Isoflurane preconditioning protects rat brain from ischemia reperfusion injury via up-regulating the HIF-1α expression through Akt/mTOR/s6K activation

The volatile anesthetic isoflurane (ISO) has been widely used in ischemia reperfusion (IR) injury because its abilities to induce and trigger recovery are faster and smoother than other agents. However, the underlying molecular mechanisms for preconditioning the ISO in protecting the brain against IR injury are still largely unclear. In this paper, we investigated the neuroprotective effect of the ISO in the in vivo and in vitro models of IR injury and evaluated the possible correlation with Akt/mTOR/s6K signaling pathway. From the in vivo studies, we demonstrated that ISO preconditioning alleviated the IR-induced neurological deficits, infarct volume, brain edema and cell apoptosis, which were mainly due to the up-regulation of the p-Akt, p-mTOR and p-s6K proteins by the histopathological detections and Western blotting assay. The in vitro studies, demonstrated that ISO preconditioning reduced the release of OGD-induced lactate dehydrogenase (LDH) and enhanced the OGD-inhibited cell viability. It has also been observed that the hypoxia inducible factor-1 alpha (HIF-1 alpha) was increased under ISO preconditioning. Utilization of the BEZ235, a PI3K/mTOR dual inhibitor, halted the ISO-induced up-regulation of the HIF-1a, and inhibited the phosphorylation of the Akt, mTOR and s6K proteins. Besides, the ISO reduced the OGD-induced cell apoptosis, which was blocked by the BEZ235. In fact, these results thus suggest that the ISO preconditioning may provide potential neuroprotection against IR injury via up-regulating the HIF-1a expression through the Akt/mTOR/s6K activation.