Glial-derived arginine, the nitric oxide precursor, protects neurons from NMDA-induced excitotoxicity.
Excitotoxic neuronal cell death is characterized by an overactivation of glutamate receptors, in particular of the NMDA subtype, and the stimulation of the neuronal nitric oxide synthase (nNOS), which catalyses the formation of nitric oxide (NO) from l-arginine (L-Arg). At low L-Arg concentrations, nNOS generates NO and superoxide (O2(.)(-)), favouring the production of the toxin peroxynitrite (ONOO-). Here we report that NMDA application for five minutes in the absence of added L-Arg induces neuronal cell death, and that the presence of L-Arg during NMDA application prevents cell loss by blocking O2(.)(-) and ONOO- formation and by inhibiting mitochondrial depolarization. Because L-Arg is transferred from glial cells to neurons upon activation of glial glutamate receptors, we hypothesized that glial cells play an important modulator role in excitotoxicity by releasing L-Arg. Indeed, as we further show, glial-derived L-Arg inhibits NMDA-induced toxic radical formation, mitochondrial dysfunction and cell death. Glial cells thus may protect neurons from excitotoxicity by supplying L-Arg. This potential neuroprotective mechanism may lead to an alternative approach for the treatment of neurodegenerative diseases involving excitotoxic processes, such as ischemia.
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Centre de Recherche en Neurosciences Psychiatriques, University of Lausanne, 1008 Prilly Lausanne, Switzerland.
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D000818:Animals; D001120:Arginine / Q000378:metabolism* / Q000494:pharmacology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D009498:Neurotoxins / Q000378:metabolism* / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*
D018696:Neuroprotective Agents; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D001120:Arginine