title: Pyruvate protects the brain against ischemia-reperfusion injury by activating the erythropoietin signaling pathway.
abstract: OBJECTIVE
  Pyruvate is known to be cytoprotective through antioxidant and anti-inflammatory mechanisms. We tested the hypothesis that pyruvate protects the brain against ischemia-reperfusion injury by inducing endogenous erythropoietin (EPO) expression.
  
  
  METHODS
  Pyruvate's protective effect was evaluated in C6 glioma cells and HT22 neuronal cells subjected to transient oxygen glucose deprivation. Cell viability (calcein AM assay) and expression of hypoxia-inducible factor-1α, EPO, Akt and Erk (immunoblot), and EPO receptor (reverse transcription-polymerase chain reaction) were analyzed. Transient focal cerebral ischemia in rats was induced by 2 hours middle cerebral artery occlusion followed by 24 hours reperfusion. Pyruvate or saline was infused from 60 minutes occlusion until 30 minutes reperfusion. Lesion volume and DNA fragmentation were assessed by 2,3,5-triphenyltetrazolium staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, respectively. Immunoblots were conducted to determine cerebral EPO contents.
  
  
  RESULTS
  Pyruvate increased cell viability, hypoxia-inducible factor-1α, EPO, and Akt phosphorylation. Small interfering RNA suppression of hypoxia-inducible factor-1α and EPO abolished pyruvate-induced cytoprotection. In the rat stroke model, pyruvate reduced lesion volume by 84% and DNA fragmentation by 77% versus controls; increased EPO content paralleled these cerebroprotective actions of pyruvate.
  
  
  CONCLUSIONS
  Pyruvate activation of the hypoxia-inducible factor-1α-EPO signaling cascade in neurons and glia could protect the brain from ischemia-reperfusion injury.
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, USA.
authors.forename: Myoung-Gwi
authors.initials: MG
authors.lastname: Ryou
authors.forename: Ran
authors.initials: R
authors.lastname: Liu
authors.forename: Ming
authors.initials: M
authors.lastname: Ren
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.forename: Robert T
authors.initials: RT
authors.lastname: Mallet
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Yang
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019289:Pyruvic Acid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects*; D020521:Stroke / Q000378:metabolism / Q000628:therapy*
chemical_list: C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D019289:Pyruvic Acid; D051057:Proto-Oncogene Proteins c-akt