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Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock.

ABSTRACT: Resveratrol has been shown to potentiate mitochondrial function and extend longevity; however, there is no evidence to support whether resveratrol can improve survival or prolong life following hemorrhagic shock. We sought to determine whether (a) resveratrol can improve survival following hemorrhage and resuscitation and (b) prolong life in the absence of resuscitation. Using a hemorrhagic injury (HI) model in the rat, we describe for the first time that the naturally occurring small molecule, resveratrol, may be an effective adjunct to resuscitation fluid. In a series of three sets of experiments we show that resveratrol administration during resuscitation improves survival following HI (p < 0.05), resveratrol and its synthetic mimic SRT1720 can significantly prolong life in the absence of resuscitation fluid (<30 min versus up to 4 h; p < 0.05), and resveratrol as well as SRT1720 restores left ventricular function following HI. We also found significant changes in the expression level of mitochondria-related transcription factors Ppar-? and Tfam, as well as Pgc-1? in the left ventricular tissues of rats subjected to HI and treated with resveratrol. The results indicate that resveratrol is a strong candidate adjunct to resuscitation following severe hemorrhage.

SUBMITTER: Ayub A

PROVIDER: S-EPMC4503654 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock.

Ayub Ahmar A Poulose Ninu N Raju Raghavan R

Molecular medicine (Cambridge, Mass.) 20150413

Resveratrol has been shown to potentiate mitochondrial function and extend longevity; however, there is no evidence to support whether resveratrol can improve survival or prolong life following hemorrhagic shock. We sought to determine whether (a) resveratrol can improve survival following hemorrhage and resuscitation and (b) prolong life in the absence of resuscitation. Using a hemorrhagic injury (HI) model in the rat, we describe for the first time that the naturally occurring small molecule, ...[more]

PMID: 25879628

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Project description:Hemorrhagic shock (HS) may contribute to organ failure, by profoundly altering mitochondrial function. Resveratrol (RSV), a naturally occurring polyphenol, has been shown to promote mitochondrial function and regulate glucose homeostasis in diabetes. We hypothesized that RSV during resuscitation would ameliorate HS-induced mitochondrial dysfunction and improve hyperglycemia following acute blood loss.With the use a decompensated HS model, male Long-Evans rats (n = 6 per group) were resuscitated with lactated Ringer's solution with or without RSV (30 mg/kg) and were killed before hemorrhage (sham), at severe shock, following resuscitation, and 18 hours after resuscitation. At each time point, the liver and kidney mitochondria were isolated to assess individual respiratory complexes (CI, CII, and CIV) and the production of reactive oxygen species (ROS). Blood samples were assayed for glucose, insulin, corticosterone, total glucagon-like peptide (GLP-1), glucagon, and serum cytokine levels. The Homeostatic Model Assessment-Insulin Resistance index was used to quantify insulin resistance.RSV supplementation following HS significantly improved mitochondrial function and decreased mitochondrial ROS production in both liver and kidney. RSV-treated animals had significantly lower blood glucose levels following resuscitation when compared with sham animals (116.0 ± 20.2 mg/dL vs. 227.7 ± 8.3 mg/dL, p < 0.05) or those resuscitated with lactated Ringer's solution (116.0 ± 20.2 mg/dL vs. 359.0 ± 79.5 mg/dL, p < 0.05). RSV supplementation was associated with significantly decreased plasma insulin levels (1.0 ± 0.4 ng/mL vs. 6.5 ± 3.7 ng/mL, p < 0.05), increased total GLP-1 levels (385.8 ± 56.6 ng/mL vs. 187.3 ± 11.1 ng/mL, p < 0.05), and a lower natural Log Homeostatic Model Assessment-Insulin Resistance index (1.30 ± 0.42 vs. 4.18 ± 0.68, p < 0.05) but had minimal effect on plasma corticosterone, glucagon, or cytokine levels.Resuscitation with RSV restores mitochondrial function and decreases insulin resistance but may be associated with increased hypoglycemia. The observed antiglycemic effects of RSV may be mediated by decreased mitochondrial ROS and increased GLP-1 secretion.

Project description:BACKGROUND:Hemorrhage is a leading preventable cause of death. Nonselective histone deacetylase inhibitors (HDACIs), such as valproic acid (VPA), have been shown to improve outcomes in hemorrhagic shock (HS). The HDACs can be divided into four functional classes (I, IIa/IIb, III, and IV). Classes I, IIa/IIb, and III have previously been implicated in the pathophysiology of HS. This study aimed to determine which HDAC class, or classes, are responsible for the survival benefit observed with nonselective HDACIs. METHODS:Survival study: Sprague-Dawley rats were subjected to lethal HS (50% hemorrhage) and randomized to the following groups (n = 8): (1) no treatment, (2) normal saline vehicle, (3) cyclodextrin vehicle, (4) MS275 (class I HDACI), (5) VPA (class I/IIa HDACI), (6) MC1568 (class IIa HDACI), (7) ACY1083 (class IIb HDACI), and (8) EX527 (class III HDACI). Survival was monitored for 24 hours. Mechanistic study: Sprague-Dawley rats were subjected to sublethal HS (40% hemorrhage) and randomized to the same groups (n = 3), excluding EX527, based on results of the survival study. Tissues were harvested at 3 hours posttreatment, and expression of phosphorylated-AKT, β-catenin, acetylated histones H3 and H4, and acetylated α-tubulin were analyzed in myocardial tissue. RESULTS:Survival rate was 12.5% in the untreated group, and did not improve with vehicle or MS275 treatment. EX527 improved survival to 50%, although this did not achieve statistical significance (p = 0.082). However, treatment with VPA, MC1568, and ACY1083 improved survival rates to 87.5%, 75%, and 75%, respectively (p < 0.05). The VPA-induced acetylation of both histones H3 and H4, while MC1568 and ACY1083 increased acetylation of histone H4. ACY1083 also induced acetylation of α-tubulin. All treatment groups, except MS275, increased phosphorylated-AKT, and β-catenin. CONCLUSION:Inhibition of HDAC classes IIa or IIb, but not class I, activates prosurvival pathways, which may be responsible for the improved outcomes in rodent models of HS.

Project description:BackgroundOutcomes following aortic occlusion for trauma and hemorrhagic shock are poor, leading some to question the clinical utility of aortic occlusion in this setting. This study evaluates neurologically intact survival following resuscitative endovascular balloon occlusion of the aorta (REBOA) versus resuscitative thoracotomy at a center with a dedicated trauma hybrid operating room with angiographic capabilities.MethodsThis retrospective cohort analysis compared patients who underwent zone 1 aortic occlusion via resuscitative thoracotomy (n = 13) versus REBOA (n = 13) for blunt or non-thoracic, penetrating trauma and refractory hemorrhagic shock (systolic blood pressure less than 90 mmHg despite volume resuscitation) at a level 1 trauma center with a dedicated trauma hybrid operating room. The primary outcome was survival to hospital discharge. The secondary outcome was neurologic status at hospital discharge, assessed by Glasgow Coma Scale (GCS) scores.ResultsOverall median age was 40 years, 27% had penetrating injuries, and 23% had pre-hospital closed-chest cardiopulmonary resuscitation. In both cohorts, median injury severity scores and head-abbreviated injury scores were 26 and 2, respectively. The resuscitative thoracotomy cohort had lower systolic blood pressure on arrival (0 [0-75] vs. 76 [65-99], p = 0.009). Hemorrhage control (systolic blood pressure 100 mmHg without ongoing vasopressor or transfusion requirements) was obtained in 77% of all REBOA cases and 8% of all resuscitative thoracotomy cases (p = 0.001). Survival to hospital discharge was greater in the REBOA cohort (54% vs. 8%, p = 0.030), as was discharge with GCS 15 (46% vs. 0%, p = 0.015).ConclusionsAmong patients undergoing aortic occlusion for blunt or non-thoracic, penetrating trauma and refractory hemorrhagic shock at a center with a dedicated, trauma hybrid operating room, nearly half of all patients managed with REBOA had neurologically intact survival. The high death rate in resuscitative thoracotomy and differences in patient cohorts limit direct comparison.

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Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock.

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Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock.

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