title: Hypothermia-induced ischemic tolerance is associated with Drp1 inhibition in cerebral ischemia-reperfusion injury of mice.
abstract: Excessive mitochondrial fission activation has been implicated in cerebral ischemia-reperfusion (IR) injury. Hypothermia is effective in preventing cerebral ischemic damage. However, effects of hypothermia on ischemia-induced mitochondrial fission activation is not well known. Therefore, the aim of this study was to investigate whether hypothermia protect the brain by inhibiting mitochondrial fission-related proteins activation following cerebral IR injury. Adult male C57BL/6 mice were subjected to transient forebrain ischemia induced by 15min of bilateral common carotid artery occlusion (BCCAO). Mice were divided into three groups (n=48 each): Hypothermia (HT) group, with mild hypothermia (32-34°C) for 4h; Normothermia (NT) group, similarly as HT group except for cooling; Sham group, with vessels exposed but without occlusion or cooling. Hematoxylin and eosin (HE), Nissl staining, Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and behavioral testing (n=6 each) demonstrated that hypothermia significantly decreased ischemia-induced neuronal injury. The expressions of Dynamin related protein 1 (Drp1) and Cytochrome C (Cyto C) (n=6 each) in mice hippocampus were measured at 3, 6, 24, and 72h of reperfusion. IR injury significantly increased expressions of total Drp1, phosphorylated Drp1 (P-Drp1 S616) and Cyto C under normothermia. However, mild hypothermia inhibited Drp1 activation and Cyto C cytosolic release, preserved neural cells integrity and reduced neuronal necrosis and apoptosis. These findings indicated that mild hypothermia-induced neuroprotective effects against ischemia-reperfusion injury is associated with suppressing mitochondrial fission-related proteins activation and apoptosis execution.
authors.affiliation: Department of Anesthesiology, Qingdao Municipal Hospital, Dalian Medical University, Dalian, China; Department of Anesthesiology, Women's Hospital, School of Medicine, Zhejiang University, Xueshi Road 1, Hangzhou, Zhejiang 310006, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Anesthesiology, Qingdao Central Hospital, Shandong, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Qingdao Municipal Hospital, Dalian Medical University, Dalian, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Hepatobiliary Surgery, Qingdao Municipal Hospital, Shandong, China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Anesthesiology, Qingdao Municipal Hospital, Dalian Medical University, Dalian, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Shandong, China.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Shandong, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Qingdao Municipal Hospital, Dalian Medical University, Dalian, China.
authors.forename: Dengyang
authors.initials: D
authors.lastname: Han
authors.affiliation: Department of Anesthesiology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Shandong, China. Electronic address: chenhuailongdr@163.com.
authors.forename: Huailong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Qingdao Municipal Hospital, Dalian Medical University, Dalian, China; Department of Anesthesiology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Shandong, China. Electronic address: wangmingshandr@163.com.
authors.forename: Mingshan
authors.initials: M
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D045304:Cytochromes c / Q000378:metabolism; D034281:Dynamins / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007036:Hypothermia, Induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D017966:Pyramidal Cells / Q000473:pathology; D021641:Recognition, Psychology; D015427:Reperfusion Injury / Q000473:pathology / Q000628:therapy
chemical_list: D045304:Cytochromes c; C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: Apoptosis; Drp1; Hypothermia; Ischemia-reperfusion injury; Mitochondria fission