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.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Georgetown University
United States
Zip Code
Wrathall, Jean R; Emch, Gregory S (2006) Effect of injury severity on lower urinary tract function after experimental spinal cord injury. Prog Brain Res 152:117-34
Teng, Yang Dong; Bingaman, Marian; Taveira-DaSilva, Angelo M et al. (2003) Serotonin 1A receptor agonists reverse respiratory abnormalities in spinal cord-injured rats. J Neurosci 23:4182-9
Wasserman, Adam M; Ferreira Jr, Manuel; Sahibzada, Niaz et al. (2002) GABA-mediated neurotransmission in the ventrolateral NTS plays a role in respiratory regulation in the rat. Am J Physiol Regul Integr Comp Physiol 283:R1423-41
Grossman, S D; Wolfe, B B; Yasuda, R P et al. (2000) Changes in NMDA receptor subunit expression in response to contusive spinal cord injury. J Neurochem 75:174-84
Sahibzada, N; Ferreira, M; Wasserman, A M et al. (2000) Reversal of morphine-induced apnea in the anesthetized rat by drugs that activate 5-hydroxytryptamine(1A) receptors. J Pharmacol Exp Ther 292:704-13
Doherty, J; Gale, K; Eagles, D A (2000) Evoked epileptiform discharges in the rat anterior piriform cortex: generation and local propagation. Brain Res 861:77-87
Wasserman, A M; Sahibzada, N; Hernandez, Y M et al. (2000) Specific subnuclei of the nucleus tractus solitarius play a role in determining the duration of inspiration in the rat. Brain Res 880:118-30
Masco, D; Sahibzada, N; Switzer, R et al. (1999) Electroshock seizures protect against apoptotic hippocampal cell death induced by adrenalectomy. Neuroscience 91:1315-9
Kozikowski, A P; Araldi, G L; Tuckmantel, W et al. (1999) 1-amino-APDC, a partial agonist of group II metabotropic glutamate receptors with neuroprotective properties. Bioorg Med Chem Lett 9:1721-6
Dunah, A W; Yasuda, R P; Luo, J et al. (1999) Biochemical studies of the structure and function of the N-methyl-D-aspartate subtype of glutamate receptors. Mol Neurobiol 19:151-79

Showing the most recent 10 out of 108 publications