title: Sevoflurane preconditioning-induced neuroprotection is associated with Akt activation via carboxy-terminal modulator protein inhibition.
abstract: BACKGROUND
  Sevoﬂurane preconditioning has a neuroprotective effect, but the underlying mechanism is not fully understood. The aim of the present investigation was to evaluate whether sevoflurane-induced cerebral preconditioning involves inhibition of carboxy-terminal modulator protein (CTMP), an endogenous inhibitor of Akt, in a rat model of focal cerebral ischaemia.
  
  
  METHODS
  Male Sprague-Dawley rats were exposed to 2.7% sevoflurane for 45 min. One hour later, rats were subjected to 60 min of focal cerebral ischaemia. The phosphoinositide 3-kinase inhibitors wortmannin and LY294002 were administered 10 min before preconditioning. Rats in the lentiviral transduction group received an intracerebroventricular injection of lentiviral vector Ubi-MCS-CTMP 3 days before ischaemia. Neurological deficits and infarct volumes were evaluated 24 h and 7 days after reperfusion. Phosphorylation of Akt, glycogen synthase kinase-3β (GSK3β), and expression of CTMP were determined at 1, 3, 12, and 24 h after reperfusion. Akt activity was measured at 3 h after reperfusion.
  
  
  RESULTS
  Sevoflurane preconditioning improved neurological score and reduced infarct size at 24 h of reperfusion. Pretreatment with wortmannin or LY294002 attenuated these neuroprotective effects. Expression of CTMP correlated with reduced Akt activity after ischaemia, while sevoflurane preconditioning preserved Akt activity and increased phosphorylation of GSK3β. CTMP over-expression diminished the beneficial effects of sevoflurane preconditioning.
  
  
  CONCLUSIONS
  Activation of Akt signalling via inhibition of CTMP is involved in the mechanism of neuroprotection provided by sevoflurane preconditioning.
authors.affiliation: Department of Anaesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Anaesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: H
authors.initials: H
authors.lastname: Nie
authors.affiliation: Department of Anaesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: L
authors.initials: L
authors.lastname: Tian
authors.affiliation: Department of Anaesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: L
authors.initials: L
authors.lastname: Tong
authors.affiliation: Department of Anaesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: J
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Anaesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China hldong6@hotmail.com mzkxlz@126.com.
authors.forename: H
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Anaesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China hldong6@hotmail.com mzkxlz@126.com.
authors.forename: L
authors.initials: L
authors.lastname: Xiong
mesh_terms: D065767:Activation, Metabolic / Q000187:drug effects; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000517:prevention & control; D019194:Ischemic Preconditioning / Q000379:methods* / Q000523:psychology; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018685:Anesthetics, Inhalation; C541471:CTMP protein, rat; D002352:Carrier Proteins; D008738:Methyl Ethers; D018696:Neuroprotective Agents; D000077149:Sevoflurane; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: CTMP protein, rat; anaesthetics volatile, sevoﬂurane; brain ischaemia; neuroprotection; preconditioning