Takeuchi Hiroki, Yanagida Takashi, Inden Masatoshi, Takata Kazuyuki, Kitamura Yoshihisa, Yamakawa Kentaro, Sawada Hideyuki, Izumi Yasuhiko, Yamamoto Noriyuki, Kihara Takeshi, Uemura Kengo, Inoue Haruhisa, Taniguchi Takashi, Akaike Akinori, Takahashi Ryosuke, Shimohama Shun
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
J Neurosci Res. 2009 Feb;87(2):576-85. doi: 10.1002/jnr.21869.
Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic (DA) neuronal cell loss in the substantia nigra. Although the entire pathogenesis of PD is still unclear, both environmental and genetic factors contribute to neurodegeneration. Epidemiologic studies show that prevalence of PD is lower in smokers than in nonsmokers. Nicotine, a releaser of dopamine from DA neurons, is one of the candidates of antiparkinson agents in tobacco. To assess the protective effect of nicotine against rotenone-induced DA neuronal cell toxicity, we examined the neuroprotective effects of nicotine in rotenone-induced PD models in vivo and in vitro. We observed that simultaneous subcutaneous administration of nicotine inhibited both motor deficits and DA neuronal cell loss in the substantia nigra of rotenone-treated mice. Next, we analyzed the molecular mechanisms of DA neuroprotective effect of nicotine against rotenone-induced toxicity with primary DA neuronal culture. We found that DA neuroprotective effects of nicotine were inhibited by dihydro-beta-erythroidine (DHbetaE), alpha-bungarotoxin (alphaBuTx), and/or PI3K-Akt/PKB (protein serine/threonine kinase B) inhibitors, demonstrating that rotenone-toxicity on DA neurons are inhibited via activation of alpha4beta2 or alpha7 nAChRs-PI3K-Akt/PKB pathway or pathways. These results suggest that the rotenone mouse model may be useful for assessing candidate antiparkinson agents, and that nAChR (nicotinic acetylcholine receptor) stimulation can protect DA neurons against degeneration.
帕金森病（PD）是第二常见的神经退行性疾病，其特征是黑质中多巴胺能（DA）神经元细胞丢失。尽管PD的整个发病机制仍不清楚，但环境和遗传因素均导致神经退行性变。流行病学研究表明，吸烟者中PD的患病率低于不吸烟者。尼古丁是一种从DA神经元释放多巴胺的物质，是烟草中抗帕金森病药物的候选物质之一。为了评估尼古丁对鱼藤酮诱导的DA神经元细胞毒性的保护作用，我们在体内和体外鱼藤酮诱导的PD模型中研究了尼古丁的神经保护作用。我们观察到，同时皮下注射尼古丁可抑制鱼藤酮处理小鼠黑质中的运动功能障碍和DA神经元细胞丢失。接下来，我们用原代DA神经元培养分析了尼古丁对鱼藤酮诱导毒性的DA神经保护作用的分子机制。我们发现，尼古丁的DA神经保护作用被二氢-β-刺桐啶（DHbetaE）、α-银环蛇毒素（αBuTx）和/或PI3K-Akt/PKB（蛋白丝氨酸/苏氨酸激酶B）抑制剂抑制，表明鱼藤酮对DA神经元的毒性是通过α4β2或α7烟碱型乙酰胆碱受体（nAChRs）-PI3K-Akt/PKB途径或多条途径的激活而被抑制。这些结果表明，鱼藤酮小鼠模型可能有助于评估抗帕金森病候选药物，并且nAChR刺激可以保护DA神经元免于退变。
