• Hongying Xu, Yong Li, Rongqiang Liu, Lin Wu, Chunling Zhang, Nan Ding, Aiying Ma, Jincheng Zhang, and Xuemeng Xie.
• Department of Critical Care Medicine, Affiliated Hospital of Jining Medical University, Jining 272029, PR China.
• Neuropeptides. 2019 Aug 1; 76: 101936.

AbstractMitochondrial 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.Copyright © 2019 Elsevier Ltd. All rights reserved.

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