Wang Wenya, Yang Yi, Ying Chunyi, Li Wenming, Ruan Haolan, Zhu Xiaonan, You Yan, Han Yifan, Chen Ruzhu, Wang Yizheng, Li Mingtao
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Neuropharmacology. 2007 Jun;52(8):1678-84. doi: 10.1016/j.neuropharm.2007.03.017. Epub 2007 Apr 19.
Glycogen synthase kinase-3beta (GSK-3beta) is closely involved in neuronal apoptosis and pathogenesis of many neurodegenerative diseases, such as Alzheimer's disease. However, whether GSK-3beta mediates apoptosis of dopaminergic neurons in Parkinson's disease remains elusive. In this study, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism models, we investigated whether MPTP induces apoptosis of dopaminergic neurons through a GSK-3beta-dependent pathway. MPTP caused a rapid activation of GSK-3beta, evidenced by the decrease in level of phospho-Ser9 of GSK-3beta and the increase in level of phospho-Ser396 of tau, a known GSK-3beta substrate. Blockage of GSK-3beta activity by its two specific inhibitors, indirubin-3'-oxime and AR-A014418, prevented dopaminergic neurons from MPTP-induced apoptosis. Additionally, inhibition of GSK-3beta activity restored the depletion of striatal dopamine and ameliorated behavioral impairments caused by MPTP. These results indicate that GSK-3beta is a critical intermediate of MPTP neurotoxicity, and inhibition of GSK-3beta may provide a novel strategy to treat Parkinson's disease.
糖原合酶激酶-3β（GSK-3β）与神经元凋亡以及许多神经退行性疾病（如阿尔茨海默病）的发病机制密切相关。然而，GSK-3β是否介导帕金森病中多巴胺能神经元的凋亡仍不清楚。在本研究中，我们使用1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的帕金森病模型，研究MPTP是否通过GSK-3β依赖性途径诱导多巴胺能神经元凋亡。MPTP导致GSK-3β快速激活，这可通过GSK-3β磷酸化Ser9水平降低以及已知的GSK-3β底物tau的磷酸化Ser396水平升高得到证明。其两种特异性抑制剂靛玉红-3'-肟和AR-A014418对GSK-3β活性的阻断，可防止多巴胺能神经元发生MPTP诱导的凋亡。此外，抑制GSK-3β活性可恢复纹状体多巴胺的耗竭，并改善MPTP引起的行为障碍。这些结果表明，GSK-3β是MPTP神经毒性的关键中间体，抑制GSK-3β可能为治疗帕金森病提供一种新策略。
