Inhibition of human microsomal PGE2 synthase-1 reduces seizure-induced increases of P-glycoprotein expression and activity at the blood-brain barrier

Emma L.B. Soldner, Anika M.S. Hartz, Shin Ichi Akanuma, Anton Pekcec, Henri Doods, Richard J. Kryscio, Ken Ichi Hosoya, Björn Bauer

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

The cause of antiseizure drug (ASD) resistance in epilepsy is poorly understood. Here, we focus on the transporter P-glycoprotein (P-gp) that is partly responsible for limited ASD brain uptake, which is thought to contribute to ASD resistance. We previously demonstrated that cyclooxygenase-2 (COX-2) and the prostaglandin E receptor, prostanoid E receptor subtype 1, are involved in seizure-mediated P-gp up-regulation. Thus, we hypothesized that inhibiting microsomal prostaglandin E2 (PGE2) synthase-1 (mPGES-1), the enzyme generating PGE2, prevents blood-brain barrier P-gp up-regulation after status epilepticus (SE). To test our hypothesis, we exposed isolated brain capillaries to glutamate ex vivo and used a combined in vivo-ex vivo approach by isolating brain capillaries from humanized mPGES-1 mice to study P-gp levels. We demonstrate that glutamate signaling through the NMDA receptor, cytosolic phospholipase A2, COX-2, and mPGES-1 increases P-gp protein expression and transport activity levels. We show that mPGES-1 is expressed in human, rat, and mouse brain capillaries. We show that BI1029539, an mPGES-1 inhibitor, prevented up-regulation of P-gp expression and transport activity in capillaries exposed to glutamate and in capillaries from humanized mPGES-1 mice after SE. Our data provide key signaling steps underlying seizure-induced P-gp up-regulation and suggest that mPGES-1 inhibitors could potentially prevent P-gp up-regulation in epilepsy.—Soldner, E. L. B., Hartz, A. M. S., Akanuma, S.-I., Pekcec, A., Doods, H., Kryscio, R. J., Hosoya, K.-I., Bauer, B. Inhibition of human microsomal PGE2 synthase-1 reduces seizure-induced increases of P-glycoprotein expression and activity at the blood-brain barrier. FASEB J. 33, 13966-13981 (2019). www.fasebj.org.

Original languageEnglish
Pages (from-to)13966-13981
Number of pages16
JournalFASEB Journal
Volume33
Issue number12
DOIs
StatePublished - Dec 2019

Bibliographical note

Funding Information:
The authors thank members of the B.B. and A.M.S.H. laboratories for proofreading the manuscript. The authors acknowledge Dr. Marion Bankstahl and Dr. Wolfgang Löscher (both from the University of Veterinary Medicine Hannover, Hannover, Germany) for help with the kainic acid mouse status epilepticus model. This project was supported by funding from Boehringer Ingelheim Pharma (Biberach, Germany), and by U.S. National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) Grant 1R01NS079507 (to B.B.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS or the NIH. The authors declare no conflicts of interest.

Funding Information:
The authors thank members of the B.B. and A.M.S.H. laboratories for proofreading the manuscript. The authors acknowledge Dr. Marion Bankstahl and Dr. Wolfgang Löscher (both from the University of Veterinary Medicine Hannover, Hannover, Germany) for help with the kainic acid mouse status epilepticus model. This project was supported by funding from Boehringer Ingelheim Pharma (Biberach, Germany), and by U.S. National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) Grant 1R01NS079507 (to B.B.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS or the NIH. The authors declare no conflicts of interest.

Publisher Copyright:
© FASEB.

Keywords

  • ABCB1/MDR1
  • epilepsy
  • neurovasculature

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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