This proposal seeks support for a comprehensive clinical and laboratory center for the study of head injury. Our primary objective is to evaluate the efficacy of either IV administered superoxidase dismutase or scopolamine in improving morbidity and mortality in several head-injury humans. The rationale of this approach rests upon key laboratory tory findings which indicate that traumatic brain injury is associated withth the generation of damaging oxygen radicals which adversely influence the cerebral vasculature and the release of excitatory neurotransmittter which contribute to pathologic agonist-receptor interactions. The efficacy of these drugs will be assessed in a collaborative three- arm trialhere at the Medical College of Virginia and at the Maryland Institute for Emergency Medical Services Systems. Standardized outcome measures will be used by both groups and will be complemented by clinical studies directed toward assessment of cerebrovascular damage and brain function using non-invasive measures. The proposed laboratory studies will complement the clinical trial while providing new insights into those mechanisms possibly amenable to future therapeutic intervention. Having made the seminal observations regarding the damaging consequences of oxygen radicals and excessive neurotransmitter release, we now extend these observations along new lines of inquiry. The possible co- involvement of cholinergic muscarinic and glutamate NMDA receptors will be explored. Age related changes will be considered as will the protective effect of endogenous and exogenous opioid peptides. The interactive role of altered bloodbrain barrier status as well as other contributing forms of vascular compromise will be evaluated. Lastly, the potential that the increased release of excitatory transmitters contributes to radical formation will be explored. The goals of the proposed laboratory studies will further complement the trial and thus, will continue our longstanding tradition of strong clinical and laboratory interaction. Through the accomplishment of these goals we feel confident that we will be capable of improving outcome in patients with severe head injury.
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