Suppressing pro-inflammatory prostaglandin signaling attenuates excitotoxicity-associated neuronal inflammation and injury

• Type of Material: Article
• Authors: Jianxiong Jiang, University of Tennessee; Ying Yu, University of Tennessee; Erika Reime Kinjo, University of Cincinnati; Yifeng Du, University of Cincinnati; Phuong Nguyen Hoang, University of Tennessee; Raymond Dingledine, Emory University
• Language: English
• Date: 2019-05-01
• Publisher: Elsevier Science Ltd.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Elsevier Ltd.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuropharm.2019.02.011
• Title of Journal or Parent Work: Neuropharmacology
• Volume: 149
• Start Page: 149
• End Page: 160
• Grant/Funding Information: This work was supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) grants R00NS082379 (J.J.), R01NS100947 (J.J.), R21NS109687 (J.J.), and R01NS097776 (R.D.).
• Keywords: Seizures; PGE(2); Epilepsy; Neurosciences; Inhibition; Excitotoxicity; Pilocarpine; Induced standard epilepticus; Seizure; Cyclooxygenase 2; Neurosciences & Neurology; Delayed mortality; Science & Technology; Prostaglandin; EP2 receptor; Blood-brain barrier; Kainate; Neuroprotection; Life Sciences & Biomedicine; Targets; Pharmacology & Pharmacy; Brain inflammation
• Research Categories: Chemistry, Biochemistry; Biology, Neuroscience; Health Sciences, Pharmacology

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.