associated neurotoxic effects (3.Block M.L. Zecca L. Hong J.S. Nat. Rev. Neurosci. 2007; 8: 57-69Crossref PubMed Scopus (3108) Google Scholar). Microglia respond to toxic agents, such as the bacterial endotoxin lipopolysaccharide (LPS) 2The abbreviations used are:LPSlipopolysaccharideIFNγinterferon γROSreactive oxygen speciesMAPKmitogen-activated protein kinaseiNOSinducible nitric-oxide synthaseTNFαtumor necrosis factor-αmGluRmetabotropic glutamate receptorCHPG(RS)-2-chloro-5-hydroxyphenylglycineMTEP3-(2-methyl-1,3-thiazol-4-yl)ethynylpyridinesiRNAsmall interference RNAPBSphosphate-buffered salinePIphosphoinositideANOVAanalysis of varianceH2DCFDA2′,7′-dichlorodihydrofluorescein diacetateCPCCOEt7-(hydroxyimino)cyclopropabchromen-1a-carboxylate ethyl ester. and cytokines (e.g. interferon-γ (IFNγ)), by releasing reactive oxygen species (ROS) (4.Qin L. Liu Y. Wang T. Wei S.J. Block M.L. Wilson B. Liu B. Hong J.S. J. Biol. Chem. 2004; 279: 1415-1421Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 5.Pawate S. Shen Q. Fan F. Bhat N.R. J. Neurosci. Res. 2004; 77: 540-551Crossref PubMed Scopus (379) Google Scholar). NADPH oxidase is an enzyme complex that plays a key role in microglial production of ROS. The NADPH oxidase complex is composed of cytosolic subunits (gp40phox, p47phox, and p67phox, and the GTP-binding protein p21-Rac1) and membrane subunits (gp91phox and p22phox) (6.Cross A.R. Segal A.W. Biochim. Biophys. Acta. 2004; 1657: 1-22Crossref PubMed Scopus (367) Google Scholar). Upon activation, protein kinase C- and MAPK-mediated phosphorylation of the cytosolic subunits results in their translocation to the membrane where they assemble with membrane subunits to form the active NADPH oxidase (7.Choi S.H. Lee D.Y. Kim S.U. Jin B.K. J. Neurosci. 2005; 25: 4082-4090Crossref PubMed Scopus (142) Google Scholar, 8.Bey E.A. Xu B. Bhattacharjee A. Oldfield C.M. Zhao X. Li Q. Subbulakshmi V. Feldman G.M. Wientjes F.B. Cathcart M.K. J. Immunol. 2004; 173: 5730-5738Crossref PubMed Scopus (159) Google Scholar, 9.Zhao X. Xu B. Bhattacharjee A. Oldfield C.M. Wientjes F.B. Feldman G.M. Cathcart M.K. J. Leukoc. Biol. 2005; 77: 414-420Crossref PubMed Scopus (56) Google Scholar). The active enzyme complex produces O2−, which is converted into superoxide-derived oxidants such as H2O2, hydroxyl radicals, and peroxynitrite (10.Patel M. Li Q.Y. Chang L.Y. Crapo J. Liang L.P. J. Neurochem. 2005; 92: 123-131Crossref PubMed Scopus (74) Google Scholar), which are highly neurotoxic (3.Block M.L. Zecca L. Hong J.S. Nat. Rev. Neurosci. 2007; 8: 57-69Crossref PubMed Scopus (3108) Google Scholar, 4.Qin L. Liu Y. Wang T. Wei S.J. Block M.L. Wilson B. Liu B. Hong J.S. J. Biol. Chem. 2004; 279: 1415-1421Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar). In addition, ROS generation has important effects on microglia themselves, facilitating pro-inflammatory pathways by activating MAPK and NFκB signaling. The latter induces transcription of pro-inflammatory mediators such as iNOS, nitric oxide (NO), and tumor necrosis factor-α (TNFα); these factors induce a self-propagating cycle that causes prolonged microglial activation and neuroinflammation. Considerable evidence suggests that the over-activation of NADPH oxidase plays a key role in inflammation-mediated neurodegeneration and may therefore be an important target for therapeutic intervention (11.Zhang D. Hu X. Wei S.J. Liu J. Gao H. Qian L. Wilson B. Liu G. Hong J.S. J. Neuroinflamm. 2008; 5: 21Crossref PubMed Scopus (39) Google Scholar, 12.Qian L. Xu Z. Zhang W. Wilson B. Hong J.S. Flood P.M. J. Neuroinflamm. 