title: Neuroprotection induced by sevoflurane-delayed post-conditioning is attributable to increased phosphorylation of mitochondrial GSK-3β through the PI3K/Akt survival pathway.
abstract: OBJECTIVE
  Post-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.
  
  
  METHODS
  Adult male Sprague-Dawley rats were subjected to focal cerebral ischemia. Sevoflurane post-conditioning was achieved by administration of 2.5% sevoflurane for 60 min, 15 min after reperfusion. Phosphorylated Akt-Ser473 and GSK-3β-Ser9 in the cytosol and mitochondria of the ischemic penumbra were evaluated 4, 12, 24, and 72 h after reperfusion. Neurological deficit score and activity of caspase-3 and -9 were evaluated 24 and 72 h after reperfusion. Apoptosis, as measured by TUNEL staining and cerebral infarct size,was determined 24h after reperfusion.
  
  
  RESULTS
  Sevoflurane-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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Department of Anesthesiology, Affiliated Xiangya Hospital of Central South University, Changsha 410078, Hunan Province, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Anesthesiology, Affiliated Xiangya Hospital of Central South University, Changsha 410078, Hunan Province, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Xia
authors.affiliation: Department of Anesthesiology, Affiliated Xiangya Hospital of Central South University, Changsha 410078, Hunan Province, China.
authors.forename: Zhi-gang
authors.initials: ZG
authors.lastname: Cheng
authors.affiliation: Department of Anesthesiology, Affiliated Xiangya Hospital of Central South University, Changsha 410078, Hunan Province, China. Electronic address: bennydoctor@live.cn.
authors.forename: Qulian
authors.initials: Q
authors.lastname: Guo
mesh_terms: D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002545:Brain Ischemia / Q000628:therapy*; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D008738:Methyl Ethers / Q000008:administration & dosage / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D015427:Reperfusion Injury / Q000517:prevention & control*; D000077149:Sevoflurane; D015398:Signal Transduction
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D018696:Neuroprotective Agents; D000077149:Sevoflurane; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: Apoptosis; Focal cerebral ischemia; Glycogen synthase kinase 3β (GSK-3β); PI3K/Akt; Post-conditioning; Sevoflurane