Research article summary (published 11 Apr 2009):

Activation of metabotropic glutamate receptor 5 modulates microglial reactivity and neurotoxicity by inhibiting NADPH oxidase.

Full Abstract

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-gamma, as indicated by a reduction in the expression of inducible nitric-oxide synthase, production of nitric oxide and tumor necrosis factor-alpha, 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 p22(phox) or gp91(phox) 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.

Author information

Author/s: Loane, David J (DJ); Stoica, Bogdan A (BA); Pajoohesh-Ganji, Ahdeah (A); Byrnes, Kimberly R (KR); Faden, Alan I (AI);

Affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, D C 20057, USA. djl42(-atsign-)georgetown.edu

Grants: R01 5R01NS037313-08 (Agency:NINDS NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: The Journal of biological chemistry (J Biol Chem), published in United States. (Language: eng)

Reference: 2009-Jun; vol 284 (issue 23) : pp 15629-39

Dates: Created 2009/06/01; Completed 2009/07/13; Revised 2009/07/13;

PMID: 19364772, status: MEDLINE (last retrieval date: 7/24/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals Animals, Newborn Brain - drug effects; metabolism Cells, Cultured Cerebral Cortex - drug effects; metabolism Excitatory Amino Acid Agonists - pharmacology Glycine - analogs & derivatives; pharmacology Immunohistochemistry Methoxyhydroxyphenylglycol - analogs & derivatives; pharmacology Microglia - physiology

Microglia - physiology NADPH Oxidase - antagonists & inhibitors Neurotoxins - antagonists & inhibitors Nitric Oxide - metabolism Phenylacetates - pharmacology RNA Interference Rats Rats, Sprague-Dawley Reactive Oxygen Species - metabolism Receptors, Metabotropic Glutamate - genetics; metabolism

Associated Chemicals: 2-chloro-5-hydroxyphenylglycine (0) ; Excitatory Amino Acid Agonists (0) ; Neurotoxins (0) ; Phenylacetates (0) ; Reactive Oxygen Species (0) ; Receptors, Metabotropic Glutamate (0) ; metabotropic glutamate receptor 5 (0) ; Nitric Oxide (10102-43-9) ; dihydroxyphenylethylene glycol (3343-19-9) ; Methoxyhydroxyphenylglycol (534-82-7) ; Glycine (56-40-6) ; NADPH Oxidase (EC 1.6.3.1)

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