NMDA-dependent superoxide production and neurotoxicity.
Neuronal injury resulting from acute brain insults and some neurodegenerative diseases implicates N-methyl-D-aspartate (NMDA) glutamate receptors. The fact that antioxidants reduce some types of brain damage suggests that oxygen radicals may have a role. It has been shown that mutations in Cu/Zn-superoxide dismutase (SOD), an enzyme catalysing superoxide (O2.-) detoxification in the cell, are linked to a familial form of amyotrophic lateral sclerosis (ALS). Here we report that O2.- is produced upon NMDA receptor stimulation in cultured cerebellar granule cells. Electron paramagnetic resonance was used to assess O2.- production that was due in part to the release of arachidonic acid. Activation of kainic acid receptors, or voltage-sensitive Ca2+ channels, did not produce detectable O2.-. We also find that the nitrone DMPO (5,5-dimethyl pyrroline 1-oxide), used as a spin trap, is more efficient than the nitric oxide synthase inhibitor, L-NG-nitro-arginine, in reducing NMDA-induced neuronal death in these cultures.
Lafon-Cazal
M
M
Centre CNRS-INSERM de Pharmacologie-Endocrinologie, Montpellier, France.
Pietri
S
S
Culcasi
M
M
Bockaert
J
J
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D003198:Computer Simulation; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D051379:Mice; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D011796:Quinacrine / Q000494:pharmacology; D017470:Receptors, Glutamate / Q000378:metabolism; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D019820:Xanthine; D014969:Xanthine Oxidase / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D000594:Amino Acid Oxidoreductases; D016718:Arachidonic Acid; D001120:Arginine; D015220:Calcium Channels; D003497:Cyclic N-Oxides; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D011796:Quinacrine; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D013482:Superoxide Dismutase; D013481:Superoxides; D019820:Xanthine; D014969:Xanthine Oxidase; D014970:Xanthines; C017245:5,5-dimethyl-1-pyrroline-1-oxide