Tetramethylpyrazine Analogue CXC195 Protects Against Dopaminergic Neuronal Apoptosis via Activation of PI3K/Akt/GSK3β Signaling Pathway in 6-OHDA- Induced Parkinson's Disease Mice
Tetramethylpyrazine Analogue CXC195 Protects Against Dopaminergic Neuronal Apoptosis via Activation of PI3K/Akt/GSK3β Signaling Pathway in 6-OHDA- Induced Parkinson's Disease Mice
复制标题
四甲基吡嗪类似物 CXC195 通过激活 6-OHDA 诱导的帕金森病小鼠中的 PI3K/Akt/GSK3 beta 信号通路来防止多巴胺能神经元凋亡
DOI：
10.1007/s11064-016-2148-x
复制
发表时间：
2017-04-01
影响因子：
4.4
通讯作者：
Liu, Huiqing
中科院分区：
文献类型：
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作者：
Chen, Lin;Cheng, Li;Liu, Huiqing
帕金森病（Parkinson's disease，PD）是一种进行性神经退行性疾病，以运动系统障碍为特征，导致多巴胺能（dopaminergic，DA）神经元丢失。CXC 195是一种新型的川芎嗪衍生物，由于其抗凋亡活性而显示出最强的神经保护作用。然而，CXC 195是否保护PD中的DA神经元损伤及其有益作用的机制尚不清楚。我们研究的目的是探讨CXC 195的潜在神经保护作用，并阐明其对6-羟基多巴胺（6-OHDA）诱导的PD小鼠模型的作用机制。CXC 195给药改善了由6-OHDA诱导的PD小鼠中的DA神经变性。我们进一步的研究结果证实，CXC 195在10 mg/ kg剂量下的治疗通过降低6-OHDA损伤小鼠中切割的caspase-3和Bax的水平以及增加Bcl-2的水平来显著抑制细胞凋亡。同时，6-OHDA还降低了磷酸化Akt的量，同时增加了GSK-3 β活性（Ser 9处磷酸化GSK-3 β的量降低），这被CXC 195阻止。一种特异性PI 3 K抑制剂Wortmannin显著地消除了CXC 195引起的变化。我们的研究首次证实CXC 195通过其抗凋亡作用对6-OHDA诱导的PD模型的DA神经元变性具有保护作用，PI 3 K/ Akt/GSK 3 β信号通路参与了CXC 195的保护作用。
Parkinson's disease (PD) is a progressive neurodegenerative disorder and characterized by motor system disorders resulting in loss of dopaminergic (DA) neurons. CXC195, a novel tetramethylpyrazine derivative, has been shown strongest neuroprotective effects due to its antiapoptotic activity. However, whether CXC195 protects against DA neuronal damage in PD and the mechanisms underlying its beneficial effects are unknown. The purpose of our study was to investigate the potential neuroprotective role of CXC195 and to elucidate its mechanism of action against 6-hydroxydopamine (6-OHDA)-induced mouse model of PD. CXC195 administration improved DA neurodegeneration in PD mice induced by 6-OHDA. Our further findings confirmed treatment of CXC195 at the dose of 10 mg/ kg significantly inhibited the apoptosis by decreasing the level of cleaved caspase-3 and Bax, and increasing the level of Bcl-2 in 6-OHDA-lesioned mice. Meanwhile, 6-OHDA also decreased the amount of phosphorylated Akt while increased GSK-3 beta activity (the amount of phosphorylated GSK-3 beta at Ser9 was decreased) which was prevented by CXC195. Wortmannin, a specific PI3K inhibitor, dramatically abolished the changes induced by CXC195. Our study firstly demonstrated that CXC195 protected against DA neurodegeneration in 6-OHDA-induced PD model by its anti-apoptotic properties and PI3K/ Akt/ GSK3 beta signaling pathway was involved in it.