title: Inhibition of mitochondrial permeability transition pore opening contributes to the neuroprotective effects of ischemic postconditioning in rats.
abstract: Ischemic postconditioning (IPost) has been shown to attenuate cerebral ischemia-reperfusion injury. However, the mechanism remains elusive. Because opening of the mitochondrial permeability transition pore (MPTP) is a crucial determinant of cell death after ischemia-reperfusion, we hypothesized that the neuroprotective effect of IPost may be associated with inhibition of MPTP opening. In part 1 of this study, pentobarbital-anesthetized rats subjected to middle cerebral artery occlusion for 90 min, followed by reperfusion for 72 h, were assigned to receive one of the following treatments: three cycles of IPost (15s each), intracerebroventricular injection of saline (control), administration of the MPTP inhibitor cyclosporin A (CsA) (2 μmol/L, 15 μL) or its vehicle alcohol, administration of the MPTP opener atractyloside (Atr) (2 mmol/L, 15 μL), or IPost plus CsA/Atr treatment. Neurological deficit scores (NDS) and infarct volumes were assessed. Mitochondrial ultrastructure and swelling were also examined after reperfusion. In part 2, control and IPost groups underwent ischemia (90 min) and reperfusion (15 min). CsA and Atr groups were treated as described in part 1. Brain mitochondria were isolated after reperfusion and MPTP activity was evaluated. IPost or CsA treatment significantly improved NDS and reduced infarction volume, while Atr reversed the neuroprotective effects of IPost, and attenuated the decrease in mitochondrial swelling induced by IPost or CsA. Thus, inhibiting MPTP opening may play a crucial role in the neuroprotective effects of IPost, which may have potential clinical value against cerebral ischemia-reperfusion injury.
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Qi
authors.initials: Q
authors.lastname: Luan
authors.forename: Hailong
authors.initials: H
authors.lastname: Dong
authors.forename: Wenying
authors.initials: W
authors.lastname: Song
authors.forename: Keliang
authors.initials: K
authors.lastname: Xie
authors.forename: Lichao
authors.initials: L
authors.lastname: Hou
authors.forename: Lize
authors.initials: L
authors.lastname: Xiong
mesh_terms: D000818:Animals; D001278:Atractyloside / Q000494:pharmacology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D016572:Cyclosporine / Q000494:pharmacology; D057775:Ischemic Postconditioning; D008297:Male; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D001278:Atractyloside; D016572:Cyclosporine