Activation of Metabotropic Glutamate Receptor 5 Modulates Microglial Reactivity and Neurotoxicity by Inhibiting NADPH Oxidase

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.