Prostaglandin E2 EP2 Receptor Signaling Aggravates Intracerebral Hemorrhage-Induced Brain Injury

Inflammation after intracerebral hemorrhage (ICH) is a key component to secondary brain injury, a major cause of morbidity and disability after ICH. Prostaglandin E2 (PGE2) plays an important role in modulating inflammatory responses and in many neurologic disorders. PGE2 binds with high affinity to the G-protein-coupled receptors EP1, EP2, EP3, and EP4, which collectively mediate its neuroimmunomodulatory effects. We and others have documented that the EP2 receptor mediates the neuroprotective properties of PGE2 in neuronal cultures and in the middle cerebral artery occlusion model of ischemia/reperfusion-induced brain injury. The present study aimed to investigate the role of EP2 receptor signaling on anatomical and functional outcomes after ICH. The collagenase model was used to induce an ICH in wildtype (WT) and EP2-/- mice (n=8-11/group). After 72h, mice were sacrificed and brains collected for Cresyl Violet staining and lesion volume quantification. The EP2-/- displayed significantly reduced lesion volumes when compared to WT controls (pu003c0.005). The EP2-/- also showed reduced cortical and striatal microglial activation (pu003c0.05), and less cortical astrocyte activation (pu003c0.05). Collectively, these results suggest that PGE2-EP2 receptor signaling aggravates ICH-induced brain injury in vivo, which is in contrast to previous reports in stroke models, highlighting the dynamic role of the EP2 receptor in modulating inflammatory responses following brain damage. Further investigations are necessary in order to identify the mechanism of EP2-mediated hematoma resolution. Additional studies using a selective EP2 receptor antagonist could lead to the development of improved drugs that minimize the side effects often associated with anti-inflammatory medications in order to help prevent or improve neurologic recovery following ICH.