Because of widespread axonal damage in most cases of prolonged traumatic coma, we have termed this clinical-pathological condition diffuse axonal injury (DAI). DAI comprises 44% of sever head injuries, is responsible for one-third of all head injury deaths, and is the greatest cause of vegetative and severely impaired survivors. In addition, axonal damage occurs to a lesser degree each year in several million Americans who sustain concussion and focal brain injuries. There is no known therapy specific for axonal injury or DAI. In our previous work, we have determined that axonal damage occurs principally at the node of Ranvier and that many axons are not severed at the time of injury, but undergo a progressive degeneration that leads to secondary axotomy after several days. We have held that a better understanding of the events leading the secondary axotomy may allow therapeutic intervention to prevent it from occurring, thereby permitting axonal repair and restitution of function to occur. In this proposal, we will extend these observations on the theme of diffuse Axonal Injury and test the hypothesis that secondary axotomy and traumatic neuronal dysfunction is a product of two factors: calcium mediated damage at the site of injury and the effects of receptor mediated events. The latter can be produced either as a result of axonal damage or by direct damage to dendritic or perikaryal elements. To address this hypothesis, our goals are 1) to define the relationship of histologic patterns of axonal damage and neurotransmitter receptor abnormality in human and experimental head injury, 2) to determine the role of calcium in cytoskeletal degradation by electron microscopic immunohistochemistry and to assess the effect on calcium mediated damage by voltage dependent calcium channel blockade, inhibition of calcium activated proteases and mitigation of the calcium activated phospholipase cascade, 3) to determine, by unit recordings, microiontophoretic application receptor agonists and antagonists and in-situ hybridization of heat shock proteins, the mechanisms of perikaryal overexcitation after injury and the influence of perikaryal changes on axonal damage, 4) to assess the degree that receptor mediated mechanisms affect axonal and neuronal survival by treatment with low threshold calcium channel, NMDA or non-NMDA antagonists, 5) to develop animate and inanimate models of axonal injury and DAI that are clinically realistic, and 6) to define the effects of neuroprotective agents that can lead to clinical treatment trials.

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