Rifampicin inhibits rotenone-induced microglial inflammation via enhancement of autophagy
Rifampicin inhibits rotenone-induced microglial inflammation via enhancement of autophagy
复制标题
利福平通过增强自噬抑制鱼藤酮诱导的小胶质细胞炎症
DOI：
10.1016/j.neuro.2017.09.015
复制
发表时间：
2017-12-01
期刊：
影响因子：
3.4
通讯作者：
Tao, Enxiang
中科院分区：
文献类型：
--
作者：
Liang, Yanran;Zhou, Tianen;Tao, Enxiang
线粒体和自噬功能障碍以及神经炎症与帕金森病（PD）的病理生理有关。鱼藤酮是一种线粒体复合体I的抑制剂，被认为是一种与帕金森病相关的环境神经毒素。我们之前的研究报道了利福平抑制鱼藤酮诱导的小胶质细胞激活和促炎介质的产生，但其确切机制尚未完全阐明。分别用利福平和0.1 μ M鱼藤酮单独或联合氯喹预处理BV2细胞2 h。本研究表明，利福平预处理可减轻鱼藤酮诱导的IL-1 β和IL-6的释放，并且当氯喹抑制自噬时，其作用被抑制。此外，50 μ M利福平预处理显著提高了SH-SY5Y细胞与鱼tenone处理的BV2细胞在transwell共培养系统中共培养的活力。氯喹部分消除了利福平预处理的神经保护作用。利福平预处理显著逆转鱼藤酮诱导的线粒体膜电位降低和活性氧积累。我们认为利福平介导的抗炎和抗氧化作用的机制是增强自噬。事实上，利福平预处理的BV2细胞中LO-II/LC3-I的比例明显高于未预处理的细胞。荧光和电镜分析表明，在利福平预处理的细胞中，与线粒体共定位的溶酶体增加，这证实了受损的线粒体通过自噬（线粒体自噬）被清除。综上所述，这些数据提供了进一步的证据，证明利福平对鱼藤酮诱导的小胶质细胞炎症具有神经保护作用，部分是通过自噬途径。利福平调节自噬是一种新的PD治疗策略。(C) 2017 Elsevier B.V.版权所有
Mitochondrial and autophagic dysfunction, as well as neuroinflammation, are associated with the pathophysiology of Parkinson's disease (PD). Rotenone, an inhibitor of mitochondrial complex I, has been associated as an environmental neurotoxin related to PD. Our previous studies reported that rifampicin inhibited microglia activation and production of proinflammatory mediators induced by rotenone, but the precise mechanism has not been completely elucidated. BV2 cells were pretreated for 2 h with rifampicin followed by 0.1 mu M rotenone, alone or in combination with chloroquine. Here, we demonstrate that rifampicin pretreatment alleviated rotenone induced release of IL-1 beta and IL-6, and its effects were suppressed when autophagy was inhibited by chloroquine. Moreover, preconditioning with 50 mu M rifampicin significantly increased viability of SH-SY5Y cells cocultured with rotenone treated BV2 cells in the transwell coculture system. chloroquine partially abolished the neuroprotective effects of rifampicin pretreatment. Rifampicin pretreatment significantly reversed rotenone-induced mitochondrial membrane potential reduction and reactive oxygen species accumulation. We suggest that the mechanism for rifampicin-mediated anti-inflammatory and antioxidant effects is the enhancement of autophagy. Indeed, the ratio of LO-II/LC3-I in rifampicin-pretreated BV2 cells was significantly higher than that in cells without pretreatment. Fluorescence and electron microscopy analyses indicate an increase of lysosomes colocalized with mitochondria in cells pretreated with rifampicin, which confirms that the damaged mitochondria were cleared through autophagy (mitophagy). Taken together, the data provide further evidence that rifampicin exerts neuroprotection against rotenone-induced microglia inflammation, partially through the autophagy pathway. Modulation of autophagy by rifampicin is a novel therapeutic strategy for PD. (C) 2017 Elsevier B.V. All rights reserved.