Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan.
J Pharmacol Sci. 2010;112(3):327-35. doi: 10.1254/jphs.09302fp. Epub 2010 Mar 2.
Although a blockade of acetylcholine esterase has been reported to suppress neuronal cell death induced by exogenous glutamate and beta-amyloid, information is still limited regarding the neuroprotective effects of the acetylcholine esterase inhibitor donepezil. We histologically examined the effects of donepezil on neuronal injury induced by ischemia-reperfusion. Intravenous and intravitreous treatment with donepezil 15 min prior to ischemia dramatically reduced the retinal damage. The protective effect of donepezil in the ganglion cell layer was not affected by mecamylamine, a nicotinic acetylcholine-receptor antagonist, nor scopolamine, a muscarinic acetylcholine-receptor antagonist. The protective effect of donepezil in the inner plexiform layer was reduced not by mecamylamine, but by scopolamine. Neostigmine, a choline-esterase inhibitor, and pilocarpine, a muscarinic acetylcholine-receptor agonist, have protective effects in the inner plexiform layer and the inner nuclear layer. These results suggest that not only the activation of acetylcholine receptors but also a mechanism unrelated to acetylcholine-esterase inhibition contribute to the protective effect of donepezil on the ganglion cells in the ischemic-reperfused rat retina. Donepezil may be useful as a therapeutic drug against retinal diseases that cause neuronal cell death such as glaucoma with high intraocular pressure.
虽然已有报道称乙酰胆碱酯酶抑制剂能抑制外源性谷氨酸和β-淀粉样蛋白诱导的神经元细胞死亡，但关于乙酰胆碱酯酶抑制剂多奈哌齐的神经保护作用的信息仍然有限。我们通过组织学方法研究了多奈哌齐对缺血再灌注诱导的神经元损伤的影响。缺血前 15 分钟静脉和玻璃体内给予多奈哌齐可显著减轻视网膜损伤。烟碱型乙酰胆碱受体拮抗剂美金刚和毒蕈碱型乙酰胆碱受体拮抗剂东莨菪碱对多奈哌齐在神经节细胞层的保护作用无影响。多奈哌齐对内丛状层的保护作用不受美金刚的影响，但受东莨菪碱的影响。胆碱酯酶抑制剂新斯的明和毒蕈碱型乙酰胆碱受体激动剂毛果芸香碱对内丛状层和内核层均有保护作用。这些结果表明，多奈哌齐对缺血再灌注大鼠视网膜神经节细胞的保护作用不仅与乙酰胆碱受体的激活有关，而且与乙酰胆碱酯酶抑制无关的机制也有关。多奈哌齐可能对治疗青光眼等引起神经元细胞死亡的眼部疾病有用，这些疾病与高眼压有关。
