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. 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