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

Alicia Guemez-Gamboa, Ana María Estrada-Sánchez, Teresa Montiel, Blanca Páramo, Lourdes Massieu*, Julio Morán

*Corresponding author for this work

Research output: Contribution to journalArticle

38 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1020-1035
Number of pages16
JournalJournal of neuropathology and experimental neurology
Volume70
Issue number11
DOIs
StatePublished - Nov 1 2011

Keywords

  • Calpain
  • Excitotoxicity
  • Glutamate receptors
  • NADPH oxidase
  • Oxidative damage
  • Striatum

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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