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.
DESIGN: Laboratory investigation.
SETTING: University research laboratory.
SUBJECTS: : Sprague-Dawley rats.
INTERVENTIONS: 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.
MEASUREMENTS AND MAIN 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.