COX-2 Pathophysiology in Spinal Cord Injury

Traumatic spinal cord injury (SCI) results in a loss of vOluntary motor and sensory function below the site of injury and affects some 300,000 individuals in the United States with -10,000 new cases each year. Pathophysiological secondary responses following the initial insult promote additional and extensive damage occurring hours to weeks following injury and, therefore, are amenable to therapeutic interventions. Current therapies provide, at best, modest improvement of function and alternative strategies are warranted. The studies proposed in this application are designed to identify and better characterize the pathophysiological consequences of cyclooxygenase (COX) expression in traumatic spinal cord injury (SCI). Despite evidence of a pathological role for COX-2 induction in several models of central nervous system (CNS) injury, the role of the two COX isoforms (COX-1 and COX-2) as a mediators of cell death following SCI is unclear. The overall objective of the proposed experiments is to provide evidence that COX functions as an intracellular activator of cytotoxic oxidative damage and a mediator of apoptotic cell death following SCI. Specific Aim 1 will use pharmacological strategies and a number of biochemical assays to examine the contribution of COX-1 and COX-2 to oxidative damage. Studies in Specific Aim 2 will document conclusively, that COX expression occurs in cells that are undergoing apoptotic cell death following SCt (Aim 2a). and demonstrate that inhibiting the actions of either COX isoform reduces the appearance of apoptotic markers (Aim 2b). Studies proposed in Specific Aim 2 are a logical extension of Aim 1 as several studies have demonstrated that oxidative damage contributes to apoptotic cell death. Finally, Specific Aim 3 will demonstrate the therapeutic potential of blocking the actions of COX-1 or COX-2 in SCI. This will include a battery of behavioral tests that are highly sensitive to changes in sensorimotor and coordinated locomotor function. In addition, histological and morphological studies will be performed to document long term cell survival, improved tissue sparing at the injury epicenter, and enhanced myelination in fiber tracks distant to the site of injury. The outcome of these studies will document the pathophysiological involvement of COX expression in cell death following SCI, which has clear clinical implications for developing therapies in the treatment of SCI in humans.