Mitochondrial dysfunction plays a critical role in brain injury after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Our recent study demonstrated that ghrelin protected against post-resuscitation brain injury with an elevated expression of mitochondrial uncoupling protein 2 (UCP2). However, the effects of ghrelin on mitochondrial dysfunction after CA are not clear. In the present study, the protective role of ghrelin was evaluated on mitochondrial dysfunction and the subsequent damage induced by CA in rats. In addition, mitochondrial unfolded protein response (UPRmt), an intrinsic cytoprotective pathway, was observed at the same time. Either vehicle (saline) or ghrelin (80 μg/kg) was injected blindly immediately after 6 min of CA and successful resuscitation. Neurological deficit was evaluated 6 h after CA and then cortex was collected for assessments. As a result, we found that ghrelin significantly improved the neurological deficit score in rats after CA. The functional analysis of isolated mitochondria revealed that ghrelin improved the mitochondrial ATP synthesis capacity and significantly reduced the reactive oxygen species (ROS) leakage after 6 h of CA. Concomitantly, we observed an increased ATP level and an attenuated oxidative stress in ghrelin treated animals. Moreover, ghrelin markedly improved the mitochondrial morphology compared with the vehicle animals. Further research revealed that ghrelin treatment significantly activated the UPRmt as demonstrated by the increased expression of heat shock protein 60 (HSP60), heat shock protein 10 (HSP10), caseinolytic protease 1 (CLPP1), and high-temperature requirement protein A2 (HTRA2). Our results suggest that ghrelin protected against cerebral mitochondria dysfunction after CA and the mechanism may involve a UPRmt pathway.

中文翻译：

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ghrelin对心脏骤停复苏后脑线粒体的保护作用

线粒体功能障碍在心脏骤停 (CA) 和心肺复苏 (CPR) 后的脑损伤中起着关键作用。我们最近的研究表明，生长素释放肽可以通过线粒体解偶联蛋白 2 (UCP2) 的升高表达来防止复苏后脑损伤。然而，ghrelin对CA后线粒体功能障碍的影响尚不清楚。在本研究中，评估了生长素释放肽对大鼠线粒体功能障碍和 CA 诱导的后续损伤的保护作用。此外，同时观察到线粒体未折叠蛋白反应（UPRmt），一种内在的细胞保护途径。在 CA 和成功复苏 6 分钟后立即盲注射赋形剂（盐水）或生长素释放肽（80 μg/kg）。CA 后 6 小时评估神经功能缺损，然后收集皮质进行评估。结果，我们发现生长素释放肽显着改善了 CA 后大鼠的神经功能缺损评分。分离线粒体的功能分析表明，在 CA 6 小时后，ghrelin 提高了线粒体 ATP 合成能力并显着减少了活性氧 (ROS) 泄漏。同时，我们观察到生长素释放肽治疗动物的 ATP 水平增加，氧化应激减弱。此外，与载体动物相比，ghrelin 显着改善了线粒体形态。进一步的研究表明，ghrelin 治疗显着激活了 UPRmt，如热休克蛋白 60 (HSP60)、热休克蛋白 10 (HSP10)、酪蛋白水解蛋白酶 1 (CLPP1)、和高温需求蛋白 A2 (HTRA2)。我们的结果表明，ghrelin 可防止 CA 后脑线粒体功能障碍，其机制可能涉及 UPRmt 途径。