title: Induction of nuclear receptors and drug resistance in the brain microvascular endothelial cells treated with antiepileptic drugs.
abstract: Our work contributes to the understanding of the mechanisms of drug resistance in epilepsis. This study aimed to investigate i) the levels of expression of P-glycoprotein (P-gp), and multidrug resistance-associated proteins (MRP)1 and 2, ii) the activation of the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), and iii) the relationship between increased P-gp and MRPs expression and PXR and CAR activation, in immortalized rat brain microvascular endothelial cell lines, GPNT and RBE4, following treatment with the antiepileptic drugs (AEDs), topiramate, phenobarbital, carbamazepine, tiagabine, levetiracetam, and phenytoin, using Western blotting and immunocytochemistry methods. Carbamazepine, phenobarbital and phenytoin induced the highest levels of P-gp and MPRs expression that was associated with increased activation of PXR and CAR receptors as compared to levetiracetam, tiagabine and topiramate. We conclude that P-gp and MRPs are differently overexpressed in GPNT and RBE4 by various AEDs and both PXR and CAR are involved in the drug-resistant epilepsy induced by carbamazepine, phenobarbital and phenytoin.
authors.affiliation: Department of Physiological Sciences, University of Catania, V.le A. Doria 6 Catania, 95125, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Lombardo
authors.forename: Rosalia
authors.initials: R
authors.lastname: Pellitteri
authors.forename: Michael
authors.initials: M
authors.lastname: Balazy
authors.forename: Venera
authors.initials: V
authors.lastname: Cardile
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000166:cytology; D002461:Cell Line, Transformed; D000090702:Constitutive Androstane Receptor; D042783:Endothelial Cells / Q000187:drug effects*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D000077297:Pregnane X Receptor; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D000090702:Constitutive Androstane Receptor; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors