Davenport C J, Monyer H, Choi D W
Department of Neurology, Stanford University Medical Center, CA 94305.
Eur J Pharmacol. 1988 Sep 1;154(1):73-8. doi: 10.1016/0014-2999(88)90365-2.
Addition of the acetylcholinesterase inhibitor 1,2,3,4-tetra-9-hydroaminoacridine (THA) at 1-3 mM markedly reduced the neuronal cell loss that otherwise followed brief exposure of murine cortical cell cultures to 500 microM N-methyl-D-aspartate (NMDA). This novel antagonism was selective for NMDA receptor-mediated toxicity, as it extended to glutamate toxicity but not to quisqualate toxicity, and was THA concentration-dependent between 100 microM and 3 mM, with IC50 approximately 500 microM. The antagonism was probably not due to enhancement of endogenous cholinergic action, as it was not mimicked by acetylcholine, carbachol, or bethanechol; rather, it likely reflected a recently described interaction of THA with the phencyclidine receptor. Exploration of structural specificity revealed some partial neuron-protection with high concentrations of other cholinesterase inhibitors--physostigmine, neostigmine, and edrophonium, but not the structurally related potassium channel blocker, 4-aminopyridine. Further examination of correlations between THA-like structure, and neuron-protective activity, may provide useful insights in the development of new antagonists of NMDA receptor-mediated neurotoxicity.
在小鼠皮质细胞培养物短暂暴露于500微摩尔N-甲基-D-天冬氨酸（NMDA）后，添加1至3毫摩尔的乙酰胆碱酯酶抑制剂1,2,3,4-四-9-氢氨基吖啶（THA）可显著减少神经元细胞损失。这种新型拮抗作用对NMDA受体介导的毒性具有选择性，因为它扩展至谷氨酸毒性，但对喹啉酸毒性无效，并且在100微摩尔至3毫摩尔之间呈THA浓度依赖性，IC50约为500微摩尔。这种拮抗作用可能不是由于内源性胆碱能作用增强，因为乙酰胆碱、卡巴胆碱或贝胆碱无法模拟这种作用；相反，它可能反映了最近描述的THA与苯环利定受体的相互作用。对结构特异性的探索发现，高浓度的其他胆碱酯酶抑制剂——毒扁豆碱、新斯的明和依酚氯铵具有一定的部分神经元保护作用，但结构相关的钾通道阻滞剂4-氨基吡啶则没有。进一步研究THA样结构与神经元保护活性之间的相关性，可能为开发新的NMDA受体介导的神经毒性拮抗剂提供有用的见解。
