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Inhibition of human microsomal PGE2 synthase‐1 reduces seizure‐induced increases of P‐glycoprotein expression and activity at the blood‐brain barrier
Author(s) -
Soldner Emma L. B.,
Hartz Anika M. S.,
Akanuma ShinIchi,
Pekcec Anton,
Doods Henri,
Kryscio Richard J.,
Hosoya KenIchi,
Bauer Björn
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201901460rr
Subject(s) - p glycoprotein , ex vivo , status epilepticus , prostaglandin , glutamate receptor , in vivo , epilepsy , pharmacology , receptor , nmda receptor , prostaglandin e , blood–brain barrier , prostaglandin d2 , chemistry , biology , endocrinology , biochemistry , central nervous system , neuroscience , multiple drug resistance , microbiology and biotechnology , antibiotics
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 E 2 (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