2007; 4: 23Crossref PubMed Scopus (126) Google Scholar). lipopolysaccharide interferon γ reactive oxygen species mitogen-activated protein kinase inducible nitric-oxide synthase tumor necrosis factor-α metabotropic glutamate receptor (RS)-2-chloro-5-hydroxyphenylglycine 3-(2-methyl-1,3-thiazol-4-yl)ethynylpyridine small interference RNA phosphate-buffered saline phosphoinositide analysis of variance 2′,7′-dichlorodihydrofluorescein diacetate 7-(hydroxyimino)cyclopropabchromen-1a-carboxylate ethyl ester. Metabotropic glutamate receptors (mGluRs) have been considered promising targets for neuroprotective drug discovery, and many studies have focused on modulating mGluR activity in neurons (13.Lea 4th, P.M. Faden A.I. CNS Drug Rev. 2006; 12: 149-166Crossref PubMed Scopus (146) Google Scholar, 14.Movsesyan V.A. Faden A.I. J. Neurotrauma. 2006; 23: 117-127Crossref PubMed Scopus (28) Google Scholar, 15.Faden A.I. Ivanova S.A. Yakovlev A.G. Mukhin A.G. J. Neurotrauma. 1997; 14: 885-895Crossref PubMed Scopus (75) Google Scholar, 16.Faden A.I. O'Leary D.M. Fan L. Bao W. Mullins P.G. Movsesyan V.A. Exp. Neurol. 2001; 167: 435-444Crossref PubMed Scopus (89) Google Scholar). However, mGluRs are also expressed on astrocytes (17.D'Antoni S. Berretta A. Bonaccorso C.M. Bruno V. Aronica E. Nicoletti F. Catania M.V. Neurochem. Res. 2008; 33: 2436-2443Crossref PubMed Scopus (91) Google Scholar, 18.Schools G.P. Kimelberg H.K. J. Neurosci. Res. 1999; 58: 533-543Crossref PubMed Scopus (100) Google Scholar) and microglia (19.Biber K. Laurie D.J. Berthele A. Sommer B. Tölle T.R. Gebicke-Härter P.J. van Calker D. Boddeke H.W. J. Neurochem. 1999; 72: PubMed Scopus Google Scholar, J. Neurosci. 23: PubMed Google Scholar), their in have to mGluRs are receptors that which have been into on their and of group II mGluRs and induce microglial activation, and to and neuronal M.L. J. Neurochem. PubMed Scopus Google Scholar, F. J. Neurosci. 2005; 25: PubMed Scopus Google Scholar). In activation of microglial group III receptors and may be protective J. Neurosci. 23: PubMed Google Scholar). the group I receptors and mGluR5 has been to be expressed in microglia (19.Biber K. Laurie D.J. Berthele A. Sommer B. Tölle T.R. Gebicke-Härter P.J. van Calker D. Boddeke H.W. J. Neurochem. 1999; 72: PubMed Scopus Google role in microglial activation and has been In activation of mGluR5 can neuronal in cell Faden A.I. PubMed Scopus Google Scholar, V.A. Faden A.I. J. Neurochem. 2004; PubMed Scopus Google Scholar), and mGluR5 have been to be such effects are to actions the mGluR5 receptor 4th, P.M. Movsesyan V.A. Faden A.I. J. 2005; PubMed Scopus Google Scholar). In activation of neuronal cell death Faden A.I. PubMed Scopus Google Scholar), selective are neuroprotective in and in A.I. O'Leary D.M. Fan L. Bao W. Mullins P.G. Movsesyan V.A. Exp. Neurol. 2001; 167: 435-444Crossref PubMed Scopus (89) Google Scholar, Z. Zhang X. H.M. Wang J. Neurosci. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, K. B. A. W. J. 2007; PubMed Scopus Google Scholar). Group I mGluRs are to and and activation of protein kinase Although and mGluR5 signaling they have in central nervous system Faden A.I. PubMed Scopus Google Scholar). In this and of microglial activation were used in BV2 and primary microglial cultures to the of mGluR5 receptor activation on microglial and We that microglia mGluR5 which activation the of inflammatory mediators and Moreover, demonstrate that the protective effects of microglial mGluR5 activation are mediated the of the NADPH oxidase and suggest that this novel to reduce may have therapeutic relevance for many neurological disorders that exhibit microglial-mediated neurodegeneration. microglial were and as J. S. A. Movsesyan V. Faden A.I. 2006; PubMed Scopus Google Scholar). the brain and in cultures were for with in with and the the cells were for and microglia were and as cultures with The BV2 microglial cell by The cells were and in with in a The mGluR5 CHPG to group mGluR and the ethyl were in to microglia for to or and The mGluR5 a and to CHPG were and to the RNA a of for and gp91phox were BV2 