Concussive brain injury is estimated to affect more than 500,000 Americans each year. The long-term results are often tragic both for the victim and for the family. In addition to mortality, the brain injury may result in the loss or substantial impairment of motor, sensory, and/or cognitive function. At the present time there are no effective treatment regimens that reliably and significantly improve the outcome following concussive brain injury. Until recently, it was commonly held that the brain was not able to recover from traumatic damage. Studies with methylprednisolone have demonstrated that early treatment following spinal cord trauma may significantly improve the clinical outcome. While no such treatment currently exists for brain trauma, it is now accepted that there is a series of early biochemical changes that occur within the first few minutes to hours. However, defining the window of opportunity to treat has not been possible in the past. We postulate that these early changes predispose the brain to secondary ischemic injury following trauma. This project is designed to characterize and modify the early and late cellular changes leading to secondary injury. We will demonstrate the time course for the early production free-radicals, leukotrienes, specific mRNAs, and oxidized proteins following concussive injury. Changes in enzymatic activity of marker enzymes (glutamine synthetase and ornithine decarboxylase) will be determined at different times following brain trauma. In addition, we will define the anatomic distribution of these changes in cellular function using histochemical staining for free-radical production, in inhibition of leukotriene synthesis, an inhibition of ornithine decarboxylase will be use as tools to understand the potential roles of each of these processes in the early changes following brain trauma. In addition, the effect of administration of insulin-like growth factor (IGF) on the post-concussive outcome measures described above will be determined. Once characterized, the parametric evaluation of the post-traumatic period with respect to intervention with free radical scavengers and growth factor will begin to describe the therapeutic window in the treatment of brain trauma.
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