PGE ₂ signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia

Abstract

Significance Stroke is the leading cause of disability and fifth leading cause of mortality in the United States. Previous studies demonstrate a highly protective effect of inhibiting cyclooxygenase-2 (COX-2) after stroke, indicating that downstream PGE 2 signaling pathways cause cerebral ischemic injury. Using conditional knockout strategies to study the role of PGE 2 EP2 signaling in a model of cerebral ischemia, we determine that neuronal EP2 signaling, which is highly induced following cerebral ischemia, increases cerebral injury. We demonstrate that EP2 blockade in adult mice is highly cerebroprotective and myeloid EP2 signaling increases the poststroke innate immune response. Additionally, the present results differ from previous studies of congenitally null EP2 mice, reflecting a potential confounding effect of congenital deletion of EP2.