Traumatic spinal cord injury (SCI) results in mechanical injury, tissue loss and consequent functional deficits. In addition, the initial mechanical injury is followed by biochemical alterations that are believed to cause secondary injury that adds to the overall functional impairment. Our objective is to gain an increased understanding of these secondary injury processes that can be used as the basis for effective therapies to reduce the consequences of SCI. Progress in the initial project period has strongly supported our original hypothesis that excitatory amino acids (EAA) play an important role in secondary injury. We have found that several antagonists of EAA receptors, administered at the time of or after SCI, can significantly reduce long-term functional deficits that result from a standardized experimental contusion. Further, we have obtained, for the first time, evidence implicating local non-NMDA receptors at the injury site in contributing to overall functional deficits. Based on these results, we now have three specific aims. 1) To investigate the therapeutic potential of our findings, we will determine whether EAA antagonists are effective under conditions characteristic of a clinical trial, such as delayed systemic administration, varying injury severity, animals of both sexes, and the presence of other drugs now routinely administered to SCI patients. Our approach will be to use a standardized rat model of graded thoracic contusive injury and examine the effects on hindlimb function as measured by a battery of behavioral tests over 4 weeks or more after SCI. 2) To further characterize EAA-mediated secondary injury, we will use EAA antagonists as probes to examine the time course, location(s) and receptor type(s) involved. The antagonists will be introduced focally by stereotaxically guided microinjection into the injury site, adjacent, or distal spinal cord tissue. The degree to which functional deficits are ameliorated will be determined by behavioral testing. 3) To examine the anatomical basis of the reduced hindlimb functional deficits after thoracic SCI that we observe with EAA antagonists, we will determine whether effective treatment is associated with significant changes in the effects of injury on neurons, axons or glia adjacent to the injury site and/or distal effects, at the lumbar enlargement. Spinal cord tissue at various times after SCI, with or without the administration of EAA antagonists, will be examined by morphometric, immunocytochemical and molecular techniques. The overall results from this project should contribute to our understanding of SCI and the progress towards more effective therapy for SCI patients.
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