Department of Neurology, The Sun Yat-sen Memorial Hospital of Sun Yat-sen University, No. 107 Yanjiang West Road, Guangzhou, 510080, Guangdong, China.
Department of Neurology, Shenzhen Nanshan District Xili People's Hospital, No. 2051 Xili Liuxian Avenue, Shenzhen, 518055, China.
Neurochem Res. 2018 Apr;43(4):886-893. doi: 10.1007/s11064-018-2494-y. Epub 2018 Feb 12.
In addition to its original application for treating tuberculosis, rifampicin has multiple potential neuroprotective effects in chronic neurodegenerative diseases including Parkinson's disease (PD) and Alzheimer's disease. Inflammatory reactions and the PI3K/Akt pathway are strongly implicated in dopaminergic neuronal death in PD. This study aims to investigate whether rifampicin protects rotenone-lesioned SH-SY5Y cells via regulating PI3K/Akt/GSK-3β/CREB pathway. Rotenone-treated SH-SY5Y cells were used as the cell model to investigate the neuroprotective effects of rifampicin. Cell viability and apoptosis of SH-SY5Y cells were determined by CCK-8 assay and flow cytometry, respectively. The expression of Akt, p-Akt, GSK-3β, p-GSK-3β, CREB and p-CREB were measured by Western blot. Our results showed that the cell viability and level of phospho-CREB significantly decreased in SH-SY5Y cells exposed to rotenone when compared to the control group. Both the cell viability and the expression of phospho-CREB in cells pretreated with rifampicin were higher than those of cells exposed to rotenone alone. Moreover, pretreatment of SH-SY5Y cells with rifampicin enhanced phosphorylation of Akt and suppressed activity of GSK-3β. The addition of LY294002, a PI3K inhibitor, could suppress phosphorylation of Akt and CREB and activate GSK-3β, resulting in abolishment of neuroprotective effects of rifampicin on cells exposed to rotenone. Rifampicin provides neuroprotection against dopaminergic degeneration, partially via the PI3K/Akt/GSK-3β/CREB signaling pathway. These findings suggest that rifampicin could be an effective and promising neuroprotective candidate for treating PD.
除了最初用于治疗肺结核，利福平在包括帕金森病（PD）和阿尔茨海默病在内的慢性神经退行性疾病中具有多种潜在的神经保护作用。炎症反应和 PI3K/Akt 通路强烈参与 PD 中多巴胺能神经元的死亡。本研究旨在探讨利福平是否通过调节 PI3K/Akt/GSK-3β/CREB 通路来保护鱼藤酮损伤的 SH-SY5Y 细胞。用鱼藤酮处理 SH-SY5Y 细胞作为细胞模型来研究利福平的神经保护作用。通过 CCK-8 测定和流式细胞术分别测定 SH-SY5Y 细胞的活力和凋亡。通过 Western blot 测定 Akt、p-Akt、GSK-3β、p-GSK-3β、CREB 和 p-CREB 的表达。我们的结果表明，与对照组相比，暴露于鱼藤酮的 SH-SY5Y 细胞的细胞活力和磷酸化 CREB 水平显着降低。用利福平预处理的细胞的细胞活力和磷酸化 CREB 的表达均高于单独暴露于鱼藤酮的细胞。此外，利福平预处理 SH-SY5Y 细胞可增强 Akt 的磷酸化并抑制 GSK-3β 的活性。添加 PI3K 抑制剂 LY294002 可抑制 Akt 和 CREB 的磷酸化并激活 GSK-3β，从而消除利福平对暴露于鱼藤酮的细胞的神经保护作用。利福平提供对多巴胺能变性的神经保护作用，部分通过 PI3K/Akt/GSK-3β/CREB 信号通路。这些发现表明，利福平可能是治疗 PD 的一种有效且有前途的神经保护候选药物。
