Ethanol and excitotoxicity in cultured cortical neurons: differential sensitivity of N-methyl-D-aspartate and sodium nitroprusside toxicity.
Neural injury due to ischemia and related insults is thought to involve the action of excitatory amino acids at N-methyl-D-aspartate receptors, which results in the influx of extracellular Ca2+ and the generation of nitric oxide. Because ethanol inhibits physiologic responses to excitatory amino acids, we examined its effect on toxicity induced by N-methyl-D-aspartate and by the nitric oxide donor sodium nitroprusside in neuron-enriched cultures prepared from rat cerebral cortex. Both N-methyl-D-aspartate and sodium nitroprusside were cytotoxic, as measured by the release of lactate dehydrogenase and by microfluorescent determination of cell viability. Ethanol (3-1,000 mM) protected cultures from N-methyl-D-aspartate but not sodium nitroprusside toxicity, and the ability of a series of n-alkanols to reproduce the effect of ethanol was related to carbon-chain length. Neuroprotection by ethanol was accompanied by a decrease in the N-methyl-D-aspartate-evoked elevation of free intracellular Ca2+ and did not appear to involve gamma-aminobutyric acid- or cyclic GMP-mediated mechanisms. These findings suggest that ethanol inhibits excitotoxicity at an early step in the N-methyl-D-aspartate signaling pathway, probably by reducing Ca2+ influx, and not by interfering with the action of nitric oxide.
Lustig
H S
HS
Department of Neurology, University of California, San Francisco 94110.
von Brauchitsch
K L
KL
Chan
J
J
Greenberg
D A
DA
D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology / Q000502:physiology*; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis / Q000187:drug effects / Q000502:physiology
D016194:Receptors, N-Methyl-D-Aspartate; D009599:Nitroprusside; D009569:Nitric Oxide; D000431:Ethanol; D016202:N-Methylaspartate; D007770:L-Lactate Dehydrogenase; D002118:Calcium