title: Neuroprotective effects of erythropoietin against sevoflurane-induced neuronal apoptosis in primary rat cortical neurons involving the EPOR-Erk1/2-Nrf2/Bach1 signal pathway.
abstract: OBJECTIVE
  Erythropoietin (EPO)-induced activation of the EPO receptor (EPOR) against sevoflurane-induced neuronal apoptosis is an effective intervention, but the underlying mechanism is poorly understood. Previous studies have shown that alteration of the nuclear factor erythroid 2-related factor (Nrf2)/BTB-to-CNC homology 1 (Bach1) ratio by extracellular signal-related kinases (Erk) 1/2 ameliorates the oxidative stress which occurs in human macrophages. In this study, we determined whether or not EPO attenuates sevoflurane-induced neuronal apoptosis via the EPOR-Erk1/2-Nrf2/Bach1 signal pathway.
  
  
  METHODS
  Primary rat cortical neurons were exposed to 4% sevoflurane for 6h. Neuronal viability, injury, apoptosis, and oxidative stress were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), propidium iodide uptake (PI), malondialdehyde (MDA), and superoxide dismutase (SOD) assays. A real-time PCR assay was used to measure EPOR expression. Western blotting was used to assess Nrf2, Bach1, and heme oxygenase-1 (HO-1) expression.
  
  
  RESULTS
  Sevoflurane exposure increased cell apoptosis, injury, and MDA (P<0.05), but decreased cell viability and the Nrf2:Bach1 ratio (P<0.05), and down-regulated superoxide dismutase (SOD; P<0.05), while EPO partially rescued the neurotoxicity induced by sevoflurane (P<0.05). Inhibition of EPOR via EPO-specific monoclonal antibody or Erk1/2 phosphorylation via PD98059 reversed the protective effect of EPO (P<0.05).
  
  
  CONCLUSIONS
  The neuroprotective effects of EPO against sevoflurane-induced neuronal apoptosis in primary rat cortical neurons involves the EPOR-Erk1/2-Nrf2/Bach1 signal pathway.
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, Cangzhou Central Hospital, Cangzhou, China. Electronic address: azai2010@126.com.
authors.forename: Li-Min
authors.initials: LM
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: Wenbo
authors.initials: W
authors.lastname: Sun
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D050976:Basic-Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008738:Methyl Ethers / Q000633:toxicity*; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077149:Sevoflurane
chemical_list: C486316:Bach1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D008738:Methyl Ethers; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D000077149:Sevoflurane
keywords: Erythropoietin; Extracellular signal-related kinases 1/2; Neurotoxicity; Sevoflurane