CASPASE MEDIATED NEURONAL DEATH AFTER HEAD INJURY

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Caspase activation is the first committed step in the programmed-cell death cascade, a tightly regulated sequence of cellular and molecular events that systematically leads to the death of a cell. Increasing evidence suggests that activation of caspases produces secondary neuronal death after traumatic brain injury in experimental models. Importantly, pharmacologic and molecular inhibitors of the caspases attenuate programmed cell-death after cerebral ischemia and traumatic brain injury in rodents, although reports are limited. Our hypothesis is that activation of caspases after traumatic brain injury contributes to neuronal death and that inhibiting induction and/or activity of caspases reduces secondary neuropathologic injury after traumatic brain injury. Specific aims to address this hypothesis will: 1) characterize the temporal, regional, cellular, and subcellular expression and activity of Caspase-3 using a rat model that mimics severe human traumatic brain injury, 2) examine the upstream regulation the upstream regulation of caspases by cytosolic cytochrome c and nitric oxide after severe traumatic brain injury in rats and mice, 3) test the effects of several pharmacologic caspase inhibitors on neuropathologic and functional outcome after severe traumatic brain injury in rats, 4) examine the expression of other caspases (Caspases-2 and -9) after severe traumatic brain injury in rats, and 5) examine the expression of currently identified caspase (Caspases -2 -9) after severe traumatic brain injury in rats, and 5) examine the expression of currently identified caspases (Caspases 1-10) after severe traumatic brain injury in humans. Traumatic brain injury is a major cause of mortality and morbidity in adults and children in the United States. Secondary brain injury contributes to mortality and morbidity in adults and children in the United States. Secondary rain injury contributes to mortality and morbidity and currently only few, non-specific therapies are available. Caspase-mediated programmed-cell death may contribute to secondary neuronal death after traumatic brain injury in experimental models and in humans as well. Pharmacologic treatment strategies aimed at reducing caspase induction and/or activation to subsequently reduce secondary neuronal death will be tested in models of traumatic brain injury in vivo. If caspase inhibitors reduce programmed-cell death and improve neurologic outcome after severe traumatic brain injury in vivo, a novel, clinically relevant treatment strategy for victims of severe head injury will be available.