Inhibiting the PGE₂ Receptor EP2 Mitigates Excitotoxicity and Ischemic Injury

Prostaglandin E2 (PGE₂) is elevated in the brain by excitotoxic insults and, in turn, aggravates the neurotoxicity mainly through acting on its Gα_s-coupled receptor EP2, inspiring a therapeutic strategy of targeting this key proinflammatory pathway. Herein, we investigated the effects of several highly potent and selective small-molecule antagonists of the EP2 receptor on neuronal excitotoxicity both in vitro and in vivo. EP2 inhibition by these novel compounds largely decreased the neuronal injury in rat primary hippocampal cultures containing both neurons and glia that were treated with N-methyl-d-aspartate and glycine. Using a bioavailable and brain-permeant analogue TG6-10-1 that we recently developed to target the central EP2 receptor, we found that the poststroke EP2 inhibition in mice decreased the neurological deficits and infarct volumes as well as downregulated the prototypic inflammatory cytokines in the brain after a transient ischemia. Our preclinical findings together reinforced the notion that targeting the EP2 receptor represents an emerging therapeutic strategy to prevent the neuronal injury and inflammation following ischemic stroke.