白藜芦醇通过SIRT1/AMPK信号通路减轻MPTP诱导的小鼠多巴胺能神经元丢失

Neuroprotective effect of resveratrol against MPTP-induced dopaminergic neuronal loss via the SIRT1 / AMPK signaling pathway in mice

目的观察白藜芦醇(RV)对帕金森病(PD)小鼠的神经保护作用,并探索其发挥神经保护作用的可能机制。方法将48只小鼠随机分为CON组、MPTP组、RV+MPTP组和EX527+RV+MPTP组,每组12只。腹腔注射MPTP建立PD小鼠模型,并给予RV灌胃、SIRT1特异性抑制剂EX257腹腔注射处理,利用免疫荧光、western blot等检测相关蛋白表达。结果给予RV后,与MPTP组相比,RV+MPTP组SIRT1蛋白表达显著增加(P<0.001),p-AMPK蛋白水平显著升高(P<0.01),Cleaved caspase 3蛋白水平显著下降(P<0.01),小鼠黑质区TH阳性神经元丢失率明显降低,纹状体组织中TH蛋白表达显著增加(P<0.01)。给予EX527后,阻断了RV的上述作用,p-AMPK蛋白水平显著降低(P<0.01),Cleaved caspase 3显著升高(P<0.01),小鼠黑质区TH阳性神经元丢失率明显升高,纹状体组织中TH蛋白表达显著下降(P<0.001)。结论 RV可能通过激活SIRT1/AMPK信号通路,SIRT1与AMPK相互调控,减少MPTP小鼠黑质区多巴胺能神经元丢失。

Objective To investigate the neuroprotective effect of resveratrol（ RV） in mice with Parkinson＇s disease（ PD） and its possible mechanisms. Methods A total of 48 mice were divided into CON group,MPTP group,RV ＋ MPTP group,and EX527 ＋ RV＋ MPTP group,with 12 mice in each group. Intraperitoneal injection of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine（ MPTP） was used to establish the mouse model of PD,and RV gavage and intraperitoneal injection of the silent information regulation 2 homolog 1（ SIRT1） specific inhibitor EX527 were given. Immunofluorescence assay and Western blot were performed to measure the expression of related proteins. Results After administration of RV,compared with the MPTP group,the RV ＋ MPTP group showed significantly increased protein expression of SIRT1 and p-AMP-activated protein kinase（ AMPK）,significantly reduced protein expression of cleaved caspase 3,significantly reduced TH-positive neuronal loss in the substantia nigra,and significantly increased expression of TH protein（ all P 0. 01）. The administration of EX527 inhibited the above effects of RV and caused a significant reduction in the protein expression of p-AMPK（ P 0. 01）,as well as significantly increased protein expression of cleaved caspase 3（ P 0. 01）,significantly increased TH-positive neuronal loss in the substantia nigra,and significantly reduced expression of TH protein（ P 0. 001）. Conclusions RV can activate the SIRT1 / AMPK signaling pathway,regulate SIRT1 and AMPK,and thus reduce dopaminergic neuronal loss in the substantia nigra of mice treated with MPTP.