Abstract W P260: Role of the Prostaglandin E2 EP1 Receptor in Traumatic Brain Injury

Abstract

Introduction: Brain injuries promote upregulation of so-called proinflammatory prostaglandin E2 leading to overactivation of a class of its cognate G-protein coupled receptors, notably EP1, which is considered as a promising target for treatment of ischemic stroke and, possibly, other neurological disorders involving excitotoxicity. However, our recent data suggest that of EP1 receptor in intracerebral hemorrhage may play a protective role. The goal of this study was to investigate a translational potential of EP1 receptor for treatment of traumatic brain injury (TBI). Methods: The acute brain injury was induced using controlled cortical impact (CCI) in wildtype (WT) and genetic EP1 receptor knockout mice (EP1-/-). Neurological deficit scores (NDS) and anatomical brain pathology were accessed at 48h after injury. Results: CCI resulted in significant cortical lesions, localized hippocampal edema and neurological deficits compared to animals from sham group underwent craniotomy only. The NDS after CCI were significantly higher in older mice (7-11mo) compared to young adult animals (2-4mo) in both WT and EP1-/- groups. Treatment with a selective antagonist SC-51089 with repeated doses of 20-100μg/kg after CCI had no significant effects on cortical lesions, hippocampal edema and NDS in young adult mice of both WT and EP1-/- genotypes. Post-treatment with 17-pt-PGE2 (300μg/kg) had no significant effects on anatomical brain pathology in young adult mice, but improved NDS at 24h in WT but not in EP1-/- mice. Immunohistochemistry revealed significant increases in GFAP and Iba1 immunoreactivity in selected brain regions surrounding injury suggesting astrogliosis and microglia activation. EP1 receptor knockout had no effects on GFAP and Iba1 expression in young adult mice, whereas lead to a significant attenuation of GFAP immunoreactivity in older mice. Conclusions: This study provides, for the first time, a clarification on the role of EP1 receptor in a preclinical model of contusive TBI. The results suggest that EP1 receptor might be involved in complex pathways differentially associated with neurological deficits. In addition, this study provides further clarification on clinical use of EP1 receptor ligands for treatment of acute brain injuries.