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The Role of Toll-Like Receptor 4 in the Secondary Pathogenesis of Spinal Cord InjurySpinal cord injury (SCI) is a leading cause of paralysis and disability worldwide, however no successful treatments have been developed partly due to a lack of understanding of SCI pathophysiology. This study established a model of compression SCI for investigation of the proinflammatory receptor, toll-like receptor 4. The model was validated measuring motor function, lesion size, Fluoro-Jade B staining, and western blots of PARP cleavage and 3-nitrotyrosine. Western blots and immunohistochemistry showed a biphasic upregulation of TLR4 in neurons after injury with peaks at 6 and 48 hours post-SCI. TLR4 mutant mice showed diminished lesion size, Fluoro-Jade B and hydroethidine staining, as well as improved motor function; and pre-treatment with TLR4 antagonist, VGX-1027, in wild type (WT) mice improved motor function as well. GP91 expression was unchanged in TLR4 mutants, suggesting changes in superoxide production may be NOX2 independent. This study suggests that targeting TLR4 may be viable therapeutic strategy for the repair/treatment of SCI.