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

Abstract

BACKGROUND AND PURPOSEThe 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 APPROACHIn 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 RESULTSMitochondrial 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 IMPLICATIONSOur 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. AbbreviationsCCA, common carotid arteries; Drp-1, dynamin-related protein 1; H/I, hypoxia/ischaemia; IPC, ischaemic preconditioning; mtDrp-1, mitochondrial Drp-1; OGD, oxygen glucose deprivation; 4-VO, four-vessel occlusion

Evaluation of temperature induction in focal ischemic thermocoagulation model

“…Nonetheless, the opposite direction of movement changes after ischemic induction was reported with an increased number of vertical and horizontal movements in open field test between ischemic and sham groups at seven days after ischemic induction. This behavioral change was justified by a loss of habituation in the ischemic group [ 55 ]. In our results, the 300°C and 400°C groups showed this variation in slow vertical and horizontal movement parameter (Actimeter) in comparison with control and sham groups.…”

Mitochondrial fission and fusion in secondary brain damage after CNS insults

“…18,41,43,44,101 However, other studies showed that following either permanent focal or global ischemia, pharmacological inhibition or knockdown of Drp1 leads to accumulation of damaged mitochondria, inhibition of mitophagy, and aggravation of infarct volume and neurological deEcits. 45,102 Similarly, Drp1 expression has been shown to decrease after OGD and furthermore its inhibition does not rescue neurons from OGD-mediated cell death, although imbalance favoring fusion over fission has been proposed to be a beneficial response of neurons to OGD. 103 Therefore, it appears that mitochondrial fragmentation mediated by Drp1 and the neuroprotective effect upon its inhibition depend on type, severity, and duration of stroke.…”

Mitophagy, a potential therapeutic target for stroke

“…Mitophagy can be down-regulated by the loss of Drp-1-mediated fission under pathological stress. Inhibiting Drp-1 expression by Mdivi1 decreased mitophagy, but didn’t change the expression level of LC3B and p62 in the CA3 of the hippocampus, indicated that Drp-1-mediated mitophagy by specifically initiating mitophagy rather than increasing the overall autophagy [ 87 ].…”