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Valproic Acid for the Treatment of Hemorrhagic Shock: A Dose Escalation Study
*Jennifer Lu, *Yongqing Li, *Baoling Liu, *Eugene Y. Fukudome, *Zhengcai Liu, *Wei Chong, *Guang Jin, *Marc A deMoya, George C. Velmahos, *David R. King, *Hasan B. Alam
Massachusetts General Hospital/Harvard, Boston, MA
Objective: Valproic acid (VPA), a histone deacetylase inhibitor, causes an increase in protein acetylation and improves survival in models of lethal hemorrhage when given in a dose of 300 mg/kg. While doses lower than 250 mg/kg don’t have this property, it remains unknown whether higher doses of VPA would further enhance acetylation and its downstream cellular effects. A dose response study was performed to answer this question. Design: Controlled in vivo study.
Setting: University hospital research laboratory.
Subjects: Male Sprague Dawley rats
Interventions: Male SD rats were subjected to volume-controlled hemorrhage (40% total blood volume) and 30 min shock, followed by random treatment of VPA: 300 mg/kg, 400 mg/kg, and 450 mg/kg (given IV over 10 min) or saline. Liver tissue was collected at 1, 6, or 16 h (n=3/group/timepoint) after treatment.
Main Outcome Measure(s): All of the VPA treated animals survived, but those that received the 450 mg/kg dose demonstrated a greater spike in mean arterial pressure during treatment. Histone 3 acetylation in response to VPA was measured through Western Blot, as were protein levels.
Results: Acetylation of histone H3 on lysine 9 was higher in all the VPA groups compared to control 1h after treatment. However, by 6h and 16h post-treatment, only the 450 mg/kg group showed significantly greater acetylation. Additionally, during the first 6h after treatment, expression of PI3K and phospho-GSK3b (pro-survival PI3K/Akt pathway) signaling proteins increased upon VPA treatment.
Conclusions: Larger doses of VPA result in higher levels of histone acetylation, and a temporary increased activation of cellular signaling proteins. This suggests that administering higher and/or repeated doses may further enhance the protective effects of VPA.
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