Abstract
Hemorrhagic shock leads to whole body hypoxia and nutrient deprivation resulting in organ dysfunction and mortality. Previous studies demonstrated that resveratrol, dichloroacetate, and niacin improve organ function and survival in rats following hemorrhagic shock injury (HI). We hypothesized that a combinatorial formula that collectively promotes survival will decrease the dose of individual compounds toward effective therapy for HI. Sprague-Dawley rats were subjected to HI by withdrawing 60% blood volume. NiDaR (Niacin-Dichloroacetate-Resveratrol; 2 mg/kg dose of each) or vehicle was administered following the shock in the absence of fluid resuscitation, and survival monitored. In order to study alterations in molecular mediators, separate groups of rats were administered NiDaR or vehicle along with resuscitation fluid, following HI. We observed significant improvement (p < 0.05) in survival following HI in animals that received NiDaR, in the absence of fluid resuscitation. In NiDaR treated animals that received resuscitation fluid, MAP was significantly increased compared to Veh-treated rats. HI-induced increase in systemic IL-6 levels and tissue expression of IL-6, IL-10, IL-1β, and IL-18 genes in the heart were attenuated with NiDaR treatment. NiDaR promoted autophagy following HI as demonstrated by reduced p-mTOR, increased p-ULK1 and p-Beclin. The combinatorial formula, NiDaR, reduced inflammation, promoted autophagy, and reduced doses of individual compounds used, and may be more effective in genetically heterogeneous population. In conclusion our experiments demonstrated that the combinatorial drug treatment has salutary effect in rats following HI.
Highlights
Trauma is the leading cause of death in the 1–45 years age group [1, 2]
We found that dichloroacetate (DCA), a classic inhibitor of pyruvate dehydrogenase kinase (Pdk), significantly improved organ function and survival following hemorrhagic shock injury (HI) [6]
It may be noted that when fluid resuscitation is not performed following hemorrhagic shock, in our model, MAP reaching 30 mmHg has been observed to be a point of no return for the rats
Summary
Hemorrhage is a common cause of death following traumatic injuries [1,2,3]. The availability of adjuncts that complement limited or no resuscitation may play critical role in prolonging life following hemorrhagic shock. Our experiments using a rat model of hemorrhagic shock injury (HI) demonstrated that in the absence of volume replacement, a protracted metabolic homeostasis may be achieved using. Combination Therapy for Hemorrhagic Shock agents that potentiate cellular energetics [5,6,7]. Cellular energetics is an important determining factor in maintaining homeostatic balance [7,8,9]. Our studies unequivocally showed that the naturally occurring SIRT1 activator, resveratrol (RSV), can prolong survival in experimental rats following HI in the absence of fluid resuscitation [5]. The effect of resveratrol in improving organ function in experimental animals subjected to hemorrhagic shock has been described by many laboratories [10,11,12,13,14]
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