title: Mitochondrial division inhibitor 1 (Mdivi-1) offers neuroprotection through diminishing cell death and improving functional outcome in a mouse model of traumatic brain injury.
abstract: Mitochondria dysfunction, an enormous potential crisis, has attracted increasing attention. Disturbed regulation of mitochondrial dynamics, the balance of mitochondrial fusion and fission, has been implicated in neurodegenerative diseases, such as Parkinson׳s disease and cerebral ischemia/reperfusion. However the role of mitochondrial dynamics in traumatic brain injury (TBI) has not been illuminated. The aim of the present study was to investigate the role of Mdivi-1, a small molecule inhibitor of a key mitochondrial fission protein dynamin-related protein 1 (Drp1), in TBI-induced cell death and functional outcome deficits. Protein expression of Drp1 was first investigated. Outcome parameters consist of motor test, Morris water maze, brain edema and lesion volume. Cell death was detected by propidium iodide (PI) labeling, and mitochondrial morphology was assessed using transmission electron microscopy. In addition, the expression of apoptosis-related proteins cytochrome c (cyt-c) and caspase-3 was investigated. Our findings showed that up-regulation of Drp1 expression started at 1h post-TBI and peaked at 24 h, but inhibition of Drp1 by Mdivi-1 significantly alleviated TBI-induced behavioral deficits and brain edema, reduced morphological change of mitochondria, and decreased TBI-induced cell death together with lesion volume. Moreover, treatment with Mdivi-1 remarkably inhibited TBI-induced the release of cyt-c from mitochondria to cytoplasm, and activation of caspase-3 at 24 h after TBI. Taken together, these data imply that inhibition of Drp1 may help attenuate TBI-induced functional outcome and cell death through maintaining normal mitochondrial morphology and inhibiting activation of apoptosis.
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Shui-Xiu
authors.initials: SX
authors.lastname: Xia
authors.affiliation: Department of Forensic Medicine, Wannan Medical College, Wuhu 241002, China.
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Li
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Zhang
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Wuzhong Branch, Suzhou Public Security Bureau, Suzhou 215128, China.
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Li
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou 215123, China. Electronic address: zufengwang@suda.edu.cn.
authors.forename: Zu-Feng
authors.initials: ZF
authors.lastname: Wang
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou 215123, China. Electronic address: clluo@suda.edu.cn.
authors.forename: Cheng-Liang
authors.initials: CL
authors.lastname: Luo
authors.affiliation: Department of Forensic Medicine, Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Lu-Yang
authors.initials: LY
authors.lastname: Tao
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D034281:Dynamins / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D011897:Random Allocation; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D018696:Neuroprotective Agents; D052999:Quinazolinones; D045304:Cytochromes c; C505409:Casp3 protein, mouse; D053148:Caspase 3; C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: Apoptosis; Dynamin-related protein 1; Mitochondrial fusion; Traumatic brain injury