Mechanisms of Neuroprotective Effects of Nicotine and Acetylcholinesterase Inhibitors: Role of α4 and α7 Receptors in Neuroprotection
Mechanisms of Neuroprotective Effects of Nicotine and Acetylcholinesterase Inhibitors: Role of α4 and α7 Receptors in Neuroprotection
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DOI：
10.1007/s12031-009-9236-1
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发表时间：
2010-01-01
影响因子：
3.1
通讯作者：
Izumi, Yasuhiko
中科院分区：
文献类型：
--
作者：
Akaike, Akinori;Takada-Takatori, Yuki;Izumi, Yasuhiko
谷氨酸和其他兴奋性氨基酸诱导的神经毒性与多种神经退行性疾病有关，包括缺氧缺血性事件、创伤、阿尔茨海默病和帕金森病。我们研究了烟碱乙酰胆碱受体（nAChRs）在兴奋性毒性事件中中枢神经系统神经元存活中的作用。尼古丁和其他尼古丁受体激动剂通过α 4和α 7 nachr保护皮层神经元免受谷氨酸神经毒性，至少部分是通过抑制胚胎大鼠大脑皮层近纯神经元培养物的凋亡过程。多奈哌齐、加那他明和他克林，这些治疗性乙酰胆碱酯酶（AChE）抑制剂目前被用于治疗阿尔茨海默病，也可以保护神经细胞免受谷氨酸神经毒性的影响。尼古丁和AChE抑制剂的保护作用被nAChR拮抗剂所拮抗。此外，尼古丁和这些乙酰胆碱酯酶抑制剂诱导nachr上调。非受体型酪氨酸激酶Fyn和双活化激酶2的抑制剂抑制了多奈哌齐和加兰他明的神经保护作用。此外，磷脂酰肌醇3-激酶（PI3K）抑制剂也抑制了AChE抑制剂的神经保护作用。多奈哌齐和加兰他明处理后，PI3K的效应因子Akt的磷酸化和抗凋亡蛋白Bcl-2的表达水平升高。这些结果表明，尼古丁以及乙酰胆碱酯酶抑制剂多奈哌齐和加兰他明通过α 4和α 7 nachr和PI3K-Akt通路预防谷氨酸神经毒性。
Neurotoxicity induced by glutamate and other excitatory amino acids has been implicated in various neurodegenerative disorders including hypoxic ischemic events, trauma, and Alzheimer's and Parkinson's diseases. We examined the roles of nicotinic acetylcholine receptors (nAChRs) in survival of CNS neurons during excitotoxic events. Nicotine as well as other nicotinic receptor agonists protected cortical neurons against glutamate neurotoxicity via alpha 4 and alpha 7 nAChRs at least partly by inhibiting the process of apoptosis in near-pure neuronal cultures obtained from the cerebral cortex of fetal rats. Donepezil, galanatamine and tacrine, therapeutic acetylcholinesterase (AChE) inhibitors currently being used for treatment of Alzheimer's disease also protected neuronal cells from glutamate neurotoxicity. Protective effects of nicotine and the AChE inhibitors were antagonized by nAChR antagonists. Moreover, nicotine and those AChE inhibitors induced up-regulation of nAChRs. Inhibitors for a non-receptor-type tyrosine kinase, Fyn, and janus-activated kinase 2, suppressed the neuroprotective effect of donepezil and galantamine. Furthermore, a phosphatidylinositol 3-kinase (PI3K) inhibitor also suppressed the neuroprotective effect of the AChE inhibitors. The phosphorylation of Akt, an effector of PI3K, and the expression level of Bcl-2, an anti-apoptotic protein, increased with donepezil and galantamine treatments. These results suggest that nicotine as well as AChE inhibitors, donepezil and galantamine, prevent glutamate neurotoxicity through alpha 4 and alpha 7 nAChRs and the PI3K-Akt pathway.