microglia in were with the using of cells were with CHPG for with and for an used in and were by using RNA The of in BV2 microglia as by cells the knockdown by BV2 and primary microglia were in a of cells were for with with and for an were in and in for by with for were in in for by in primary and The cells were with for by and for and with The were and on a using using of the using the and a BV2 in were with to the cell membrane with and with CHPG were for in to The by of and were with for The of by on The were with and to in The were with of and of were the with of The were with and by BV2 and primary in were for with with and and for the indicated were by with a cell and on were with and for The in and The were on for and for The cell the protein and were were by membrane and blocked for a of in in were with for mGluR5 p22phox gp91phox and in were in in the or for were and protein were using were to and using a were by analysis using The data represents the of target protein by the of the in and are expressed in production using the to the A used for in were as the were using and the results were expressed in ROS were by 2′,7′-dichlorodihydrofluorescein diacetate BV2 microglia were with CHPG or and with for The cells were with for in using and of and are as of NADPH oxidase activity using a for NADPH oxidase in the as J. M. J. 2007; PubMed Scopus Google Scholar). BV2 in were with CHPG or and with for and membrane were by for to and and the for to a were with and in with the of NADPH a of for in the were in a and are as of BV2 microglia were for with CHPG with and and for BV2 microglia to and the cells were and for a death by to the cell death by the in BV2 in data are as the and they were using a or by the were using the for were considered for mGluRs have been on microglia and immune the role of group I mGluRs on microglia have been demonstrate the expression of mGluR5 on studies using mGluR5 and a of activated were on BV2 microglia that been in the or of for mGluR5 in and and the microglia a cell to an with analysis that mGluR5 expressed in BV2 microglia and expression of the group I in these cells when the expression of these receptors in primary mGluR5 to be highly expressed in and expression and by activation of mGluR5 receptors results in activation, phosphoinositide protein kinase activation, and demonstrate that mGluR5 receptors on microglia are signaling of the receptor were of a selective mGluR5 were to BV2 and of CHPG with a increase activation and the of mGluR5 receptors on mGluR5 can modulate microglial activation, BV2 microglia were in and mGluR5 were or in for and the cells were by for a microglia as a of The selective mGluR5 significantly attenuated production in a CHPG reduced production by and this used for Moreover, a that mGluR5 receptor activation by the group I mGluR agonist in the of a also in of production in response to In that in the of an mGluR5 production in BV2 In addition, the mGluR5 antagonist CHPG of production when to the cells to CHPG that CHPG the mGluR5 of CHPG or in the of in microglial activation or the of knockdown of the mGluR5 receptor reduced protective effects In BV2 microglia that expressed CHPG in a reduction in pro-inflammatory In in BV2 microglia CHPG in a These data that an loss of the of CHPG when the mGluR5 receptor knocked down in BV2 microglia The of on the actions of CHPG to mGluR5 protein knockdown a of in BV2 microglia These data suggest that the mGluR5 receptor the actions of CHPG in Upon activation, microglia exert neurotoxic effects by releasing pro-inflammatory mediators such as and We the of microglial activation to mGluR5 activation the of pro-inflammatory of protein significantly of and of of BV2 microglia with CHPG significantly attenuated the expression of and expression also in primary in expression that significantly reduced by CHPG