MITOCHONDRIAL DYSFUNCTION AFTER EXPERIMENTAL TRAUMATIC BRAIN INJURY -COMBINED EFFICACY OF SNX-111 AND U-101033E

We recently demonstrated that posttraumatic administration of the N-ty pe calcium channel blocker SNX-111 (S) and a novel blood-brain barrier penetrating antioxidant U-101033E (U), significantly alleviated mitoc hondrial dysfunction induced by traumatic brain injury (TBI) in rats. The present study was designed to determine whether a combination of S and U, which act on different biochemical mechanisms of secondary bra in injury, would be more efficacious than either drug alone. Brain mit ochondria from injured and uninjured hemispheres were isolated and exa mined at 12 h post TBI induced by a severe controlled cortical impact injury. S at 1.0 mg/kg significantly increased both State 3 and 4 rate s and produced a slight increase in P/O ratio, and there was virtually no change in RCI, U at 1.0 mg/kg did not show any protection. However , the combined treatment of S at 1.0 mg/kg and U at 1.0 mg/kg eliminat ed the uncoupling effect of S, and restored not only State 3 rates and P/O ratios but also RCI to near sham values. These results provide fu rther evidence that both reactive oxygen species and perturbation of c ellular calcium homeostasis participate in the pathogenesis of TBI-ind uced mitochondrial dysfunction, and support the idea of using combined therapy with lower drug doses.