AMELIORATION OF MITOCHONDRIAL-FUNCTION BY A NOVEL ANTIOXIDANT U-101033E FOLLOWING TRAUMATIC BRAIN INJURY IN RATS

In the present study, a severe traumatic brain injury (TBI) was produc ed over the right parietal cortex of rats using the controlled cortica l impact injury (CCII) model, TBI perturbed calcium homeostasis and im paired electron transfer and energy coupling activities of forebrain m itochondria isolated from injured hemispheres with a maximal injury at 12-72 h, Efficacy of the blood-brain barrier penetrating antioxidant U-101033E on TBI-induced mitochondrial impairment was evaluated, In th e dose-response experiment, two i.v. boluses (vehicle or 1-10 mg/kg of U-101033E) were administered at 5 min and 2h post-TBI, Forebrain mito chondria from each hemisphere were examined at 12 h post-injury, With respect to forebrain mitochondrial dysfunction, the drug showed a bell -shaped dose-response curve with an optimal dose of 3 mg/kg (n = 5, p < 0.05 vs, vehicle), In the time-course experiment, two i.v. boluses o f 3 mg U-101033E/kg (the optimal dose) were given at 5 min and 2 h pos t-injury and forebrain mitochondria were examined at 6 h-14 days post- injury, U-101033E significantly restored electron transfer, energy cou pling capacity, and Ca2(+) transport capacity during 6 h to 14 days po st-injury, Our data indicate that the antioxidant U-101033E administer ed post-injury at proper dosage can effectively restore TBI-induced mi tochondrial dysfunction and support the contention that oxidative stre ss plays an important role in the pathogenesis of TBI.