Hypothermia and valproic acid activate prosurvival pathways after hemorrhage

Ted Bambakidis, Simone E. Dekker, Baoling Liu, Jake Maxwell, Kiril Chtraklin, Durk Linzel, Yongqing Li, Hasan B. Alam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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. Materials and 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.

Original languageEnglish (US)
Pages (from-to)159-165
Number of pages7
JournalJournal of Surgical Research
Volume196
Issue number1
DOIs
StatePublished - Jun 1 2015
Externally publishedYes

Keywords

  • Apoptosis
  • Hemorrhagic shock
  • Hypothermia
  • Resuscitation

ASJC Scopus subject areas

  • Surgery

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