Roflupram exerts neuroprotection via activation of CREB/PGC-1 alpha signalling in experimental models of Parkinson's disease
Roflupram exerts neuroprotection via activation of CREB/PGC-1 alpha signalling in experimental models of Parkinson's disease
复制标题
Roflupram 在帕金森病实验模型中通过激活 CREB/PGC-1 α 信号传导发挥神经保护作用
DOI：
10.1111/bph.14983
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发表时间：
2020
影响因子：
7.3
通讯作者：
Wang Haitao
中科院分区：
文献类型：
--
作者：
Zhong Jiahong;Dong Wenli;Qin Yunyun;Xie Jinfeng;Xiao Jiao;Xu Jiangping;Wang Haitao
背景和目的罗氟普兰能改善认知功能，抑制脑内神经炎症。然而，罗氟普兰对帕金森病（PD）的有益作用仍然未知。因此，我们的目的是阐明ROF在PD实验模型中的药理作用和作用机制。实验方法我们使用了暴露于1-甲基-4-苯基碘化吡啶（MPP+）的SH-SY 5 Y细胞的体外PD模型。通过MTT法和流式细胞术分析细胞活力和凋亡。通过线粒体追踪器、Seahorse分析仪和MitoSOX‐Red染料测量线粒体形态、线粒体呼吸能力和ROS。对于体内PD模型，使用行为测试、尼氏染色和免疫组织化学来评价罗氟普兰的保护作用。通过Western blotting分析TH、cAMP反应元件结合蛋白（CREB）和PPARγ共激活因子-1 α（PGC-1α）的水平。Key ResultsRoflupram减少MPP+诱导的SH-SY 5 Y细胞和人多巴胺能神经元的凋亡。罗氟普兰还增加线粒体呼吸能力，减少ROS产生，并恢复线粒体形态。罗氟普兰逆转MPP+诱导的磷酸化CREB、PGC-1α和TH的减少。这些保护作用被PKA抑制剂H-89或PGC-1α siRNA阻断。在用MPTP治疗的小鼠中，罗氟普兰显著改善了运动功能。结论：罗氟普仑通过CREB/PGC-1α通路保护PD模型多巴胺能神经元，抑制其凋亡。因此，罗氟普兰具有作为PD治疗中的保护性药物的潜力。
Background and PurposeRoflupram improves cognition and limits neuroinflammation in the brain. However, the beneficial effects of roflupram on Parkinson's disease (PD) remain unknown. Therefore, we aimed to elucidate the pharmacological effects and mechanisms of action of ROF in experimental models of PD.Experimental ApproachWe used an in vitro PD model of SH‐SY5Y cells exposed to 1‐methyl‐4‐phenylpyridinium iodide (MPP+). Cell viability and apoptosis were analysed via the MTT assay and flow cytometry. Mitochondrial morphology, mitochondrial respiratory capacity, and ROS were measured by a mitochondrial tracker, Seahorse Analyzer, and a MitoSOX‐Red dye. For in vivo PD model, behavioural tests, Nissl staining, and immunohistochemistry were used to evaluate protection by roflupram. The levels of TH, cAMP response element‐binding protein (CREB), and PPARγ coactivator‐1α (PGC‐1α) were analysed by western blotting.Key ResultsRoflupram decreased MPP+‐induced apoptosis in SH‐SY5Y cells and human dopaminergic neurons. Roflupram also increased mitochondrial respiratory capacity, decreased ROS production, and restored mitochondrial morphology. Roflupram reversed the MPP+‐induced reductions of phosphorylated CREB, PGC‐1α and TH. These protective effects were blocked by the PKA inhibitor H‐89 or by PGC‐1α siRNA. In mice treated with MPTP, roflupram significantly improved motor functions. Roflupram prevented both dopaminergic neuronal loss and the reduction of phosphorylated CREB and PGC‐1α in the substantia nigra and striatum.Conclusion and ImplicationsRoflupram protected dopaminergic neurons from apoptosis via the CREB/PGC‐1α pathway in PD models. Hence, roflupram has potential as a protective drug in the treatment of PD.