title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, 1110 North Stonewall Avenue, Oklahoma City, OK 73117, USA.
authors.forename: Geeta
authors.initials: G
authors.lastname: Rao
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, 1110 North Stonewall Avenue, Oklahoma City, OK 73117, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, 1110 North Stonewall Avenue, Oklahoma City, OK 73117, USA.
authors.forename: Andria
authors.initials: A
authors.lastname: Hedrick
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, 1110 North Stonewall Avenue, Oklahoma City, OK 73117, USA. Electronic address: vawasthi@ouhsc.edu.
authors.forename: Vibhudutta
authors.initials: V
authors.lastname: Awasthi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010725:Phosphocreatine / Q000378:metabolism; D010881:Piperidones / Q000494:pharmacology*; D019289:Pyruvic Acid / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: C524042:3,5-bis(2-fluorobenzylidene)piperidin-4-one; D001597:Benzylidene Compounds; D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D010881:Piperidones; D010725:Phosphocreatine; D009243:NAD; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D020932:Nerve Growth Factor
keywords: Brain; Cerebral metabolism; Hypovolemic shock; Resuscitation; Trauma