Neuroprotection induced by sevoflurane-delayed post-conditioning is attributable to increased phosphorylation of mitochondrial GSK-3β through the PI3K/Akt survival pathway

Abstract

Background and purposePost-conditioning with volatile anesthetics can create ischemic tolerance against cerebral ischemia–reperfusion injury. The present study was designed to determine whether delayed exposure to sevoflurane could induce ischemic tolerance and if this effect was dependent on increasing phosphorylated Akt-Ser473 and GSK-3β-Ser9 expression in the mitochondria, via a mechanism involving the PI3K/Akt pathway. MethodsAdult male Sprague–Dawley rats were subjected to focal cerebral ischemia. Sevoflurane post-conditioning was achieved by administration of 2.5% sevoflurane for 60min, 15min after reperfusion. Phosphorylated Akt-Ser473 and GSK-3β-Ser9 in the cytosol and mitochondria of the ischemic penumbra were evaluated 4, 12, 24, and 72h after reperfusion. Neurological deficit score and activity of caspase-3 and -9 were evaluated 24 and 72h after reperfusion. Apoptosis, as measured by TUNEL staining and cerebral infarct size,was determined 24h after reperfusion. ResultsSevoflurane-delayed post-conditioning significantly increased levels of phosphorylated Akt-Ser473 and GSK-3β-Ser9 in the mitochondria and inhibited the activities of caspase-3 and -9, showing an improved neurological deficit score and a decreased infarct size. However, LY294002, a selective PI3K inhibitor, not only eliminated the neuroprotection of sevoflurane, as indicated by an increased infarct size and a larger number of TUNEL-positive cells, but also reversed the elevation of p-Akt and p-GSK-3β expression in the mitochondria induced by sevoflurane post-conditioning. ConclusionsOur data suggested that delayed application of sevoflurane after reperfusion provides neuroprotection by activating phosphorylated Akt-Ser473 and GSK-3β-Ser9 in the mitochondria via the PI3K/Akt pathway.