A selective inhibitor of Drp1, mdivi-1, acts against cerebral ischemia/reperfusion injury via an anti-apoptotic pathway in rats

Neurosci Lett. 2013 Feb 22;535:104-9. doi: 10.1016/j.neulet.2012.12.049. Epub 2013 Jan 9.

Abstract

Mitochondrial division inhibitor (mdivi-1) is a derivative of quinazolinone that acts as a selective inhibitor of a mitochondrial fission protein Drp1. A previous study demonstrated that as a selective inhibitor of Drp1, mdivi-1 has a protective effect in an experimental model of heart ischemia/reperfusion injury. In this study, we investigated the protective effects of mdivi-1 on cerebral ischemia/reperfusion injury in a middle cerebral artery occlusion mouse model. We found that mdivi-1 (1.2mg/kg) significantly reduced cerebral damage induced by ischemia/reperfusion. This neuroprotective effect was dose-dependent. Mdivi-1 treatment blocked apoptotic cell death in cerebral ischemia/reperfusion injury, and significantly decreased the expression of Drp1 and Cytochrome C. These results suggest that mdivi-1 exerts neuroprotective effects against nerve injury after cerebral ischemia/reperfusion, and the underlying mechanism may be through the prevention of Cytochrome C release and suppression of the mitochondrial apoptosis pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Brain Ischemia / drug therapy
  • Brain Ischemia / etiology
  • Brain Ischemia / pathology*
  • Cytochromes c / genetics
  • Cytochromes c / metabolism
  • Dynamins / antagonists & inhibitors*
  • Dynamins / genetics
  • Dynamins / metabolism
  • Infarction, Middle Cerebral Artery / complications
  • Male
  • Neurons / drug effects
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Quinazolinones / pharmacology*
  • Quinazolinones / therapeutic use
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Reperfusion Injury / drug therapy
  • Reperfusion Injury / etiology
  • Reperfusion Injury / pathology*

Substances

  • 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
  • Neuroprotective Agents
  • Quinazolinones
  • RNA, Messenger
  • Cytochromes c
  • Dnm1l protein, rat
  • Dynamins