A Combination Treatment Strategy for Hemorrhagic Shock in a Rat Model Modulates Autophagy

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.

Rapid senescence‐like response after acute injury

“…As D is a tyrosine kinase inhibitor, its potency with respect to other molecular pathways cannot be ignored in acute injury conditions, as opposed to its safe use in age‐associated senescence. To further confirm whether the senescence markers are altered when pharmacological interventions improve organ function after HI, we tested rats treated with NiDaR (niacin, dichloroacetate, and resveratrol), a drug combination that improved organ function and survival following HI (Chu, Schwartz, Diamond, & Raju, 2019). The protocol used for the HI procedure and NiDaR treatment was identical to the one used for the D + Q treatment (Chu et al, 2019).…”

“…To further confirm whether the senescence markers are altered when pharmacological interventions improve organ function after HI, we tested rats treated with NiDaR (niacin, dichloroacetate, and resveratrol), a drug combination that improved organ function and survival following HI (Chu, Schwartz, Diamond, & Raju, 2019). The protocol used for the HI procedure and NiDaR treatment was identical to the one used for the D + Q treatment (Chu et al, 2019). The NiDaR treatment after HI did not inhibit the emergence of a senescence‐like molecular process in the liver, as we found the levels of CDK2, CDK4, CDK6, and p21 to be similar to the levels in the livers of animals subjected to HI without NiDaR treatment (Figure 2f).…”

Irisin Preserves Cardiac Performance and Insulin Sensitivity in Response to Hemorrhage

“…Hemorrhages also lead to an overactivated immune system that releases pro-inflammatory cytokines [ 18 , 19 , 20 ]. In our study we confirmed this understanding and found that hemorrhages induced the expression of pro-inflammatory cytokines, TNF-α, and IL-1.…”

A narrative review of prehospital hemorrhagic shock treatment with non‐blood product medications

“…A third study demonstrating survival benefit utilized a combination drug (NiDaR, niacin, dichloroacetate, and resveratrol) with each component given intravenously and at a lower dose (2 mg/kg) than when studied individually. MAP, lactate, and inflammatory marker levels also improved among niacin recipients 33 . While doses, routes, and in the case of the last study, concurrent medications administered vary across the reviewed studies, the possibility of benefit of niacin in hemorrhagic shock is supported in these rodent models.…”