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

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.