title: Activation of NOX2 by the stimulation of ionotropic and metabotropic glutamate receptors contributes to glutamate neurotoxicity in vivo through the production of reactive oxygen species and calpain activation.
abstract: Prolonged activation of glutamate receptors leads to excitotoxicity. Several processes such as reactive oxygen species (ROS) production and activation of the calcium-dependent protease, calpain, contribute to glutamate-induced damage. It has been suggested that the ROS-producing enzyme, NADPH oxidase (NOX), plays a role in excitotoxicity. Studies have reported NOX activation after NMDA receptor stimulation during excitotoxic damage, but the role of non-NMDA and metabotropic receptors is unknown. We evaluated the roles of different glutamate receptor subtypes on NOX activation and neuronal death induced by the intrastriatal administration of glutamate in mice. In wild-type mice, NOX2 immunoreactivity in neurons and microglia was stimulated by glutamate administration, and it progressively increased as microglia became activated; calpain activity was also induced. By contrast, mice lacking NOX2 were less vulnerable to excitotoxicity, and there was reduced ROS production and protein nitrosylation, microglial reactivity, and calpain activation. These results suggest that NOX2 is stimulated by glutamate in neurons and reactive microglia through the activation of ionotropic and metabotropic receptors. Neuronal damage involves ROS production by NOX2, which, in turn, contributes to calpain activation.
authors: Departamento de Desarrollo Neuronal y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México.
authors: Alicia
authors: A
authors: Guemez-Gamboa
authors: Ana María
authors: AM
authors: Estrada-Sánchez
authors: Teresa
authors: T
authors: Montiel
authors: Blanca
authors: B
authors: Páramo
authors: Lourdes
authors: L
authors: Massieu
authors: Julio
authors: J
authors: Morán
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004347:Drug Interactions; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005452:Fluoresceins; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000633:toxicity; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000378:metabolism*; D009930:Organic Chemicals; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D058468:Receptors, Ionotropic Glutamate / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013997:Time Factors
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D018683:Excitatory Amino Acid Agents; D005452:Fluoresceins; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D009930:Organic Chemicals; C105949:Pirb protein, mouse; D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; D058468:Receptors, Ionotropic Glutamate; D018094:Receptors, Metabotropic Glutamate; C435731:fluoro jade; D018698:Glutamic Acid; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D002154:Calpain; D010751:Phosphopyruvate Hydratase