title: Valproic acid for the treatment of hemorrhagic shock: a dose-optimization study.
abstract: BACKGROUND
  Valproic acid (VPA) has been shown to improve survival in animal models of hemorrhagic shock at a dose of 300 mg/kg. Our aim was to identify the ideal dose through dose-escalation, split-dosing, and dose de-escalation regimens.
  
  
  METHODS
  Rats were subjected to sublethal 40% hemorrhage and treated with vehicle or VPA (dose of 300, 400, or 450 mg/kg) after 30 min of shock. Acetylated histones and activated proteins from the PI3K-Akt-GSK-3β survival pathway at different time points were quantified by Western blot analysis. In a similar model, a VPA dose of 200 mg/kg followed 2 h later by another dose of 100 mg/kg was administered. Finally, animals were subjected to a lethal 50% hemorrhage and VPA was administered in a dose de-escalation manner (starting at dose of 300 mg/kg) until a significant drop in percent survival was observed.
  
  
  RESULTS
  Larger doses of VPA resulted in greater acetylation of histone 3 and increased activation of PI3K pathway proteins. Dose-dependent differences were significant in histone acetylation but not in the activation of the survival pathway proteins. Split-dose administration of VPA resulted in similar results to a single full dose. Survival was as follows: 87.5% with 300 and 250 mg/kg of VPA, 50% with 200 mg/kg of VPA, and 14% with vehicle-treated animals.
  
  
  CONCLUSIONS
  Although higher doses of VPA result in greater histone acetylation and activation of prosurvival protein signaling, doses as low as 250 mg/kg of VPA confer the same survival advantage in lethal hemorrhagic shock. Also, VPA can be given in a split-dose fashion without a reduction in its cytoprotective effectiveness.
authors.affiliation: Division of Trauma, Emergency Surgery and Surgical Critical Care, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: John O
authors.initials: JO
authors.lastname: Hwabejire
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lu
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Li
authors.forename: Ihab
authors.initials: I
authors.lastname: Halaweish
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
mesh_terms: D000107:Acetylation; D000818:Animals; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006657:Histones / Q000378:metabolism; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000401:mortality; D014635:Valproic Acid / Q000097:blood / Q000627:therapeutic use*
chemical_list: D006657:Histones; D014635:Valproic Acid; 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: Dose optimization; Hemorrhagic shock; Histone deacetylase inhibitors; Valproic acid