Stroke is characterized by an initial ischemia followed by a reperfusion that promotes cascade of damage referred to as primary injury. The loss of mitochondrial function after ischemia, which is characterized by oxidative stress and activation of apoptotic factors is considered to play a crucial role in the proliferation of secondary injury and subsequent brain neuronal cell death. Dopamine D2 receptor agonist, Ropinirole, has been found to promote neuroprotection in Parkinson´s disease and restless leg syndrome. The current study was designed to test its efficacy in preclinical model of stroke. Previously it has been demonstrated that Ropinirole mediates its neuroprotection via mitochondrial pathways. Assuming this, we investigated the effect of Ropinirole on mitochondrial dysfunction, we have shown the positive effect of Ropinirole administration on behavioral deficits and mitochondrial health in an ischemic stroke injury model of transient middle cerebral artery occlusion (tMCAO). Male Wistar rats underwent transient middle cerebral artery occlusion and then received the Ropinirole (10 mg and 20 mg/kg b.w.) at 6 h, 12 and 18 h post occlusion. Behavioral assessment for functional deficits included grip strength, motor coordination and gait analysis. Our findings revealed a significant improvement with Ropinirole treatment in tMCAO animals. Staining of isolated brain slices from Ropinirole-treated rats with 2, 3,5-triphenyltetrazolium chloride (TTC) showed a reduction in the infarct area in comparison to the vehicle group, indicating the presence of an increased number of viable mitochondria. Ropinirole treatment was also able to attenuate mitochondrial reactive oxygen species (ROS) production, as well as block the mitochondrial permeability transition pore (mPTP), in the tMCAO injury model. In addition, it was also able to ameliorate the altered mitochondrial membrane potential and respiration ratio in the ischemic animals, thereby suggesting that Ropinirole has a positive effect on mitochondrial bioenergetics. Ropinirole inhibited the translocation of cytochrome c from mitochondria to cytosol reduces the downstream apoptotic processes. In conclusion, these results demonstrate that Ropinirole treatment is beneficial in preserving the mitochondrial functions that are altered in cerebral ischemic injury and thus can help in defining better therapies.

中文翻译：

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在Wistar大鼠局灶性脑缺血后，罗匹尼罗在再灌注促进的线粒体功能障碍后诱导神经保护作用。

中风的特征在于最初的局部缺血，然后是再灌注，其促进称为原发性损伤的损伤级联。缺血后线粒体功能的丧失以氧化应激和凋亡因子的激活为特征，被认为在继发性损伤的增殖和随后的脑神经元细胞死亡中起着至关重要的作用。已发现多巴胺D2受体激动剂罗匹尼罗在帕金森氏病和躁动性腿综合征中具有促进神经保护的作用。当前的研究旨在测试其在中风临床前模型中的功效。以前已经证明罗匹尼罗通过线粒体途径介导其神经保护作用。假设这一点，我们研究了罗匹尼罗对线粒体功能障碍的影响，我们在短暂性脑中动脉阻塞（tMCAO）缺血性中风损伤模型中显示了罗匹尼罗对行为缺陷和线粒体健康的积极作用。雄性Wistar大鼠经历短暂的大脑中动脉闭塞，然后在闭塞后6小时，12和18小时接受罗匹尼罗（10 mg和20 mg / kg bw）。功能缺陷的行为评估包括握力，运动协调和步态分析。我们的发现表明，在tMCAO动物中使用罗匹尼罗治疗具有显着改善。与媒介物组相比，用2,3,5-三苯基四唑氯化物（TTC）对用罗匹尼罗治疗的大鼠分离的脑切片进行染色显示梗死面积减少，表明存在的存活线粒体数量增加。在tMCAO损伤模型中，罗匹尼罗治疗还能够减轻线粒体活性氧（ROS）的产生，并阻断线粒体通透性转换孔（mPTP）。此外，它还能够改善缺血动物的线粒体膜电位和呼吸率变化，从而表明罗匹尼罗对线粒体生物能学有积极作用。罗匹尼罗抑制细胞色素c从线粒体到胞质溶胶的转运，减少了下游的凋亡过程。总之，这些结果表明罗匹尼罗治疗有益于保留在脑缺血性损伤中改变的线粒体功能，从而有助于确定更好的疗法。以及在tMCAO损伤模型中阻断线粒体通透性过渡孔（mPTP）。此外，它还能够改善缺血动物的线粒体膜电位和呼吸率变化，从而表明罗匹尼罗对线粒体生物能学有积极作用。罗匹尼罗抑制细胞色素c从线粒体到胞质溶胶的转运，减少了下游的凋亡过程。总之，这些结果表明罗匹尼罗治疗有益于保留在脑缺血性损伤中改变的线粒体功能，从而有助于确定更好的疗法。以及在tMCAO损伤模型中阻断线粒体通透性过渡孔（mPTP）。此外，它还能够改善缺血动物的线粒体膜电位和呼吸率变化，从而表明罗匹尼罗对线粒体生物能学有积极作用。罗匹尼罗抑制细胞色素c从线粒体到胞质溶胶的转运，减少了下游的凋亡过程。总之，这些结果表明罗匹尼罗治疗有益于保留在脑缺血性损伤中改变的线粒体功能，从而有助于确定更好的疗法。它也能够改善缺血动物的线粒体膜电位和呼吸率变化，从而表明罗匹尼罗对线粒体生物能学有积极作用。罗匹尼罗抑制细胞色素c从线粒体到胞质溶胶的转运，减少了下游的凋亡过程。总之，这些结果表明罗匹尼罗治疗有益于保留在脑缺血性损伤中改变的线粒体功能，从而有助于确定更好的疗法。它也能够改善缺血动物的线粒体膜电位和呼吸率变化，从而表明罗匹尼罗对线粒体生物能学有积极作用。罗匹尼罗抑制细胞色素c从线粒体到胞质溶胶的转运，减少了下游的凋亡过程。总之，这些结果表明罗匹尼罗治疗有益于保留在脑缺血性损伤中改变的线粒体功能，从而有助于确定更好的疗法。