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 α2-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.

中文翻译：

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右美托咪定通过抑制缺血性卒中中 Drp1 相关的内皮线粒体功能障碍来维持血脑屏障完整性

中风是全球第二大死亡和长期残疾原因，缺乏有效的治疗方法。围手术期卒中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，其神经保护作用已在中风大鼠模型中得到报道，并且发现在中风前预处理 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成分，对能量的需求量很大，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 dynamin 相关蛋白 1 (Drp1) 是一种介导线粒体裂变的蛋白，通过平衡线粒体形态并确保线粒体功能的线粒体融合，本研究旨在调查 Drp1 在参与 Dex 在缺血性中风中的神经保护作用的内皮细胞中的可能作用。我们的研究结果表明，在大脑中动脉闭塞大鼠中，Dex 预处理可减少梗死体积，减轻脑含水量和 BBB 损伤，并改善神经功能评分。同时，Dex 增强氧葡萄糖剥夺人脑微血管内皮细胞的细胞活性并减少细胞凋亡 我们的研究结果表明，在大脑中动脉闭塞大鼠中，Dex 预处理可减少梗死体积，减轻脑含水量和 BBB 损伤，并改善神经功能评分。同时，Dex 增强氧葡萄糖剥夺人脑微血管内皮细胞的细胞活性并减少细胞凋亡 我们的研究结果表明，在大脑中动脉闭塞大鼠中，Dex 预处理可减少梗死体积，减轻脑含水量和 BBB 损伤，并改善神经功能评分。同时，Dex 增强氧葡萄糖剥夺人脑微血管内皮细胞的细胞活性并减少细胞凋亡体外。Dex 的这些保护作用与内皮细胞的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-肾上腺素能受体拮抗剂育亨宾和 AMP 活化蛋白激酶抑制剂化合物 C 逆转。这些发现表明涉及 Dex 在缺血性中风中的神经保护作用的新分子途径。由于 Dex 在临床上通常用作镇静药物，我们的研究结果提供了分子证据，表明它具有围手术期对缺血性卒中的神经保护作用。