Pharmacological inhibition of mitochondrial division attenuates simulated high-altitude exposure-induced cerebral edema in mice: Involvement of inhibition of the NF-κB signaling pathway in glial cells.
Pharmacological inhibition of mitochondrial division attenuates simulated high-altitude exposure-induced cerebral edema in mice: Involvement of inhibition of the NF-κB signaling pathway in glial cells.
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DOI：
10.1016/j.ejphar.2022.175137
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发表时间：
2022-07
影响因子：
5
通讯作者：
Yapeng Lu;Panpan Chang;Wangwang Ding;Jiangpei Bian;Dan Wang;Xue-ting Wang;Qian-qian Luo;Xiaomei Wu-Xiaom
中科院分区：
文献类型：
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作者：
Yapeng Lu;Panpan Chang;Wangwang Ding;Jiangpei Bian;Dan Wang;Xue-ting Wang;Qian-qian Luo;Xiaomei Wu-Xiaom
高原脑水肿(HACE)是一种严重的急性高原病，目前尚缺乏有效的治疗方法。本研究首次探讨了线粒体分裂抑制因子-1(MDVI-1)对模拟高原暴露所致小鼠脑水肿的保护作用。结果表明，MDIVI-1能有效抑制动力蛋白相关蛋白-1的磷酸化，减少水通道蛋白4的表达，减少IL-6和肿瘤坏死因子-α的分泌，减轻脑水肿。在原代培养的星形胶质细胞或小胶质细胞中，MDIVI-1显著减少缺氧诱导的DRP1的磷酸化和线粒体断裂，抑制NF-κB信号通路的激活，减少IL-6和α的分泌。此外，mdivi-1还可抑制低氧诱导的星形胶质细胞和小胶质细胞线粒体活性氧(ROS)的产生。小胶质细胞条件培养液作用于星形胶质细胞后，星形胶质细胞中p-drp1、p-p65和AQP4蛋白水平及IL-6、肿瘤坏死因子-α和IL-1β的表达水平均升高。去除H-MCM中的线粒体成分后，小胶质细胞对低氧下星形胶质细胞的影响明显减轻。经mdivi-1处理后，缺氧诱导的小胶质细胞释放的线粒体完整性明显改善。综上所述，mdivi-1抑制线粒体分裂的药理作用减轻了模拟高原暴露所致的小鼠脑水肿。抑制ROS/NF-κB信号通路可能参与了MDIVI-1的保护作用。在低氧条件下，MDIVI-1可能通过减少损伤的线粒体从小胶质细胞中释放来减弱星形胶质细胞的激活。
High-altitude cerebral edema (HACE) is the severe type of acute mountain sickness, which is still lack of effective therapy. This study investigated for the first time the protective effect of mitochondrial division inhibitor-1 (mdivi-1) against cerebral edema induced by simulated high-altitude exposure in mice. It was found that mdivi-1 effectively inhibited phosphorylation of dynamin-related protein-1 (Drp1), reduced expression of AQP4, decreased secretion of IL-6 and TNF-α, and alleviated cerebral edema in mice. In primary cultured astrocytes or microglia, mdivi-1 significantly decreased the hypoxia-induced Drp1 phosphorylation and mitochondrial fragmentation, inhibited the activation of the NF-κB signaling pathway, reduced the secretion of IL-6 and TNF-α. In addition, mdivi-1 inhibited mitochondrial reactive oxygen species (ROS) generation induced by hypoxia in both astrocytes and microglia. When astrocytes were treated with the conditioned medium of microglia exposed to hypoxia (H-MCM), the protein levels ofp-Drp1,p-p65, and AQP4 as well as the mRNA levels of IL-6, TNF-α, and IL-1β in astrocytes were increased. When the mitochondrial components in H-MCM were removed, the influence of microglia on astrocytes under hypoxia was significantly alleviated. Treated with mdivi-1, the integrity of mitochondria released from microglia induced by hypoxia were significantly improved. In conclusion, pharmacological inhibition of mitochondrial division by mdivi-1 alleviated cerebral edema induced by simulated high-altitude exposure in mice. Inhibition of ROS/NF-κB signaling pathway may contribute to the protective effect of mdivi-1. Under hypoxic conditions, mdivi-1 may attenuate the activation of astrocytes by reducing the release of damaged mitochondria from microglia.