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 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.

Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock

“…Several studies have demonstrated a decline in mitochondrial function in HI 41 , 42 . Our recent studies have shown that agents such as resveratrol and SRT1720 that have profound effects on mitochondria can rescue rats following HI in the absence of fluid resuscitation 22 .…”

Modeling traumatic brain injury combined with hemorrhagic shock in rats: Neurological assessment and PET imaging with 18F-fluorodeoxyglucaric acid

“…Chesnut et al reported that hypovolemia and hypoxia increased TBI-induced morbidity by 150% 6 . HS influences brain injury by causing ischemia, bioenergetic imbalance 21 , and promotion of excitatory signaling in the brain 38,39 . The aggravated TBI+HS tissue injury clinically manifests as increased mortality or severe neurological deficits 6,7,40,41 .…”

“…Rats in the sham group differed from mTBI rats only in that they did not receive an impact to the brain. Hemorrhagic shock: HS was performed approximately 15-30 min after rats recovered from mTBI surgery anesthesia by withdrawing blood via the arterial catheter as described previously [21][22][23] . Following the constant volume model, varying volumes of blood (0%, 35-40%, 44-46%, and 48-50% of total blood) were withdrawn at a rate of 1.0 ml/min to generate four trauma groups: mTBI alone, mTBI+HS ≤ 40% , mTBI+HS 45% , and mTBI+HS 50%, respectively.…”

In vivo 31P magnetic resonance spectroscopy study of mouse cerebral NAD content and redox state during neurodevelopment

“…This approach suffers from low detection sensitivity and limited tissue penetration, with the major drawback being that NAD + is not detected 14 . The biochemical analysis effectuated with HPLC, capillary electrophoresis or enzymatic cycling assays requires a tissue biopsy and some extraction prior to analysis 15 – 17 . This process might lead to large quantification errors for the highly sensitive redox pairs that have been shown to be rapidly altered after death 18 , 19 .…”