production in BV2 microglia and significantly and with CHPG in attenuated of production that mGluR5 activation attenuates microglia We the of the pro-inflammatory and of microglial as as with and of CHPG significantly reduced microglia as as Thus, activation of mGluR5 attenuated microglial activation and reduced the of pro-inflammatory mediators that are to induce neuronal cell when microglia to neuronal cell as by neuronal significantly However, of microglia with CHPG to and of to neurons significantly reduced neuronal cell death the neuroprotective of microglial mGluR5 ROS by NADPH oxidase is an microglial response to environmental stresses or immunological challenges that to NADPH oxidase neurotoxicity and pro-inflammatory expression in activated microglia (4.Qin L. Liu Y. Wang T. Wei S.J. Block M.L. Wilson B. Liu B. Hong J.S. J. Biol. Chem. 2004; 279: 1415-1421Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar), mGluR5 activation modulate microglial NADPH oxidase activity and the generation of ROS in We the expression of the membrane subunits of the NADPH oxidase p22phox and with for in BV2 or primary microglia p22phox and gp91phox that the membrane of activated microglia in BV2 and primary cultures. of microglia for with CHPG p22phox and gp91phox that the to analysis of p22phox and gp91phox expression by a increase in p22phox and gp91phox expression that significantly reduced by with CHPG These data demonstrate that mGluR5 activation the expression of the NADPH oxidase p22phox and gp91phox The enzymatic activity of NADPH oxidase in BV2 microglia that were for or with with CHPG or the NADPH oxidase a increase in NADPH oxidase activity of with CHPG attenuated the activity of NADPH to of the NADPH oxidase to in a reduction in NADPH oxidase activity NADPH oxidase activity also of reduced NADPH oxidase activity this intracellular ROS generation in BV2 microglia cells and is by to with ROS to form the ROS in BV2 microglia that been with for of microglia with CHPG or a reduction in intracellular ROS production in response to and and of CHPG or in the of in ROS Thus, activation of mGluR5 by CHPG p22phox and gp91phox expression and membrane the enzymatic activity of NADPH oxidase and attenuates intracellular ROS generation in microglia that of NADPH oxidase is a key which CHPG attenuates microglial activation, used to knockdown the expression of NADPH oxidase p22phox or to protein knockdown by p22phox or gp91phox protein expression reduced by and with cell and mGluR5 receptor activation by CHPG significantly attenuates and BV2 microglia and these pro-inflammatory mediators were in and cells to NADPH oxidase knockdown the protective actions of In BV2 microglia that expressed the CHPG in a reduction in In in BV2 microglia or CHPG a and CHPG in microglia in a reduction in CHPG in or microglia in a and reduction in These data that a reduction in NADPH oxidase membrane subunits p22phox or gp91phox by and results in an loss of the of These data suggest that a key which CHPG microglial activation, and the of pro-inflammatory mediators is by the NADPH oxidase effects on microglia were for an central nervous system The pro-inflammatory microglial activity S. Shen Q. Fan F. Bhat N.R. J. Neurosci. Res. 2004; 77: 540-551Crossref PubMed Scopus (379) Google Scholar) and in microglial-mediated neurotoxicity A. D. S. H. S. J. Neurosci. 2007; PubMed Scopus Google Scholar). BV2 microglia were with CHPG for and with of and for a the production of CHPG reduced production by microglia of In CHPG in microglia that microglial activation by significantly attenuated by mGluR5 the and studies suggest that mGluR5 activation key pro-inflammatory signaling pathways that are in microglial-mediated neurodegeneration. In to their expression on mGluRs are expressed on and (17.D'Antoni S. Berretta A. Bonaccorso C.M. Bruno V. Aronica E. Nicoletti F. Catania M.V. Neurochem. Res. 2008; 33: 2436-2443Crossref PubMed Scopus (91) Google Scholar, 18.Schools G.P. Kimelberg H.K. J. Neurosci. Res. 1999; 58: 533-543Crossref PubMed Scopus (100) Google Scholar, J. Neurosci. 