Abstract
BACKGROUND: Valproic acid (VPA), a histone deacetylase inhibitor, has shown improved outcomes when used as a pharmaceutical intervention in animal studies of hemorrhage, septic shock, and combined injuries. This study was designed to investigate the ability of VPA to mitigate ischemia-reperfusion injury produced by prolonged tourniquet application to an extremity. METHODS: The ischemia-reperfusion model in anesthetized rats was established using hemorrhage and a 3-hour tourniquet application. VPA was administered intravenously prior to tourniquet wear and removal. Ischemia-reperfusion injury was evaluated by investigating pathway signaling, immune modulation of cytokine release, remote organ injury, and skeletal muscle function during convalescence. RESULTS: We found that VPA sustained Protein kinase B (Akt) phosphorylation and Insulin-like growth factor signaling and modulated the systemic release of interleukin (IL)-1β, tumor necrosis factor alpha, and IL-6 after 2 hours of limb reperfusion. Additionally, VPA attenuated a loss in glomerular filtration rate at 3 days after injury. Histological and functional evaluation of extremity skeletal muscle at 3, 7, and 21 days after injury, however, demonstrated no significant differences in myocytic degeneration, necrotic formation, and maximal isometric tetanic torque. CONCLUSIONS: Our results demonstrate that VPA sustains early prosurvival cell signaling, reduces the inflammatory response, and improves renal function in a hemorrhage with prolonged ischemia and reperfusion model. However, these do not translate into meaningful preservation in limb function when applied as a pharmaceutical augmentation to tourniquet wear. LEVEL OF EVIDENCE: IV.