Sevoflurane preconditioning improves mitochondrial function and long-term neurologic sequelae after transient cerebral ischemia: role of mitochondrial permeability transition.
OBJECTIVE
Anesthetic preconditioning appears to be a viable strategy to treat ischemic cerebral injury. Here we investigated 1) whether the protection conferred by sevoflurane preconditioning sustains in time; 2) whether sevoflurane preconditioning diminishes mitochondrial dysfunction following cerebral ischemia; and 3) whether mitochondrial permeability transition pore plays a crucial role in the sevoflurane preconditioning.


METHODS
Laboratory investigation.


METHODS
University research laboratory.


METHODS
: Sprague-Dawley rats.


METHODS
Rats underwent 2 hrs of focal cerebral ischemia induced by middle cerebral artery occlusion. Preconditioning was elicited with sevoflurane (2.3%) for 60 mins at 24 hrs before ischemia. The involvement of mitochondrial permeability transition pore was determined with a mitochondrial permeability transition pore opener atractyloside and a specific mitochondrial permeability transition pore inhibitor cyclosporin A. In vitro study was performed on acutely isolated mitochondria subjected to calcium overload.


RESULTS
Sevoflurane preconditioning significantly decreased the infarct size by 35.9% (95% confidence interval 6.5-28.4, p < .001). This reduction of injury volume was associated with a long-term improvement of neurological function according to modified neurological severity score (F = 13.6, p = .001) and sticky-tape test (F = 29.1, p < .001) for 42 days after ischemia. Furthermore, sevoflurane preconditioning markedly protected mitochondria, as indicated by preserved respiratory chain complex activities and membrane potential, lowered mitochondrial hydrogen-peroxide production, and attenuated mitochondrial permeability transition pore opening. Isolated mitochondria also demonstrated a reduced sensitivity to Ca-induced mitochondrial permeability transition pore opening after pre-exposure to sevoflurane in vitro (95% confidence interval 24.2-196.5,p = .006). Inhibiting mitochondrial permeability transition pore using cyclosporin A resulted in protective effects similar to those seen with sevoflurane preconditioning, whereas pharmacologically opening the mitochondrial permeability transition pore with atractyloside abrogated all the positive effects of sevoflurane preconditioning and cyclosporin A, including suppression of mitochondrial permeability transition pore opening, counteraction of mitochondria-dependent apoptotic pathway, and subsequent histological and behavioral improvements.


CONCLUSIONS
Sevoflurane preconditioning protects mitochondria from cerebral ischemia/reperfusion injury and ameliorates long-term neurological deficits. Inhibition of mitochondrial permeability transition pore opening is a crucial step in mediating the neuroprotection of sevoflurane preconditioning.
Department of Neurology, Fourth Military Medical University, Xi'an, China. yeruid@gmail.com
Ruidong
R
Ye
Qianzi
Q
Yang
Xiangwei
X
Kong
Nanlin
N
Li
Yunxia
Y
Zhang
Junliang
J
Han
Lize
L
Xiong
Xinfeng
X
Liu
Gang
G
Zhao
D000818:Animals; D001921:Brain / Q000098:blood supply; D004195:Disease Models, Animal; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism; D019194:Ischemic Preconditioning / Q000379:methods*; D008738:Methyl Ethers / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D015427:Reperfusion Injury / Q000517:prevention & control*; D012680:Sensitivity and Specificity; D000077149:Sevoflurane; D018709:Statistics, Nonparametric
D008738:Methyl Ethers; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents; D000077149:Sevoflurane