23: PubMed Google Scholar, M.L. J. Neurochem. PubMed Scopus Google Scholar, G. L. van D. Aronica E. PubMed Scopus Google Scholar, F. V. J. T. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). In this used an microglial to the role of microglial mGluR5 receptor activation and key in primary We demonstrate that mGluR5 is expressed in the group I is this is with the of mGluR5 expression in microglia (19.Biber K. Laurie D.J. Berthele A. Sommer B. Tölle T.R. Gebicke-Härter P.J. van Calker D. Boddeke H.W. J. Neurochem. 1999; 72: PubMed Scopus Google Scholar). microglial mGluR5 receptors are as by phosphoinositide and activation of the signaling pathways when by the selective mGluR5 agonist Activation of mGluR5 the of microglial associated inflammatory mediators in response to the bacterial endotoxin and the pro-inflammatory Moreover, mGluR5 activation microglial-mediated neuronal cell that these effects were mediated by the mGluR5 receptor, a that CHPG effects were markedly reduced by a selective mGluR5 receptor antagonist or by protein knockdown using that the protective effects of mGluR5 activation are mediated by the of microglial NADPH oxidase complex because CHPG blocked NADPH oxidase enzymatic activity and reduced the expression of membrane subunits p22phox and In addition, the protective effects of CHPG were significantly reduced when the p22phox or gp91phox subunits of NADPH oxidase complex were knocked down by The pro-inflammatory mediators and have been to contribute to neuronal damage and death in and in F. J. Neurosci. 2005; 25: PubMed Scopus Google Scholar, Y. Z. J. S.H. W. J. Neurochem. PubMed Scopus Google Scholar, K. S. PubMed Scopus Google Scholar, Res. 2005; PubMed Scopus Google Scholar). is associated with neuronal cell death the production of the toxic peroxynitrite or actions on and H.M. M. Res. 2006; PubMed Scopus Google Scholar, J. Neuroinflamm. 2005; PubMed Scopus Google Scholar). of induce neuronal death by oxidase and neuronal and glutamate by receptors A. J. Neurosci. 2001; PubMed Google Scholar, S. S. A. J. Neurochem. PubMed Scopus (75) Google Scholar, J. Neurochem. PubMed Scopus Google Scholar). In this that of microglial mGluR5 receptors using and attenuates production by the expression of In addition, mGluR5 receptor activation by CHPG significantly the of a pro-inflammatory that many can also cell death by to neuronal receptors to death that X. B. Wang E. J. Neurosci. Res. 2001; PubMed Scopus Google Scholar) or by glutamate by of glutamate Res. 2005; PubMed Scopus Google Scholar). also self-propagating of microglial activation and by microglial NADPH oxidase activity and of and superoxide-derived oxidants Fan Biol. 2005; 25: PubMed Scopus Google Scholar). and are highly and production of free radicals and to cell death (10.Patel M. Li Q.Y. Chang L.Y. Crapo J. Liang L.P. J. Neurochem. 2005; 92: 123-131Crossref PubMed Scopus (74) Google Scholar). are to and damage to contribute to neuronal cell death in a of neurodegenerative (3.Block M.L. Zecca L. Hong J.S. Nat. Rev. Neurosci. 2007; 8: 57-69Crossref PubMed Scopus (3108) Google Scholar). NADPH oxidase has been implicated in the neurotoxic of neurotoxic (e.g. and (e.g. and environmental (e.g. and (e.g. (4.Qin L. Liu Y. Wang T. Wei S.J. Block M.L. Wilson B. Liu B. Hong J.S. J. Biol. Chem. 2004; 279: 1415-1421Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, M.L. X. Z. Li G. Wang T. L. Wilson B. J. Hong J.S. B. J. 2004; PubMed Scopus Google Scholar, H.M. Liu B. Hong J.S. J. Neurosci. 