Abstract
Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of severe and permanent neurologic disability after birth. The inducible cyclooxygenase COX-2, which along with COX-1 catalyzes the first committed step in prostaglandin (PG) synthesis, elicits significant brain injury in models of cerebral ischemia; however its downstream PG receptor pathways trigger both toxic and paradoxically protective effects. Here, we investigated the function of PGE(2) E-prostanoid (EP) receptors in the acute outcome of hypoxic-ischemic (HI) injury in the neonatal rat. We determined the temporal and cellular expression patterns of the EP1-4 receptors before and after HIE and tested whether modulation of EP1-4 receptor function could protect against cerebral injury acutely after HIE. All four EP receptors were expressed in forebrain neurons and were induced in endothelial cells after HIE. Inhibition of EP1 signaling with the selective antagonist SC-51089 or co-activation of EP2-4 receptors with the agonist misoprostol significantly reduced HIE cerebral injury 24 h after injury. These receptor ligands also protected brain endothelial cells subjected to oxygen glucose deprivation, suggesting that activation of EP receptor signaling is directly cytoprotective. These data indicate that the G-protein coupled EP receptors may be amenable to pharmacologic targeting in the acute setting of neonatal HIE.