Hoffman P L, Iorio K R, Snell L D, Tabakoff B
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA.
Alcohol Clin Exp Res. 1995 Jun;19(3):721-6. doi: 10.1111/j.1530-0277.1995.tb01573.x.
Ethanol, acutely, is a potent inhibitor of the function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. After chronic exposure of animals to ethanol, however, the NMDA receptor in brain is upregulated. This upregulation is associated with the occurrence of ethanol withdrawal seizures. When cultured cerebellar granule neurons are exposed chronically to ethanol, the resulting upregulation of NMDA receptor function renders the cells more susceptible to glutamate-induced neurotoxicity. The present studies show that chronic ethanol exposure produces an increase in NMDA receptor number in the cells, measured by ligand binding to intact cells. Glutamate-induced excitotoxicity, both in control and ethanol-exposed cells, is blocked by the same NMDA receptor antagonists previously shown to block ethanol withdrawal seizures in animals. In addition, glutamate neurotoxicity is blocked by acute (2-hr) pretreatment of cells with ganglioside GM1 or by chronic (3 days) treatment with the ganglioside. Acute ganglioside treatment does not interfere with the initial rise in intracellular calcium caused by glutamate, whereas this response is downregulated after chronic ganglioside treatment. These results suggest that therapeutic agents can be developed to block both ethanol withdrawal signs and the neuronal damage that accompanies ethanol withdrawal. Furthermore, chronic ganglioside treatment during ethanol exposure has the potential to prevent changes in the NMDA receptor that lead to withdrawal seizures and enhanced susceptibility to excitotoxicity.
乙醇急性作用时，是谷氨酸受体N - 甲基 - D - 天冬氨酸（NMDA）亚型功能的强效抑制剂。然而，动物长期接触乙醇后，脑中的NMDA受体上调。这种上调与乙醇戒断性癫痫发作的发生有关。当培养的小脑颗粒神经元长期暴露于乙醇时，由此导致的NMDA受体功能上调使细胞对谷氨酸诱导的神经毒性更敏感。目前的研究表明，通过配体与完整细胞结合测量，长期乙醇暴露会使细胞中NMDA受体数量增加。在对照细胞和乙醇处理的细胞中，谷氨酸诱导的兴奋毒性都被先前证明可阻断动物乙醇戒断性癫痫发作的相同NMDA受体拮抗剂所阻断。此外，用神经节苷脂GM1对细胞进行急性（2小时）预处理或用神经节苷脂进行慢性（3天）处理可阻断谷氨酸神经毒性。急性神经节苷脂处理不干扰谷氨酸引起的细胞内钙的初始升高，而慢性神经节苷脂处理后这种反应会下调。这些结果表明，可以开发治疗药物来阻断乙醇戒断症状以及伴随乙醇戒断的神经元损伤。此外，在乙醇暴露期间进行慢性神经节苷脂治疗有可能预防导致戒断性癫痫发作和增强对兴奋毒性易感性的NMDA受体变化。
