title: Targeting prostaglandin E2 EP1 receptors prevents seizure-associated P-glycoprotein up-regulation.
abstract: 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.
authors.affiliation: Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University Munich, Koeniginstr. 16, 80539 Munich, Germany.
authors.forename: Anton
authors.initials: A
authors.lastname: Pekcec
authors.forename: Bernadette
authors.initials: B
authors.lastname: Unkrüer
authors.forename: Juli
authors.initials: J
authors.lastname: Schlichtiger
authors.forename: Jonna
authors.initials: J
authors.lastname: Soerensen
authors.forename: Anika M S
authors.initials: AM
authors.lastname: Hartz
authors.forename: Björn
authors.initials: B
authors.lastname: Bauer
authors.forename: Erwin A
authors.initials: EA
authors.lastname: van Vliet
authors.forename: Jan A
authors.initials: JA
authors.lastname: Gorter
authors.forename: Heidrun
authors.initials: H
authors.lastname: Potschka
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D015153:Blotting, Western; D002196:Capillaries / Q000187:drug effects; D004567:Electrodes, Implanted; D005260:Female; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007696:Kindling, Neurologic / Q000187:drug effects; D018721:Muscarinic Agonists; D010634:Phenobarbital / Q000494:pharmacology; D010862:Pilocarpine; D051381:Rats; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000187:drug effects*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D012640:Seizures / Q000235:genetics / Q000517:prevention & control*; D013226:Status Epilepticus / Q000139:chemically induced / Q000517:prevention & control; D015854:Up-Regulation / Q000502:physiology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D018721:Muscarinic Agonists; C545637:Ptger1 protein, rat; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D010862:Pilocarpine; D010634:Phenobarbital