Neuronal cell loss following CNS injury results from apoptosis as well as necrosis. Although apoptosis has been demonstrated in brain after experimental traumatic brain injury (TBI), a critical role for apoptosis in post-traumatic tissue damage and related neurological deficits has yet to be established. Moreover, little is known about the molecular mechanisms involved in apoptosis after CNS injury. A number of studies have suggested a role for ICE or CPP32-like cysteine proteases (Called caspase-1 and caspase-3, respectively) in apoptosis of mammalian cells and the principal investigator has recently demonstrated that activation of caspase-3 is a control factor in apoptosis of cerebellar granular cells subjected to combined serum/K+ deprivation. Preliminary studies from our laboratory also indicate that activation of caspase-3 may be an important factor contributing to neuronal apoptosis following TBI in rats. The proposed studies are intended to address the following hypotheses: (1) TBI causes increased CPP32-like activity associated with neuronal apoptosis ; (2) Inhibition of caspase-3, but not ICE-like cysteine proteases (caspase-1), reduces post-traumatic apoptosis and associated neurological deficits.
Specific Aims are: (1) To characterize the degree and temporal profile of apoptosis and to delineate the cell types involved in affected brain regions following lateral fluid percussion induced TBI in rats; (2) To determine tissue and cell-type specific changes in CPP32-like activity as a function of injury severity and time after trauma, as well as to correlate such changes with neuronal apoptosis; and (3) To examine the ability of selective caspase inhibitors to reduce post-traumatic caspase activity and related neuronal apoptosis, as well as associated neurological deficits after TBI, including determination of the therapeutic window for such neuroprotective actions.
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