All ETDs from UAB

Advisory Committee Chair

Candace L Floyd

Advisory Committee Members

Etty N Benveniste

Timothy J Ness

Harald W Sontheimer

Scott M Wilson

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Spinal cord injury (SCI) is a devastating condition resulting in loss of motor function as well as sensory abnormalities. Insight into the pathophysiology of SCI progression has been gained through use of pre-clinical animal models, however these have not been successful in yielding pharmacological interventions for clinical management of SCI. One proposed reason for this discrepancy may be the use of SCI models which are not fully clinically relevant and do not assess the contribution of gray matter pathology to SCI functional outcomes. Post-SCI inflammation is well-documented and may lead to downstream loss of motor function. Additionally, inflammation is thought to play a role in the development of neuropathic pain through activation of glial cell populations. The transcription factor nuclear factor kappa B (NF-kappaB) controls the production of multiple proinflammatory mediators and is acutely upregulated post-SCI. Thus, inhibition of NF-kappaB may serve as a key target to preserve downstream motor function and inhibit neuropathic pain post-SCI. The first experiment performed describes the effect of varying impact forces of cervical hemicontusion SCI on locomotor and forelimb function as well as tissue lesion characteristics. We report that histological assessments of gray and white matter tissue damage are significantly correlated with impairments in forelimb and locomotor function. These findings indicate that both gray and white matter pathology are implicated in the loss of motor function post-cervical SCI. The second experiment describes the effect of a previously described neuroprotectant, 17beta-estradiol (E2), on functional recovery and histological lesion characteristics using this newly characterized cervical SCI model. We report that E2 administration post-SCI significantly increases forelimb and locomotor function with corresponding decreased gray and white matter tissue damage. The third experiment describes the effect of sulfasalazine (SSZ), an inhibitor of NF-kappaB, on functional recovery and neuropathic pain post-SCI. We report that SSZ administration post-SCI has no effect on functional recovery, however significantly decreases the incidence of neuropathic pain behaviors through inhibition of NF-kappaB acutely post-SCI. Collectively, this body of work describes the characterization of a clinically relevant model of cervical SCI and the promising effects of two novel pharmacological interventions on functional recovery and neuropathic pain.

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