Sevoflurane-induced delayed neuroprotection involves mitoKATP channel opening and PKC ε activation

Abstract

There is an increasing body of evidence that a brief exposure to anesthesia induces ischemic tolerance in rat brain (anesthetic preconditioning). However, it is unknown whether preconditioning with sevoflurane, a commonly used volatile anesthetic in current clinical practice, produces a delayed window of neuroprotection against ischemia and what the mechanisms are for this protection. To address these issues, adult male Sprague-Dawley rats were subjected to middle cerebral arterial occlusion (MCAO) for 2h. Sevoflurane preconditioning was induced 24h before brain ischemia by exposing the animals to sevoflurane at 1.0 minimum alveolar concentration (2.4%) in oxygen for 60min. Animals preconditioned with sevoflurane had lower neurological deficit scores and smaller brain infarct volumes than animals with brain ischemia at 6 and 24h after MCAO, respectively. Application of a selective antagonist for mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel, 5-hydroxydecanoate (5-HD, 40mg/kg i.p.) 30min before sevoflurane exposure attenuated this beneficial effect. Moreover, protein kinase C ε (PKC ε) was translocated to the membrane fraction at 6h, but not 24h, after brain reperfusion in animals preconditioned with sevoflurane and this effect was also abolished by 5-HD. We concluded that sevoflurane preconditioning induces a delayed neuroprotection and that mitochondrial K(ATP) channels and PKC ε may be involved in this neuroprotection.