title: Intracellular pH reduction prevents excitotoxic and ischemic neuronal death by inhibiting NADPH oxidase.
abstract: Sustained activation of N-methyl-d-aspartate (NMDA) -type glutamate receptors leads to excitotoxic neuronal death in stroke, brain trauma, and neurodegenerative disorders. Superoxide production by NADPH oxidase is a requisite event in the process leading from NMDA receptor activation to excitotoxic death. NADPH oxidase generates intracellular H(+) along with extracellular superoxide, and the intracellular H(+) must be released or neutralized to permit continued NADPH oxidase function. In cultured neurons, NMDA-induced superoxide production and neuronal death were prevented by intracellular acidification by as little as 0.2 pH units, induced by either lowered medium pH or by inhibiting Na(+)/H(+) exchange. In mouse brain, superoxide production induced by NMDA injections or ischemia-reperfusion was likewise prevented by inhibiting Na(+)/H(+) exchange and by reduced expression of the Na(+)/H(+) exchanger-1 (NHE1). Neuronal intracellular pH and neuronal Na(+)/H(+) exchange are thus potent regulators of excitotoxic superoxide production. These findings identify a mechanism by which cell metabolism can influence coupling between NMDA receptor activation and superoxide production.
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94121.
authors.forename: Tina I
authors.initials: TI
authors.lastname: Lam
authors.forename: Angela M
authors.initials: AM
authors.lastname: Brennan-Minnella
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Won
authors.forename: Yiguo
authors.initials: Y
authors.lastname: Shen
authors.forename: Colleen
authors.initials: C
authors.lastname: Hefner
authors.forename: Yejie
authors.initials: Y
authors.lastname: Shi
authors.forename: Dandan
authors.initials: D
authors.lastname: Sun
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Swanson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D005453:Fluorescence; D006863:Hydrogen-Ion Concentration; D007424:Intracellular Fluid / Q000737:chemistry*; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D017931:DNA Primers; D016194:Receptors, N-Methyl-D-Aspartate; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D013481:Superoxides; D019255:NADPH Oxidases
keywords: Hv1; NOX2; acidosis; cariporide