title: Mdivi-1 Alleviates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats, Possibly via Inhibition of Drp1-Activated Mitochondrial Fission and Oxidative Stress.
abstract: Mdivi-1 is a selective inhibitor of mitochondrial fission protein, Drp1, and can penetrate the blood-brain barrier. Previous studies have shown that Mdivi-1 improves neurological outcomes after ischemia, seizures and trauma but it remains unclear whether Mdivi-1 can attenuate early brain injury after subarachnoid hemorrhage (SAH). We thus investigated the therapeutic effect of Mdivi-1 on early brain injury following SAH. Rats were randomly divided into four groups: sham; SAH; SAH + vehicle; and SAH + Mdivi-1. The SAH model was induced by standard intravascular perforation and all of the rats were subsequently sacrificed 24 h after SAH. Mdivi-1 (1.2 mg/kg) was administered to rats 30 min after SAH. We found that Mdivi-1 markedly improved neurologic deficits, alleviated brain edema and BBB permeability, and attenuated apoptotic cell death. Mdivi-1 also significantly reduced the expression of cleaved caspase-3, Drp1 and p-Drp1(Ser616), attenuated the release of Cytochrome C from mitochondria, inhibited excessive mitochondrial fission, and restored the ultra-structure of mitochondria. Furthermore, Mdivi-1 reduced levels of MDA, 3-NT, and 8-OHdG, and improved SOD activity. Taken together, our data suggest that Mdivi-1 exerts neuroprotective effects against cell death induced by SAH and the underlying mechanism may be inhibition of Drp1-activated mitochondrial fission and oxidative stress.
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China.
authors.forename: Shiyi
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China.
authors.forename: Jiaxing
authors.initials: J
authors.lastname: Dai
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China.
authors.forename: Bingjie
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China.
authors.forename: Shancai
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China.
authors.forename: Ligang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China.
authors.forename: Tongyu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China.
authors.forename: PeiQuan
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery and Anesthesiology, Loma Linda University, Loma Linda, CA, 92350, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China. huaizhangshi@126.com.
authors.forename: Huaizhang
authors.identifier: http://orcid.org/0000-0003-3150-6234
authors.initials: H
authors.lastname: Shi
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D034281:Dynamins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D052999:Quinazolinones / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D052999:Quinazolinones; C519851:Dnm1l protein, rat; D034281:Dynamins
keywords: Early brain injury; Mdivi-1; Mitochondrial fission; Oxidative stress; Subarachnoid hemorrhage