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Commentary A substantial body of literature indicates that inflammation plays a key role in mediating seizure-induced brain injury and epileptogenesis leading to a quest for novel inflammatory mediators as therapeutic targets for epilepsy. Cyclooxygenase-2 (COX-2) is among several key inflammatory factors known to promote seizure-induced brain inflammation. It is rapidly induced by seizures in select brain regions and known to promote seizure-induced neuronal loss, leukocyte infiltration, astrogliosis, microglial activation, and breakdown of the blood–brain barrier (BBB). COX-2 has been explored as a therapeutic target for neuroprotection in epilepsy using a variety of approaches (1). While global inhibition of COX2 by genetic or pharmacologic approaches was complicated by its early protective versus delayed deleterious role in seizure-induced brain injury, a greater clarity was observed in a conditional knock-out mouse in which the COX-2 gene was selectively deleted postnatally in forebrain neurons specifically upregulating COX-2 after seizures. Forebrain-specific conditional COX-2 knock-out mice demonstrated delayed neuroprotection, decreased release of inflammatory mediators, and BBB permeability after seizures (2). Prostaglandin E2 (PGE2) is a major product of COX-2 in the brain and can activate four G-protein coupled receptors (GPCRs): EP1, EP2, EP3, and EP4. Whereas, PGE2 is considered a crucial mediator of COX-2–induced events following seizures, what specific class of prostanoid receptors mediates seizure-induced inflammation and neuronal death is unknown and the subject of investigation by Jiang et al. (3). Of the four receptors, EP2 receptor is expressed in both neurons and glia, and its activation is thought to promote inflammation and neurotoxicity in animal models of several neurodegenerative diseases. However, EP2 activation by PGE2 has been shown to be neuroprotective after ischemia and to promote spatial learning (3, 4). In an effort to elucidate EP2’s functions, Jiang et al. have previously utilized a high-throughput cell-based timeresolved fluorescence resonance energy transfer (TR-FRET) assay to identify selective allosteric potentiators of the human EP2 receptor, which conferred neuroprotection against NMDA-induced excitotoxicity in cultured hippocampal neurons (5). These initial studies accompanied by the observation that EP2 activation has some pathological consequences such as potentiation of inflammatory responses, allowed them to hypothesize that pharmacologic blockade of the PGE2/EP2 signaling might represent an innovative approach to mitigate delayed inflammation and neuronal damage induced by prolonged status epilepticus (SE). In earlier studies, the group developed a brain-permeable small molecule EP2 antagonist (TG4-155) that completely suppressed the induction of COX-2 mRNA in cultured microglia by EP2 activation and significantly reduced hippocampal neuronal injury in mice following pilocarpine-induced SE. However, Inhibition of the Prostaglandin Receptor EP2 Following Status Epilepticus Reduces Delayed Mortality and Brain Inflammation.

StEPing “EP2” to Prevent Status Epilepticus–Induced Mortality and Inflammation