Lustig H S, von Brauchitsch K L, Chan J, Greenberg D A
Department of Neurology, University of California, San Francisco 94110.
J Neurochem. 1992 Dec;59(6):2193-200. doi: 10.1111/j.1471-4159.1992.tb10111.x.
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.
缺血及相关损伤所致的神经损伤被认为涉及兴奋性氨基酸在N-甲基-D-天冬氨酸受体上的作用，这会导致细胞外Ca2+内流并产生一氧化氮。由于乙醇会抑制对兴奋性氨基酸的生理反应，我们研究了其对由N-甲基-D-天冬氨酸和一氧化氮供体硝普钠在从大鼠大脑皮层制备的富含神经元的培养物中诱导的毒性的影响。通过乳酸脱氢酶的释放和细胞活力的微荧光测定来衡量，N-甲基-D-天冬氨酸和硝普钠均具有细胞毒性。乙醇（3 - 1000 mM）可保护培养物免受N-甲基-D-天冬氨酸的毒性影响，但不能保护其免受硝普钠的毒性影响，并且一系列正构烷醇重现乙醇作用的能力与碳链长度有关。乙醇的神经保护作用伴随着N-甲基-D-天冬氨酸诱发的细胞内游离Ca2+升高的降低，并且似乎不涉及γ-氨基丁酸或环鸟苷酸介导的机制。这些发现表明，乙醇可能通过减少Ca2+内流，而非通过干扰一氧化氮的作用，在N-甲基-D-天冬氨酸信号通路的早期阶段抑制兴奋性毒性。
