Targeting prostaglandin E2 EP1 receptors prevents seizure-associated P-glycoprotein up-regulation

Anton Pekcec, Bernadette Unkrüer, Juli Schlichtiger, Jonna Soerensen, Anika M.S. Hartz, Björn Bauer, Erwin A. Van Vliet, Jan A. Gorter, Heidrun Potschka

Research output: Contribution to journalArticlepeer-review

88 Scopus citations


Up-regulation of the blood-brain barrier efflux transporter P-glycoprotein in central nervous system disorders results in restricted brain access and limited efficacy of therapeutic drugs. In epilepsies, seizure activity strongly triggers expression of P-glycoprotein. Here, we identified the prostaglandin E2 receptor, EP1, as a key factor in the signaling pathway that mediates seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier. In the rat pilocarpine model, status epilepticus significantly increased P-glycoprotein expression by 92 to 197% in the hippocampal hilus and granule cell layer as well as the piriform cortex. The EP1 receptor antagonist 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(4- pyridinyl)propyl]hydrazide hydrochloride (SC-51089) abolished seizure-induced P-glycoprotein up-regulation and retained its expression at the control level. The control of P-glycoprotein expression despite prolonged seizure activity suggests that EP1 receptor antagonism will also improve antiepileptic drug efficacy. Preliminary evidence for this concept has been obtained using a massive kindling paradigm during which animals received a subchronic SC-51089 treatment. After withdrawal of the EP1 receptor antagonist, a low dose of the P-glycoprotein substrate phenobarbital resulted in an anticonvulsant effect in this pretreated group, whereas the same dosage of phenobarbital did not exert a significant effect in the respective control group. In conclusion, our data demonstrate that EP1 is a key signaling factor in the regulatory pathway that drives P-glycoprotein up-regulation during seizures. These findings suggest new intriguing possibilities to prevent and interrupt P-glycoprotein overexpression in epilepsy. Future studies are necessary to further evaluate the appropriateness of the strategy to enhance the efficacy of antiepileptic drugs.

Original languageEnglish
Pages (from-to)939-947
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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