Drp-1, a potential therapeutic target for brain ischaemic stroke

Br J Pharmacol. 2016 May;173(10):1665-77. doi: 10.1111/bph.13468. Epub 2016 Apr 7.

Abstract

Background and purpose: The resistance of CA3 neurons to ischaemia and the ischaemic tolerance conferred by ischaemic preconditioning (IPC) are two well-established endogenous neuroprotective mechanisms. Elucidating the molecules involved may help us find new therapeutic targets. Thus, we determined whether dynamin-related protein 1 (Drp-1) is involved in these processes.

Experimental approach: In vivo, we subjected rats to either 10 min severe global ischaemia using a four-vessel occlusion (4-VO) model or 2 min IPC before the onset of 4-VO. In vitro, we performed oxygen glucose deprivation (OGD) studies in rat hippocampal neurons. Drp-1 was silenced or inhibited by siRNA or pharmacological inhibitor Mdivi1. To assess whether mitochondrial Drp-1 alters neuronal vulnerability to ischaemic injury, various approaches were used including western blot, immunohistochemistry, immunofluorescence staining and electron microscopy. Hippocampal function was assessed using an open-field test.

Key results: Mitochondrial dynamin-related protein 1 (mtDrp-1) was selectively induced by ischaemia in hippocampal CA3 neurons. In hippocampal CA1 neurons, mtDrp-1 was not affected by ischaemia but significantly up-regulated by IPC. Suppression of Drp-1 increased the vulnerability of cells to OGD and global ischaemia. Inhibition of Drp-1 in vivo resulted in loss of acquisition and encoding of spatial information, and also prevented ischaemia-induced mitophagy in CA3. Thus mitochondrial-mediated injury was amplified and resistance to ischaemic injury lost.

Conclusions and implications: Our findings that Drp-1 increases the resistance of neurons of hippocampal CA3 affected by global ischaemia and contributes to the tolerance conferred by IPC highlight Drp-1 as a potential therapeutic target for brain ischaemic stroke.

MeSH terms

  • Animals
  • Brain Ischemia / complications
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Dynamins / antagonists & inhibitors
  • Dynamins / deficiency
  • Dynamins / metabolism*
  • Male
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Quinazolinones / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Stroke / complications
  • Stroke / drug therapy*
  • Stroke / metabolism*
  • Stroke / pathology

Substances

  • 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
  • Quinazolinones
  • Dnm1l protein, rat
  • Dynamins