title: Drp-1, a potential therapeutic target for brain ischaemic stroke.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pharmacology, Institute of Materia Medica, Peking Union Medical College Hospital, and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: W
authors.initials: W
authors.lastname: Zuo
authors.affiliation: Department of Pharmacology, Institute of Materia Medica, Peking Union Medical College Hospital, and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: P F
authors.initials: PF
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Institute of Materia Medica, Peking Union Medical College Hospital, and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Institute of Materia Medica, Peking Union Medical College Hospital, and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Institute of Materia Medica, Peking Union Medical College Hospital, and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: N H
authors.initials: NH
authors.lastname: Chen
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D034281:Dynamins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D052999:Quinazolinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D052999:Quinazolinones; C519851:Dnm1l protein, rat; D034281:Dynamins