Ropinirole induces neuroprotection following reperfusion-promoted mitochondrial dysfunction after focal cerebral ischemia in Wistar rats
Ropinirole induces neuroprotection following reperfusion-promoted mitochondrial dysfunction after focal cerebral ischemia in Wistar rats
复制标题
DOI：
10.1016/j.neuro.2019.12.004
复制
发表时间：
2020-03-01
期刊：
影响因子：
3.4
通讯作者：
Parvez, Suhel
中科院分区：
文献类型：
--
作者：
Andrabi, Syed Suhail;Tabassum, Heena;Parvez, Suhel
中风的特征在于初始缺血，随后是促进称为原发性损伤的损伤级联的再灌注。缺血后线粒体功能的丧失，其特征在于氧化应激和凋亡因子的激活，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关键作用。多巴胺D2受体激动剂罗匹尼罗被发现可促进帕金森病和不宁腿综合征的神经保护作用。本研究旨在测试其在中风临床前模型中的疗效。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。我们已经显示了罗匹尼罗施用对短暂性大脑中动脉闭塞（tMCAO）的缺血性中风损伤模型中的行为缺陷和线粒体健康的积极影响。雄性Wistar大鼠进行短暂的大脑中动脉闭塞，然后接受罗匹尼罗（10 mg和20 mg/kg b.w.）在闭塞后6 h、12 h和18 h。功能缺陷的行为评估包括握力、运动协调和步态分析。我们的发现揭示了tMCAO动物中罗匹尼罗治疗的显著改善。用氯化2，3，5-三苯基四唑（TTC）对来自罗匹尼罗处理的大鼠的分离的脑切片进行染色，显示与媒介物组相比梗塞面积减少，表明存在增加数量的存活线粒体。在tMCAO损伤模型中，罗匹尼罗治疗还能够减弱线粒体活性氧簇（ROS）的产生，并阻断线粒体渗透性转换孔（mPTP）。此外，它还能够改善缺血动物中改变的线粒体膜电位和呼吸率，从而表明罗匹尼罗对线粒体生物能量学具有积极作用。罗匹尼罗抑制细胞色素c从线粒体到胞质溶胶的易位，减少下游凋亡过程。总之，这些结果表明，罗匹尼罗治疗有利于保护脑缺血性损伤中改变的线粒体功能，因此可以帮助确定更好的治疗方法。
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 mitochondria] 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.