Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade
Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade
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DOI：
10.1016/j.neuropharm.2006.04.007
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发表时间：
2006-09-01
影响因子：
4.7
通讯作者：
Akaike, Akinori
中科院分区：
文献类型：
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作者：
Takada-Takatori, Yuki;Kume, Toshiaki;Akaike, Akinori
我们在这里展示了目前用于治疗阿尔茨海默病的治疗性乙酰胆碱酯酶抑制剂多奈哌齐、加兰他明和他克林，以时间和浓度依赖的方式保护神经细胞免受涉及细胞凋亡的谷氨酸神经毒性。这种神经保护作用可被烟碱型乙酰胆碱受体(NAChRs)抑制剂甲氨基甲胺所拮抗。α4-NAM和α7-NAM的拮抗剂二氢β-乙二胺和甲基乌头碱分别拮抗多奈哌齐和加兰他明的保护作用，但不能拮抗他克林的保护作用。以往的报道表明，磷脂酰肌醇3-激酶(PI3K)-Akt通路参与了尼古丁诱导的神经保护。非受体类型酪氨酸激酶的抑制剂Fyn和Janus激活的激酶2抑制了多奈哌齐和加兰他明的神经保护作用，但不抑制他克林的神经保护作用。此外，PI3K抑制剂LY294002也可抑制多奈哌齐和加兰他明的神经保护作用，但不能抑制他克林的神经保护作用。多奈哌齐和加兰他敏处理后，PI3K的效应蛋白Akt的磷酸化水平和抗凋亡蛋白Bcl2的表达水平均增加，但他克林的作用不明显。这些结果表明，多奈哌齐和加兰他明通过α4和α7-nAChRs，然后是PI3K-Akt途径来预防谷氨酸的神经毒性，而他克林通过不同的途径保护神经细胞。(C)2006爱思唯尔有限公司。保留所有权利。
We show here that donepezil, galanathamine and tacrine, therapeutic acetyleholinesterase inhibitors currently being used for treatment of Alzheimer's disease, protect neuronal cells in a time- and concentration-dependent manner from glutamate neurotoxicity that involves apoptosis. The neuroprotective effects were antagonized by mecamylamine, an inhibitor of nicotinic acetylcholine receptors (nAChRs). Dihydro-beta-erythroidine and methyllycaconitine, antagonists for alpha 4-nAM and alpha 7-nAM, respectively, antagonized the protective effect of donepezil and galanthamine, but not that of tacrine. Previous reports suggest the involvement of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway in the nicotine-induced neuroprotection. Inhibitors for a non-receptor type tyrosine kinase, Fyn, and janus-activated kinase 2, suppressed the neuroprotective effect of donepezil and galanthamine, but not that of tacrine. Furthermore, LY294002, a PI3K inhibitor, also suppressed the neuroprotective effect of donepezil and galanthamine, but not that of tacrine. The phosphoryiation of Akt, an effector of PI3K, and the expression level of Bcl-2, an anti-apoptotic protein, increased with donepezil and galanthamine treatment, but not with tacrine treatment. These results suggest that donepezil and galanthamine prevent glutamate neurotoxicity through alpha 4- and alpha 7-nAChRs, followed by the PI3K-Akt pathway, and that tacrine protects neuronal cells through a different pathway. (c) 2006 Elsevier Ltd. All rights reserved.