title: Sevoflurane pre-conditioning increases phosphorylation of Erk1/2 and HO-1 expression via inhibition of mPTP in primary rat cortical neurons exposed to OGD/R.
abstract: BACKGROUND
  As an indispensable clinical inhalation anesthetic, sevoflurane is widely used for peri-operative sedation. The neuroprotective effect of sevoflurane pre-conditioning against cerebral ischemia/reperfusion has been gradually realized, but the underlying mechanism during the early reperfusion period has not been established.
  
  
  METHODS
  Primary cultured cortical neurons were treated with 2% sevoflurane pre-conditioning for 30min, exposed to oxygen-glucose deprivation for 90min, and followed by 60min of reperfusion (OGD/R). Additionally, neuronal cells were treated with an inhibitor of extracellular signal-related kinases 1 and 2 (Erk1/2) phosphorylation (PD98059), a mPTP opener (atractyloside), or a mPTP opening inhibitor (cyclosporine A) before sevoflurane pre-conditioning.
  
  
  RESULTS
  Sevoflurane pre-conditioning decreased neuronal apoptosis (assessed by TUNEL), oxidative stress (assessed by malondialdehyde [MDA], superoxide dismutase [SOD], and heme oxygenase [HO]-1), and opening of mitochondrial permeability transition pores [mPTPs] (assessed by calcein-cobalt), but increased neuronal viability (assessed by MTT) and mitochondrial membrane potential (assessed by JC-1) after OGD/R exposure compared with OGD/R treatment alone. Pre-treatment with the mPTP opener and inhibitor of Erk1/2 phosphorylation abolished the protective effect induced by sevoflurane pre-conditioning. Pre-treatment with the mPTP opener attenuated the phosphorylation of Erk1/2 in mitochondria of neuronal cultures exposed to OGD/R induced by sevoflurane pre-conditioning. The mPTP opening inhibitor, like sevoflurane pre-conditioning, increased phosphorylation of Erk1/2 after OGD/R exposure, while PD98059 failed to reverse inhibition of mPTP opening in cultures exposed to OGD/R induced by sevoflurane pre-conditioning.
  
  
  CONCLUSIONS
  The neuroprotective mechanism of sevoflurane pre-conditioning might be associated with increased Erk1/2 phosphorylation in mitochondria via inhibition of mPTP opening in the early reperfusion period.
authors.affiliation: Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China. Electronic address: azai2010@126.com.
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Zhang
authors.affiliation: Department of Gerontology, Cangzhou Central Hospital, Cangzhou, China.
authors.forename: Dong-Xue
authors.initials: DX
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China.
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China.
authors.forename: Wen-Bo
authors.initials: WB
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital, China Medical University, Shenyang, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001278:Atractyloside / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008738:Methyl Ethers / Q000494:pharmacology*; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D000077149:Sevoflurane
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D008738:Methyl Ethers; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents; D001278:Atractyloside; D000077149:Sevoflurane; D016572:Cyclosporine; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C535149:Mapk1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Extracellular signal-related kinases 1/2; Inhalation anesthetics; Mitochondria; Pre-conditioning