title: Hypothermia and valproic acid activate prosurvival pathways after hemorrhage.
abstract: BACKGROUND
  Therapeutic hypothermia (hypo) and valproic acid (VPA, a histone deacetylase inhibitor) have independently been shown to be protective in models of trauma and hemorrhagic shock but require logistically challenging doses to be effective. Theoretically, combined treatment may further enhance effectiveness, allowing us to use lower doses of each modality. The aim of this study was to determine whether a combination of mild hypo and VPA treatments would offer better cytoprotection compared with that of individual treatments in a hemorrhage model.
  
  
  METHODS
  Male Sprague-Dawley rats were subjected to 40% volume-controlled hemorrhage, kept in shock for 30 min, and assigned to one of the following treatment groups: normothermia (36°C-37°C), hypo (30 ± 2°C), normothermia + VPA (300 mg/kg), and hypo + VPA (n = 5 per group). After 3 h of observation, the animals were sacrificed, liver tissue was harvested and subjected to whole cell lysis, and levels of key proteins in the prosurvival Akt pathway were measured using Western blot.
  
  
  RESULTS
  Activation of the proapoptotic protein cleaved caspase-3 was significantly lower in the combined treatment group relative to normothermia (P < 0.05). Levels of the prosurvival Bcl-2 was significantly higher in the combined treatment group relative to sham, normothermia, and normothermia + VPA groups (P < 0.005). The downstream prosurvival protein phospho-GSK-3β was significantly higher in the sham, hypo, and combined treatment groups compared with that in normothermia groups with or without VPA (P < 0.05). Levels of the prosurvival β-catenin were significantly higher in the combined treatment group relative to normothermia (P < 0.01).
  
  
  CONCLUSIONS
  This is the first in vivo study to demonstrate that combined treatment with VPA and hypo offers better cytoprotection than these treatments given independently.
authors.affiliation: Trauma Translational and Clinical Research Laboratory, Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
authors.forename: Ted
authors.initials: T
authors.lastname: Bambakidis
authors.affiliation: Trauma Translational and Clinical Research Laboratory, Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan; Department of Anesthesiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Simone E
authors.initials: SE
authors.lastname: Dekker
authors.affiliation: Trauma Translational and Clinical Research Laboratory, Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.affiliation: Trauma Translational and Clinical Research Laboratory, Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
authors.forename: Jake
authors.initials: J
authors.lastname: Maxwell
authors.affiliation: Trauma Translational and Clinical Research Laboratory, Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
authors.forename: Kiril
authors.initials: K
authors.lastname: Chtraklin
authors.affiliation: Trauma Translational and Clinical Research Laboratory, Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan; Department of Emergency Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Durk
authors.initials: D
authors.lastname: Linzel
authors.affiliation: Trauma Translational and Clinical Research Laboratory, Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Trauma Translational and Clinical Research Laboratory, Department of Surgery, University of Michigan Hospital, Ann Arbor, Michigan. Electronic address: alamh@med.umich.edu.
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
mesh_terms: D000107:Acetylation; D000818:Animals; D062186:Arterial Pressure; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D007036:Hypothermia, Induced; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000401:mortality / Q000503:physiopathology / Q000628:therapy*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D014635:Valproic Acid
keywords: Apoptosis; Hemorrhagic shock; Hypothermia; Resuscitation