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Author Notes:

To whom correspondence should be addressed. E-mail: jjiang3@emory.edu.

Edited by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved January 17, 2013 (received for review October 23, 2012)

Author contributions: J.J., F.E.D., and R.D. designed research; J.J., Y.Q., T.G., and W.A.P. performed research; J.J., Y.Q., W.A.P., F.E.D., and R.D. analyzed data; and J.J. and R.D. wrote the paper.

Subjects:

Research Funding:

This work was supported by the Epilepsy Foundation (J.J.); the CounterACT Program, National Institutes of Health, Office of the Director, and National Institute of Neurological Disorders and Stroke (NINDS) Grant U01NS058158 (to R.D.); and NINDS Grants R21NS074169 (to R.D.) and N01NS42359 [to F.E.D. (H. Steve White, principal investigator)].

Keywords:

  • inflammatory cytokine
  • electroencephalography
  • epileptogenesis
  • gliosis
  • neuronal injury

Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation

Tools:

Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 110, Number 9

Publisher:

, Pages 3591-3596

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Prostaglandin E2 is now widely recognized to play critical roles in brain inflammation and injury, although the responsible prostaglandin receptors have not been fully identified. We developed a potent and selective antagonist for the prostaglandin E2 receptor subtype EP2, TG6-10-1, with a sufficient pharmacokinetic profile to be used in vivo. We found that in the mouse pilocarpine model of status epilepticus (SE), systemic administration of TG6-10-1 completely recapitulates the effects of conditional ablation of cyclooxygenase-2 from principal forebrain neurons, namely reduced delayed mortality, accelerated recovery from weight loss, reduced brain inflammation, prevention of blood–brain barrier opening, and neuroprotection in the hippocampus, without modifying seizures acutely. Prolonged SE in humans causes high mortality and morbidity that are associated with brain inflammation and injury, but currently the only effective treatment is to stop the seizures quickly enough with anticonvulsants to prevent brain damage. Our results suggest that the prostaglandin receptor EP2 is critically involved in neuroinflammation and neurodegeneration, and point to EP2 receptor antagonism as an adjunctive therapeutic strategy to treat SE.

Copyright information:

Beginning with articles submitted in Volume 106 (2009) the author(s) retains copyright to individual articles, and the National Academy of Sciences of the United States of America retains an exclusive license to publish these articles and holds copyright to the collective work.

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