Dexmedetomidine maintains blood-brain barrier integrity by inhibiting Drp1-related endothelial mitochondrial dysfunction in ischemic stroke
Dexmedetomidine maintains blood-brain barrier integrity by inhibiting Drp1-related endothelial mitochondrial dysfunction in ischemic stroke
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DOI：
10.1093/abbs/gmab092
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发表时间：
2021-07-09
影响因子：
3.7
通讯作者：
Yu, Weifeng
中科院分区：
文献类型：
--
作者：
Zhou, Wei;Zhang, Yunchun;Yu, Weifeng
中风是全球第二大死亡和长期残疾原因，且缺乏有效的治疗方法。围手术期中风与更高的死亡率和残疾率相关。右美托咪定（Dex）是一种高度选择性的α2肾上腺素受体激动剂，在中风大鼠模型中具有神经保护作用，并且发现中风前预先治疗Dex可以减轻血脑屏障（BBB）的破坏。然而，潜在的机制仍然未知。由于脑内皮细胞是血脑屏障的主要组成部分，对能量的需求较高，因此内皮细胞的线粒体功能在血脑屏障的维持中发挥着重要作用。鉴于动力相关蛋白 1 (Drp1) 是一种介导线粒体裂变的蛋白质，线粒体融合可平衡线粒体形态并确保线粒体功能，本研究旨在探讨 Drp1 在内皮细胞中的可能作用，参与 Dex 对缺血性中风的神经保护作用。我们的结果表明，Dex 预处理可减少大脑中动脉闭塞大鼠的梗塞体积，减轻脑含水量和血脑屏障损伤，并改善神经系统评分。同时，Dex在体外增强氧糖剥夺人脑微血管内皮细胞的细胞活性并减少细胞凋亡。 Dex 的这些保护作用与内皮细胞线粒体形态完整性相关，由 Drp1 中丝氨酸 637 的磷酸化增加介导，并且可以被 α2-肾上腺素受体拮抗剂育亨宾和 AMP 激活蛋白激酶抑制剂化合物 C 逆转。这些发现表明，Dex 在缺血性中风中的神经保护作用涉及新的分子途径。由于 Dex 在临床上常规用作镇静药物，我们的研究结果提供了分子证据，表明它具有围手术期神经保护作用，防止缺血性中风。
Stroke is the second leading cause of death and long-term disability worldwide, which lacks effective treatment. Perioperative stroke is associated with much higher rates of mortality and disability. The neuroprotective role of dexmedetomidine (Dex), a highly selective agonist of alpha2-adrenergic receptor, has been reported in a stroke rat model, and it was found that pretreatment of Dex before stroke could alleviate blood-brain barrier (BBB) breakdown. However, the underlying mechanisms are still unknown. As the brain endothelial cells are the main constituents of BBB and in high demand of energy, mitochondrial function of endothelial cells plays an important role in the maintenance of BBB. Given that dynamin-related protein 1 (Drp1) is a protein mediating mitochondrial fission, with mitochondrial fusion that balances mitochondrial morphology and ensures mitochondria function, the present study was designed to investigate the possible role of Drp1 in endothelial cells involved in the neuroprotective effects of Dex in ischemic stroke. Our results showed that preconditioning with Dex reduced infarction volume, alleviated brain water content and BBB damage, and improved neurological scores in middle cerebral artery occlusion rats. Meanwhile, Dex enhanced cell activity and decreased cell apoptosis in oxygen-glucose deprivation human brain microvascular endothelial cells in vitro. These protective effects of Dex were correlated with the mitochondrial morphology integrality of endothelial cells, mediated by increased phosphorylation of serine 637 in Drp1, and could be reversed by alpha 2-adrenergic receptor antagonist Yohimbine and AMP-activated protein kinase inhibitor Compound C. These findings suggest new molecular pathways involved in the neuroprotective effects of Dex in ischemic stroke. As Dex is routinely used as a sedative drug clinically, our findings provide molecular evidence that it has perioperative neuroprotection from ischemic stroke.