Takada-Takatori Yuki, Kume Toshiaki, Izumi Yasuhiko, Ohgi Yuta, Niidome Tetsuhiro, Fujii Takeshi, Sugimoto Hachiro, Akaike Akinori
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women's College, Kyoto, Japan.
Biol Pharm Bull. 2009 Mar;32(3):318-24. doi: 10.1248/bpb.32.318.
Protection of neurons from neuronal damage and cell death in neurodegenerative disease is a major challenge in neuroscience research. Donepezil, galantamine and tacrine are acetylcholinesterase inhibitors used for the treatment of Alzheimer's disease, and were believed to be symptomatic drugs whose therapeutic effects are achieved by slowing the hydrolysis of acetylcholine at synaptic termini. However, recent accumulated evidence strongly suggests that these acetylcholinesterase inhibitors also possess neuroprotective properties whose mechanism is independent of acetylcholinesterase inhibition. We have shown that acetylcholinesterase inhibitors protect neurons from glutamate-induced neurotoxicity in the primary culture of rat cortical neurons. It was also found that acetylcholinesterase inhibitor treatment induces up-regulation of nicotinic receptor expression levels, a property which may also have some bearing on their therapeutic effects. We next showed that alpha4 and alpha7-nicotinic receptors play important roles in acetylcholinesterase inhibitor-induced neuroprotection and nicotinic receptor up-regulation. Our results also demonstrate the important roles of the phosphatidylinositol 3-kinase pathway downstream of nicotinic receptors in protecting neurons from death and up-regulating nicotinic receptors. This review summarizes recent findings on the roles of the nicotinic receptor in acetylcholinesterase inhibitor-induced neuroprotection and nicotinic receptor up-regulation.
在神经科学研究中，保护神经元免受神经退行性疾病中的神经元损伤和细胞死亡是一项重大挑战。多奈哌齐、加兰他敏和他克林是用于治疗阿尔茨海默病的乙酰胆碱酯酶抑制剂，被认为是对症药物，其治疗效果是通过减缓突触末端乙酰胆碱的水解来实现的。然而，最近积累的证据强烈表明，这些乙酰胆碱酯酶抑制剂还具有神经保护特性，其机制独立于乙酰胆碱酯酶抑制作用。我们已经表明，乙酰胆碱酯酶抑制剂在大鼠皮质神经元原代培养中可保护神经元免受谷氨酸诱导的神经毒性。还发现乙酰胆碱酯酶抑制剂治疗可诱导烟碱受体表达水平上调，这一特性可能也与其治疗效果有关。接下来我们表明，α4和α7烟碱受体在乙酰胆碱酯酶抑制剂诱导的神经保护和烟碱受体上调中起重要作用。我们的结果还证明了烟碱受体下游的磷脂酰肌醇3激酶途径在保护神经元免于死亡和上调烟碱受体方面的重要作用。本综述总结了关于烟碱受体在乙酰胆碱酯酶抑制剂诱导的神经保护和烟碱受体上调中的作用的最新发现。
