Inhibition of cyclooxygenase and EP3 receptor improved long term potentiation in a rat organotypic hippocampal model of repeated blast traumatic brain injury.

Abstract

Blast-induced traumatic brain injury (bTBI) is a health concern in military service members who are exposed to multiple blasts throughout their training and deployment. Our group has previously reported decreased long term potentiation (LTP) following repeated bTBI in a rat organotypic hippocampal slice culture (OHSC) model. In this study, we investigated changes in inflammatory markers like cyclooxygenase (COX) and tested the efficacy of COX or prostaglandin EP3 receptor (EP3R) inhibitors in attenuating LTP deficits. Expression of COX-2 was increased 48h following repeated injury, whereas COX-1 expression was unchanged. EP3R expression was upregulated, and cyclic adenosine monophosphate (cAMP) concentration was decreased after repeated blast exposure. Post-traumatic LTP deficits improved after treatment with a COX-1 specific inhibitor, SC-560, a COX-2 specific inhibitor, rofecoxib, a pan-COX inhibitor, ibuprofen, or an EP3R inhibitor, L-798,106. Delayed treatment with ibuprofen and L-798,106 also prevented LTP deficits. These findings suggest that bTBI induced neuroinflammation may be responsible for some functional deficits that we have observed in injured OHSCs. Additionally, COX and EP3R inhibition may be viable therapeutic strategies to reduce neurophysiological deficits after repeated bTBI.