After traumatic brain injury (TBI) prostaglandin synthesis rises acutely. While this may result in selective beneficial responses, we propose that chronic prostaglandin production contribute to free radical mediated cellular damage, vascular dysfunction, alterations in cellular metabolism, and apoptosis. These may result in secondary injuries to the brain, promote neuropathology, and worsen behavioral outcome. Cyclooxygenase-2 (COX2) is a primary inflammatory mediator that catalyzes the conversion of arachidonic acid from damaged membranes into vasoactive prostaglandins, producing reactive oxygen free radicals in the process. Under normal conditions this enzyme is not detectable, except in the brain. Its role there is not known, but the brain and its vasculature have unique regulatory pathways and metabolic requirements that differ from other organs. We have recently established that cerebral COX2 induction is an immediate early response in two models of TBI. In addition, histochemical and mRNA analyses have revealed prolonged elevations in COX2 expression in the cortex and hippocampus. Using novel techniques developed in our lab, we have confirmed a prolonged increase in COX2 protein and prostaglandin levels, as well. Improvements in postinjury behavioral recovery have been observed after treatment with a dehydroepiandrosterone (DHEA) analog that attenuates cytokine-mediated COX2 induction in vitro. Using in vivo model systems we will determine the time course and neuroanatomical localization of changes in COX2 mRNA, protein, and prostaglandin concentrations. We will begin to elucidate the mechanism(s) of action of COX2 following TBI by treating injured animals with agents that improve behavioral recovery via attenuating COX2 expression, inhibiting COX2 activity, or blocking receptor binding of the prostaglandins produced after TBI. Knowledge of these events will serve as the rational basis for pharmacological interventions to ameliorate the secondary pathologies that lead to worsening neurological and cognitive deficits in human victims of TBI.
NIH ExPorter
NIH ExPorter