Ethanol and Excitotoxicity in Cultured Cortical Neurons: Differential Sensitivity of N‐Methyl‐D‐Aspartate and Sodium Nitroprusside Toxicity

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Abstract
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 γ‐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.