• Jianfeng Xu, Hao Pan, Xuemeng Xie, Jincheng Zhang, Yun Wang, and Guangtian Yang.
• Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
• Neuroscience. 2018 Nov 21; 393: 24-32.

AbstractBrain damage is a leading cause of death in patients with cardiac arrest (CA). The accumulation of succinate during ischemia by succinate dehydrogenase (SDH) is an important mechanism of ischemia-reperfusion injury. It was unclear whether inhibiting the oxidation of accumulated succinate could also mitigate brain damage after CA. In this study, rats were subjected to a 6 min of CA, and cardiopulmonary resuscitation (CPR) was performed with administration of normal saline or dimethyl malonate (DMM, a competitive inhibitor of SDH). After the return of spontaneous circulation, neurological function of the rats was assessed by a tape removal test for 3 days. The rats were then sacrificed, and their brains were used to assess neuronal apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Hippocampal tissues were used for Western blotting analysis and biochemical detection. In addition, hippocampal mitochondria during CA and CPR were isolated. The relative mitochondrial membrane potential (MMP) and cytochrome C in the cytosol were detected. Our results show that DMM promoted ROSC and neurological performance in rats after CA. The TUNEL assay showed that DMM reduced neuronal apoptosis. Western blotting analysis showed that DMM inhibited the activation of caspase-3 and enhanced the expression of HIF-1α. Moreover, DMM inhibited excessive hyperpolarization of MMP after CPR, and prevented the release of cytochrome C. Therefore, inhibiting SDH by DMM alleviated brain damage after CA, and the main mechanisms included inhibiting the excessive hyperpolarization of MMP, reducing the generation of mtROS and stabilizing the structure of HIF-1α.Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

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