title: Sevoflurane postconditioning involves an up-regulation of HIF-1α and HO-1 expression via PI3K/Akt pathway in a rat model of focal cerebral ischemia.
abstract: Administration of sevoflurane at the onset of reperfusion has been confirmed to provide a cerebral protection. However, little is known about the mechanism. In this study, we tested the hypothesis that sevoflurane postconditioning induces neuroprotection through the up-regulation hypoxia inducible factor-1α (HIF-1α) and heme oxygenase-1 (HO-1) involving phosphatidylinositol-3-kinase (PI3K)/Akt pathway. In the first experiment, male Sprague-Dawley rats were subjected to focal cerebral ischemia. Postconditioning was performed by exposure to 2.5% sevoflurane immediately at the onset of reperfusion. The mRNA and protein expression of HIF-1α and its target gene, HO-1, intact neurons and the activity of caspase-3 was evaluated at 6, 24 and 72h after reperfusion. In the second experiment, we investigated the relationship between PI3K/Akt pathway and the expression of HIF-1α and HO-1 in the neuroprotection induced by sevoflurane. Cerebral infarct volume, apoptotic neuron and the expression of HIF-1α, HO-1 and p-Akt were evaluated at 24h after reperfusion. Compared with the control group, sevoflurane postconditiong significantly ameliorated neuronal injury, up-regulated mRNA and protein levels of HIF-1α and HO-1, inhibited the activity of caspase-3, and decreased the number of TUNEL-positive cells and infarct sizes. However, the selective PI3K inhibitor, wortmannin not only partly eliminated the neuroprotection of sevoflurane as shown by reducing infarct size and apoptotic neuronal cells, but also reversed the elevation of HIF-1α, HO-1 and p-Akt expression in the ischemic penumbra induced by sevoflurane. Therefore, our data demonstrate that the cerebral protection from sevoflurane postconditioning is partly mediated by PI3K/Akt pathway via the up-regulation of HIF-1α and HO-1.
authors.affiliation: Department of Anesthesiology, The Affiliated Xiangya Hospital of Center South University, Changsha, Hunan, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Ye
authors.forename: Qulian
authors.initials: Q
authors.lastname: Guo
authors.forename: Pingping
authors.initials: P
authors.lastname: Xia
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.forename: E
authors.initials: E
authors.lastname: Wang
authors.forename: Yajing
authors.initials: Y
authors.lastname: Yuan
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D057775:Ischemic Postconditioning / Q000379:methods; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology* / Q000627:therapeutic use; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077149:Sevoflurane; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008738:Methyl Ethers; D000077149:Sevoflurane; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin