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Hemorrhagic shock-induced cerebral bioenergetic imbalance is corrected by pharmacologic treatment with EF24 in a rat model.

ABSTRACT: Maintenance of cerebral viability and function is an important goal of critical care in victims of injury due to ischemia and hypovolemia. As part of the multiple organ dysfunction syndrome, the brain function after trauma is influenced by the systemic inflammatory response. We investigated the effect of EF24, an anti-inflammatory bis-chalcone, on cerebral bioenergetics in a rat model of 45% hemorrhagic shock. The rats were treated with EF24 (0.4 mg/kg) or EF24 with an artificial oxygen carrier liposome-encapsulated hemoglobin (LEH). The volume of LEH administered was equal to the shed blood. The brain was collected after 6 h of shock for biochemical assays. EF24 treatment showed significant recovery of ATP, phosphocreatine, and NAD/NADH ratio. It also increased citrate synthase activity and cytochrome c oxidase subunit IV expression which were reduced in shock brain. Furthermore, it reduced the shock-induced accumulation of pyruvate and pyruvate dehydrogenase kinase-1 expression, suggesting that EF24 treatment improves cerebral energetics by restoring perturbed pyruvate metabolism in the mitochondria. These effects of EF24 were associated with reduced poly(ADP-ribose) polymerase cleavage and a significant improvement in the levels of nerve growth factor and brain-derived neurotrophic factor in shock brain. Co-administration of LEH with EF24 was only marginally more effective as compared to the treatment with EF24 alone. These results show that EF24 treatment sets up a pro-survival phenotype in shock by resurrecting cerebral bioenergetics. Since EF24 was effective in the absence of accompanying fluid resuscitation, it has potential utility as a pre-hospital pharmacotherapy in shock due to accidental blood loss.

SUBMITTER: Rao G

PROVIDER: S-EPMC4655172 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Hemorrhagic shock-induced cerebral bioenergetic imbalance is corrected by pharmacologic treatment with EF24 in a rat model.

Rao Geeta G Xie Jun J Hedrick Andria A Awasthi Vibhudutta V

Neuropharmacology 20150729

Maintenance of cerebral viability and function is an important goal of critical care in victims of injury due to ischemia and hypovolemia. As part of the multiple organ dysfunction syndrome, the brain function after trauma is influenced by the systemic inflammatory response. We investigated the effect of EF24, an anti-inflammatory bis-chalcone, on cerebral bioenergetics in a rat model of 45% hemorrhagic shock. The rats were treated with EF24 (0.4 mg/kg) or EF24 with an artificial oxygen carrier ...[more]

PMID: 26232641

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Project description:Cerebral edema is critical to morbidity/mortality in traumatic brain injury (TBI) and is worsened by hypotension. Glibenclamide may reduce cerebral edema by inhibiting sulfonylurea receptor-1 (Sur1); its effect on diffuse cerebral edema exacerbated by hypotension/resuscitation is unknown. We aimed to determine if glibenclamide improves pericontusional and/or diffuse edema in controlled cortical impact (CCI) (5m/sec, 1?mm depth) plus hemorrhagic shock (HS) (35?min), and compare its effects in CCI alone. C57BL/6 mice were divided into five groups (n?=?10/group): naïve, CCI+vehicle, CCI+glibenclamide, CCI+HS+vehicle, and CCI+HS+glibenclamide. Intravenous glibenclamide (10?min post-injury) was followed by a subcutaneous infusion for 24?h. Brain edema in injured and contralateral hemispheres was subsequently quantified (wet-dry weight). This protocol brain water (BW)?=?80.4% vehicle vs. 78.3% naïve, p?<?0.01) but was not reduced by glibenclamide (I%BW?=?80.4%). Ipsilateral edema also developed in CCI alone (I%BW?=?80.2% vehicle vs. 78.3% naïve, p?<?0.01); again unaffected by glibenclamide (I%BW?=?80.5%). Contralateral (C) %BW in CCI+HS was increased in vehicle (78.6%) versus naive (78.3%, p?=?0.02) but unchanged in CCI (78.3%). At 24?h, glibenclamide treatment in CCI+HS eliminated contralateral cerebral edema (C%BW?=?78.3%) with no difference versus naïve. By 72?h, contralateral cerebral edema had resolved (C%BW?=?78.5?±?0.09% vehicle vs. 78.3?±?0.05% naïve). Glibenclamide decreased 24?h contralateral cerebral edema in CCI+HS. This beneficial effect merits additional exploration in the important setting of TBI with polytrauma, shock, and resuscitation. Contralateral edema did not develop in CCI alone. Surprisingly, 24?h of glibenclamide treatment failed to decrease ipsilateral edema in either model. Interspecies dosing differences versus prior studies may play an important role in these findings. Mechanisms underlying brain edema may differ regionally, with pericontusional/osmolar swelling refractory to glibenclamide but diffuse edema (via Sur1) from combined injury and/or resuscitation responsive to this therapy. TBI phenotype may mandate precision medicine approaches to treat brain edema.

Project description:BackgroundFast and effective treatment of hemorrhagic shock is one of the most important preclinical trauma care tasks e.g., in combat casualties in avoiding severe end-organ damage or death. In scenarios without immediate availability of blood products, alternate regimens of fluid resuscitation represent the only possibility of maintaining sufficient circulation and regaining adequate end-organ oxygen supply. However, the fluid choice alone may affect the extent of the bleeding by interfering with coagulation pathways. This study investigates the impact of hydroxyethyl starch (HES), gelatine-polysuccinate (GP) and balanced electrolyte solution (BES) as commonly used agents for fluid resuscitation on coagulation using a porcine hemorrhagic shock model.MethodsFollowing approval by the State and Institutional Animal Care Committee, life-threatening hemorrhagic shock was induced via arterial blood withdrawal in 24 anesthetized pigs. Isovolumetric fluid resuscitation with either HES, GP or BES (n = 3 × 8) was performed to compensate for the blood loss. Over four hours, hemodynamics, laboratory parameters and rotational thromboelastometry-derived coagulation were analyzed. As secondary endpoint the porcine values were compared to human blood.ResultsAll the agents used for fluid resuscitation significantly affected coagulation. We measured a restriction of laboratory parameters, clot development and clot firmness, particularly in HES- and GP-treated animals. Hemoglobin content dropped in all groups but showed a more pronounced decline in colloid-treated pigs. This effect was not maintained over the four-hour monitoring period.ConclusionHES, GP, and BEL sufficiently stabilized the macrocirculation, but significantly affected coagulation. These effects were most pronounced after colloid and particularly HES administration. Despite suitability for rapid hemodynamic stabilization, colloids have to be chosen with caution, because their molecular properties may affect coagulation directly and as a consequence of pronounced hemodilution. Our comparison of porcine and human coagulation showed increased coagulation activity in pig blood.

Dataset Information

Hemorrhagic shock-induced cerebral bioenergetic imbalance is corrected by pharmacologic treatment with EF24 in a rat model.

Publications

Hemorrhagic shock-induced cerebral bioenergetic imbalance is corrected by pharmacologic treatment with EF24 in a rat model.

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