23: PubMed Google Scholar, H.M. Liu B. Zhang W. Hong J.S. J. PubMed Scopus Google Scholar, L. Liu Y. Liu B. Wilson B. Hong J.S. J. Neurochem. PubMed Scopus Google Scholar, Block M.L. Zhang W. L. Wilson B. Zhang B. Hong J.S. 2005; PubMed Scopus Google Scholar, W. S. Zhang D. H. Wilson B. B. Zhang W. Hong J.S. Zhang J. 2007; PubMed Scopus Google Scholar). These are to contribute to the of neurodegenerative as such microglial NADPH oxidase plays a key role in inflammation-mediated neurodegeneration. We that mGluR5 activation NADPH oxidase activity of in a to the of the NADPH oxidase complex by mGluR5 activation the expression of the NADPH oxidase membrane p22phox and gp91phox We that this may be a key of because knockdown of p22phox or gp91phox significantly reduced the protective effects of microglial mGluR5 of these actions is a reduction of intracellular ROS generation in response to which to self-propagating microglial activation and of inflammatory The effects of microglial mGluR5 receptor activation cell death the of NADPH oxidase and pro-inflammatory mediators such as and which are neurotoxic J. Neuroinflamm. 2005; PubMed Scopus Google Scholar, A. J. Neurosci. 2001; PubMed Google Scholar, J. T. S. A. 2005; PubMed Scopus Google Scholar). NADPH ROS has been to the effects of and on the expression of and pro-inflammatory cytokines in microglia S. Shen Q. Fan F. Bhat N.R. J. Neurosci. Res. 2004; 77: 540-551Crossref PubMed Scopus (379) Google Scholar, A. A. L. J. A. M. J. Neurosci. 2008; PubMed Scopus Google Scholar). NADPH oxidase and signaling modulating transcription activation and expression S. Shen Q. Fan F. Bhat N.R. J. Neurosci. Res. 2004; 77: 540-551Crossref PubMed Scopus (379) Google Scholar). Thus, the protective effects of mGluR5 activation in microglia may in of NADPH ROS generation and the reduced expression of pro-inflammatory mediators and neurotoxic mGluR receptors expressed on microglia may also modulate microglial-mediated Activation of microglial group III mGluRs by or neurotoxicity microglial with and A J. Neurosci. 23: PubMed Google Scholar). the protective effects of group III mGluR activation in a of microglial they that activation of the group II receptor activation of microglial neurotoxicity F. V.A. S. D. J. Neurochem. 2008; PubMed Scopus Google Scholar). response is also in where activation activation may be to neurons G. G. B. A. M. M. Nicoletti F. Bruno V. J. Neurosci. 2007; PubMed Scopus Google Scholar). In the is for group I cell death Faden A.I. PubMed Scopus Google Scholar) and selective are neuroprotective A.I. O'Leary D.M. Fan L. Bao W. Mullins P.G. Movsesyan V.A. Exp. Neurol. 2001; 167: 435-444Crossref PubMed Scopus (89) Google Scholar, Z. Zhang X. H.M. Wang J. Neurosci. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, K. B. A. W. J. 2007; PubMed Scopus Google Scholar), mGluR5 activation neuronal and to in studies V.A. Faden A.I. J. Neurochem. 2004; PubMed Scopus Google Scholar). The suggest that the neuroprotective effects of CHPG may also mGluR5 of microglial when with effects on such may have neuroprotective actions D.J. Faden A.I. PubMed Scopus (100) Google Scholar). mGluR5 activation can have neuroprotective in a of CHPG reduced the and neurological Faden A.I. Res. 2001; PubMed Scopus Google Scholar). have that CHPG and B. A. A. D.J. Faden A.I. Neurol. Scopus Google Scholar). of CHPG significantly attenuated microglial activation and reduced the of neurotoxic microglial-mediated and neuronal damage to a that to progressive microglial which may contribute to the of neurodegenerative such Alzheimer and Parkinson (1.Gao H.M. Hong J.S. Trends Immunol. 2008; 29: 357-365Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar). that microglial-mediated and neuronal cell death have been implicated in mGluR5 may be a promising target for the of central nervous system and neurodegenerative disorders. We and T. for and of the and for
Loane et al. (Tue,) studied this question.