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: Jing Sun, Qi Luan, Hailong Dong, Wenying Song, Keliang Xie, Lichao Hou, Lize Xiong
• Journal: Brain research (Brain Res) Vol. 1436 Pg. 101-10 (Feb 03 2012) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 22197697 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Atractyloside
• Cyclosporine

Topics

• Animals
• Atractyloside (pharmacology)
• Brain Ischemia (drug therapy, pathology, physiopathology)
• Cyclosporine (pharmacology)
• Ischemic Postconditioning
• Male
• Microscopy, Electron, Transmission
• Mitochondria (ultrastructure)
• Mitochondrial Membrane Transport Proteins (agonists, antagonists & inhibitors, metabolism)
• Mitochondrial Permeability Transition Pore
• Random Allocation
• Rats
• Rats, Sprague-Dawley