Traumatic brain injury (TBI) induces widespread membrane depolarization which causes an excessive release of neurotransmitters. The presence of high acetylcholine and glutamate levels following injury and the effectiveness of muscarinic and NMDA antagonists indicate that these neurotransmitter systems contribute to excitotoxic pathophysiology following TBI. We hypothesize that mechanisms mediating neurological deficits produced by TBI may be similar to mechanisms of neuronal damage induced by other CNS insults, including ischemia/hypoxia and prolonged seizures. Substantial evidence supports the contention that these insults, and adaptive processes such as long term potentiation, produce their long- lasting changes in neuronal function via receptor-mediated alteration of specific calcium-dependent enzymes. This proposal will critically examine the HYPOTHESIS that TBI produces long-lasting changes in calcium-dependent, receptor-associated enzymes. Using rodent models of TBI, we will investigate the effect of injury on protein kinase C, calcium-calmodulin- dependent protein kinase II and calpain. We will examine qualitative and quantitative alterations in enzyme activities as a function of brain region, time after injury, and injury magnitude. Further, we will investigate the effects of therapeutic intervention of enzyme function and behavioral outcome.
Our SPECIFIC AIMS are 1) to perform regional enzyme analyses to determine correlation with the regional differences in brain morphopathology, 2) to assay enzyme activity as a function of injury magnitude, 3) to examine the temporal relationships between TBI-induced enzyme alterations and TBI-induced deficits in motor and spatial memory performance, 4) to investigate the effect of therapeutic intervention using hypothermia and specific enzyme inhibitors on TBI-induced enzyme alterations and neurological outcome, and 5) to initiate biochemical characterization of TBI-altered enzymes to determine the specific molecular modifications caused by injury. Little is known about the cellular changes produced by TBI which cause the development of long-lasting functional deficits. We will provide data on whether or not specific enzymatic changes contribute to the prolonged neurological deficits caused by TBI. The proposed studies will initiate systematic examination of the basic biochemical sequalae of TBI and would support the development of strategies for the management of brain injury which target more restricted features of neurochemical derangements than possible with receptor antagonists.
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