Neuroprotection against 1-Methyl-4-phenylpyridinium-induced cytotoxicity by naturally occurring polydatin through activation of transcription factor MEF2D
Neuroprotection against 1-Methyl-4-phenylpyridinium-induced cytotoxicity by naturally occurring polydatin through activation of transcription factor MEF2D
复制标题
天然存在的虎杖甙通过激活转录因子 MEF2D 对 1-甲基-4-苯基吡啶鎓诱导的细胞毒性具有神经保护作用
DOI：
10.1097/wnr.0000000000001696
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发表时间：
2021-08-11
期刊：
影响因子：
1.7
通讯作者：
Zhang, Zaijun
中科院分区：
文献类型：
--
作者：
Cao, Jie;Guo, Baojian;Zhang, Zaijun
虎杖苷是虎杖的主要活性成分。et Zucc.最近的一项研究表明，白藜芦醇苷可以防止黑质多巴胺能变性与帕金森病相关的啮齿动物模型。然而，虎杖苷的神经保护机制尚未完全阐明。在目前的研究中，虎杖苷的神经保护作用和详细的作用机制进行了研究，在帕金森病相关的细胞模型。虎杖苷剂量和时间依赖性地防止1-甲基-4-苯基吡啶离子（MPP+）引起的原代小脑颗粒神经元的神经毒性。此外，我们发现虎杖苷增强了转录因子肌细胞增强因子2D（MEF 2D）在基础和病理条件下使用荧光素酶报告基因测定的活性。此外，蛋白质印迹分析显示，虎杖苷可以下调糖原合成酶激酶3 β（GSK 3 β），这是MEF2D的负调控因子。分子对接模拟最终表明虎杖苷和GSK3 β内的疏水口袋之间的相互作用。以上结果提示，虎杖苷通过抑制GSK 3 β，增强MEF 2D，预防MPP+诱导的神经毒性，值得进一步开展抗帕金森病的研究。
Polydatin is the major active ingredient of Polygonum cuspidatum Sieb. Et Zucc. A recent study indicated that polydatin could protect against substantia nigra dopaminergic degeneration in rodent models associated with Parkinson's disease. However, mechanisms that underlie the neuroprotection of polydatin have not been fully elucidated. In the current study, the neuroprotective effects and detailed mechanisms of action of polydatin were investigated in Parkinson's disease-related cellular models. Polydatin dose- and time-dependently prevented neurotoxicity caused by 1-methyl-4-phenylpyridinium ion (MPP+) in primary cerebellar granule neurons. Moreover, we found that polydatin enhanced the activity of the transcription factor myocyte enhancer factor 2D (MEF2D) at both basal and pathological conditions using luciferase reporter gene assay. Additionally, western blot analysis revealed that polydatin could downregulate glycogen synthase kinase 3 beta (GSK3 beta), which is a negative regulator of MEF2D. Molecular docking simulations finally suggested an interaction between polydatin and a hydrophobic pocket within GSK3 beta. All these results suggest that polydatin prevents MPP+-induced neurotoxicity via enhancing MEF2D through the inhibition of GSK3 beta and that treatment with polydatin is worthy of further anti-Parkinson's disease study in future.