The mitochondrial division inhibitor mdivi-1 attenuates spinal cord ischemia-reperfusion injury both in vitro and in vivo: Involvement of BK channels

Brain Res. 2015 Sep 4;1619:155-65. doi: 10.1016/j.brainres.2015.03.033. Epub 2015 Mar 24.

Abstract

Mitochondrial division inhibitor (mdivi-1), a selective inhibitor of a mitochondrial fission protein dynamin-related protein 1 (Drp1), has been shown to exert protective effects in heart and cerebral ischemia-reperfusion models. The present study was designed to investigate the beneficial effects of mdivi-1 against spinal cord ischemia-reperfusion (SCIR) injury and its associated mechanisms. SCIR injury was induced by glutamate treatment in cultured spinal cord neurons and by descending thoracic aorta occlusion for 20 min in rats. We found that mdivi-1 (10 μM) significantly attenuated glutamate induced neuronal injury and apoptosis in spinal cord neurons. This neuroprotective effect was accompanied by decreased expression of oxidative stress markers, inhibited mitochondrial dysfunction and preserved activities of antioxidant enzymes. In addition, mdivi-1 significantly increased the expression of the large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels, and blocking BK channels by paxilline partly ablated mdivi-1 induced protection. The in vivo experiments showed that mdivi-1 treatment (1 mg/kg) overtly mitigated SCIR injury induced spinal cord edema and neurological dysfunction with no organ-related toxicity in rats. Moreover, mdivi-1 increased the expression of BK channels in spinal cord tissues, and paxilline pretreatment nullified mdivi-1 induced protection after SCIR injury in rats. Thus, mdivi-1 may be an effective therapeutic agent for SCIR injury via activation of BK channels as well as reduction of oxidative stress, mitochondrial dysfunction and neuronal apoptosis. This article is part of a Special Issue entitled SI: Spinal cord injury.

Keywords: BK channels; Mdivi-1; Mitochondrial dysfunction; Mitochondrial fission; Spinal cord ischemia–reperfusion injury.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Dynamins / antagonists & inhibitors
  • In Vitro Techniques
  • Large-Conductance Calcium-Activated Potassium Channels / metabolism*
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Oxidative Stress / drug effects
  • Quinazolinones / administration & dosage*
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / prevention & control*
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Spinal Cord Ischemia / metabolism
  • Spinal Cord Ischemia / prevention & control*

Substances

  • 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
  • Large-Conductance Calcium-Activated Potassium Channels
  • Quinazolinones
  • Dnm1l protein, rat
  • Dynamins