Mdivi-1 Alleviates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats, Possibly via Inhibition of Drp1-Activated Mitochondrial Fission and Oxidative Stress

Pei Wu, Yuchen Li, Shiyi Zhu, Chunlei Wang, Jiaxing Dai, Guang Zhang, Bingjie Zheng, Shancai Xu, Ligang Wang, Tongyu Zhang, Pei Quan Zhou, John H. Zhang, Huaizhang Shi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1449-1458
Number of pages10
JournalNeurochemical Research
Volume42
Issue number5
DOIs
StatePublished - May 1 2017

ASJC Scopus Subject Areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Keywords

  • Early brain injury
  • Mdivi-1
  • Mitochondrial fission
  • Oxidative stress
  • Subarachnoid hemorrhage
  • Rats, Wistar
  • Rats
  • Male
  • Oxidative Stress/drug effects
  • Animals
  • Brain Injuries/drug therapy
  • Mitochondrial Dynamics/drug effects
  • Dynamins/antagonists & inhibitors
  • Quinazolinones/pharmacology
  • Subarachnoid Hemorrhage/drug therapy

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