Mitochondrial division inhibitor 1 (Mdivi-1) offers neuroprotection through diminishing cell death and improving functional outcome in a mouse model of traumatic brain injury
Mitochondrial division inhibitor 1 (Mdivi-1) offers neuroprotection through diminishing cell death and improving functional outcome in a mouse model of traumatic brain injury
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线粒体分裂抑制剂 1 (Mdivi-1) 通过减少细胞死亡和改善创伤性脑损伤小鼠模型的功能结果来提供神经保护。
DOI：
10.1016/j.brainres.2015.11.016
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发表时间：
2016
期刊：
影响因子：
2.9
通讯作者：
Tao Lu-Yang
中科院分区：
文献类型：
--
作者：
Wu Qiong;Xia Shui-Xiu;Li Qian-Qian;Gao Yuan;Shen Xi;Ma Lu;Zhang Ming-Yang;Wang Tao;Li Yong-Sheng;Wang Zu-Feng;Luo Cheng-Liang;Tao Lu-Yang
线粒体功能障碍作为一种巨大的潜在危机，越来越受到人们的关注。线粒体动力学的紊乱调节，线粒体融合和分裂的平衡，已经涉及神经退行性疾病，如帕金森病和脑缺血/再灌注。然而，线粒体动力学在创伤性脑损伤（TBI）中的作用尚未阐明。本研究的目的是调查Mdivi-1，一个关键的线粒体裂变蛋白动力蛋白相关蛋白1（Drp 1）的小分子抑制剂，在TBI诱导的细胞死亡和功能结果缺陷的作用。首先研究Drp 1的蛋白表达。结果指标包括运动试验、Morris水迷宫、脑水肿和病灶体积。碘化丙啶（PI）标记检测细胞死亡，并使用透射电子显微镜评估线粒体形态。此外，还研究了凋亡相关蛋白细胞色素c（cyt-c）和caspase-3的表达。我们的研究结果表明，TBI后1 h Drp 1表达开始上调，24 h达高峰，但Mdivi-1抑制Drp 1可显著减轻TBI诱导的行为缺陷和脑水肿，减少线粒体形态学改变，减少TBI诱导的细胞死亡以及损伤体积。此外，Mdivi-1处理显著抑制TBI诱导的cyt-c从线粒体释放到细胞质，并在TBI后24 h激活caspase-3。综上所述，这些数据表明，抑制Drp 1可能有助于通过维持正常的线粒体形态和抑制细胞凋亡的激活来减弱TBI诱导的功能结果和细胞死亡。
Mitochondria dysfunction, an enormous potential crisis, has attracted increasing attention. Disturbed regulation of mitochondrial dynamics, the balance of mitochondrial fusion and fission, has been implicated in neurodegenerative diseases, such as Parkinson׳s disease and cerebral ischemia/reperfusion. However the role of mitochondrial dynamics in traumatic brain injury (TBI) has not been illuminated. The aim of the present study was to investigate the role of Mdivi-1, a small molecule inhibitor of a key mitochondrial fission protein dynamin-related protein 1 (Drp1), in TBI-induced cell death and functional outcome deficits. Protein expression of Drp1 was first investigated. Outcome parameters consist of motor test, Morris water maze, brain edema and lesion volume. Cell death was detected by propidium iodide (PI) labeling, and mitochondrial morphology was assessed using transmission electron microscopy. In addition, the expression of apoptosis-related proteins cytochrome c (cyt-c) and caspase-3 was investigated. Our findings showed that up-regulation of Drp1 expression started at 1 h post-TBI and peaked at 24 h, but inhibition of Drp1 by Mdivi-1 significantly alleviated TBI-induced behavioral deficits and brain edema, reduced morphological change of mitochondria, and decreased TBI-induced cell death together with lesion volume. Moreover, treatment with Mdivi-1 remarkably inhibited TBI-induced the release of cyt-c from mitochondria to cytoplasm, and activation of caspase-3 at 24 h after TBI. Taken together, these data imply that inhibition of Drp1 may help attenuate TBI-induced functional outcome and cell death through maintaining normal mitochondrial morphology and inhibiting activation of apoptosis.