Nicotinic Receptor Stimulation Protects Nigral Dopaminergic Neurons in Rotenone-induced Parkinson's Disease Models
Nicotinic Receptor Stimulation Protects Nigral Dopaminergic Neurons in Rotenone-induced Parkinson's Disease Models
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DOI：
10.1002/jnr.21869
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发表时间：
2009-02-01
影响因子：
4.2
通讯作者：
Shimohama, Shun
中科院分区：
文献类型：
--
作者：
Takeuchi, Hiroki;Yanagida, Takashi;Shimohama, Shun
帕金森病（PD）是第二常见的神经退行性疾病，其特征在于黑质中的多巴胺能（DA）神经元细胞损失。虽然PD的整个发病机制尚不清楚，但环境和遗传因素都有助于神经退行性变。流行病学研究表明，吸烟者的PD患病率低于非吸烟者。尼古丁是DA能神经元释放多巴胺的一种物质，是烟草中抗帕金森病药物的候选者之一。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，我们在体内和体外研究了尼古丁在鱼藤酮诱导的PD模型中的神经保护作用。我们观察到，同时皮下注射尼古丁抑制运动缺陷和DA神经元细胞的损失，在黑质的罗丹酮治疗的小鼠。接下来，我们用原代培养的DA神经元分析了尼古丁对鱼藤酮诱导的DA神经元毒性的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-赤藓糖醇（DH β E）、α-银环蛇毒素（α-BuTx）和/或PI 3 K-Akt/PK B（蛋白丝氨酸/苏氨酸激酶B）抑制剂抑制，表明鱼藤酮对DA神经元的毒性通过激活α 4 β 2或α 7 nAChRs-PI 3 K-Akt/PK B通路而被抑制。这些结果表明，鱼藤酮小鼠模型可能是有用的候选抗帕金森病药物的评估，和nAChR（烟碱乙酰胆碱受体）刺激可以保护DA神经元的变性。(C)2008 Wiley-Liss，Inc.
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 rote none-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 (DH beta E), alpha-bungarotoxin (alpha BuTx), and/or PI3K-Akt/PKB (protein serine/threonine kinase B) inhibitors demonstrating that rotenone-toxicity on DA neuron's are inhibited via activation of alpha 4 beta 2 or alpha 7 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. (C) 2008 Wiley-Liss, Inc.