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Abstract
Glutamate receptor-mediated excitotoxicity is a common pathogenic process in many
neurological conditions including epilepsy. Prolonged seizures induce elevations in
extracellular glutamate that contribute to excitotoxic damage, which in turn can trigger
chronic neuroinflammatory reactions, leading to secondary damage to the brain. Blocking
key inflammatory pathways could prevent such secondary brain injury following the
initial excitotoxic insults. Prostaglandin E2 (PGE 2 ) has emerged as an important
mediator of neuroinflammation-associated injury, in large part via activating its
EP2 receptor subtype. Herein, we investigated the effects of EP2 receptor inhibition
on excitotoxicity-associated neuronal inflammation and injury in vivo . Utilizing
a bioavailable and brain-permeant compound, TG6–10–1, we found that pharmacological
inhibition of EP2 receptor after a one-hour episode of kainate-induced status epilepticus
(SE) in mice reduced seizure-promoted functional deficits, cytokine induction, reactive
gliosis, blood-brain barrier impairment, and hippocampal damage. Our preclinical findings
endorse the feasibility of blocking PGE 2 /EP2 signaling as an adjunctive strategy
to treat prolonged seizures. The promising benefits from EP2 receptor inhibition should
also be relevant to other neurological conditions in which excitotoxicity-associated
secondary damage to the brain represents a pathogenic event.