Targeting prostaglandin receptor EP2 for adjunctive treatment of status epilepticus

Status epilepticus (SE) is an emergency condition that can cause permanent brain damage or even death when generalized convulsive seizures last longer than 30 min. Controlling the escalation and propagation of seizures quickly and properly is crucial to the prevention of irreversible neuronal death and the associated morbidity. However, SE often becomes refractory to current anticonvulsant medications, which primarily act on ion channels and commonly impose undesired effects. Identifying new molecular targets for SE might lead to adjunctive treatments that can be delivered even when SE is well established. Recent preclinical studies suggest that prostaglandin E2 (PGE₂) is an essential inflammatory mediator for the brain injury and morbidity following prolonged seizures via activating four G protein-coupled receptors, namely, EP1-EP4. Given that EP2 receptor activation has been identified as a common culprit in several inflammation-associated neurological conditions, such as strokes and neurodegenerative diseases, selective small-molecule antagonists targeting EP2 have been recently developed and utilized to suppress PGE₂-mediated neuroinflammation. Transient inhibition of the EP2 receptor by these bioavailable and brain-permeable antagonists consistently showed marked anti-inflammatory and neuroprotective effects in several rodent models of SE yet had no noticeable effect on seizures per se. This review provides overviews and perspectives of the EP2 receptor as an emerging target for adjunctive treatment, together with the current first-line anti-seizure drugs, to prevent acute brain inflammation and damage following SE.