Induction of nuclear receptors and drug resistance in the brain microvascular endothelial cells treated with antiepileptic drugs

Curr Neurovasc Res. 2008 May;5(2):82-92. doi: 10.2174/156720208784310196.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Analysis of Variance
  • Animals
  • Anticonvulsants / pharmacology*
  • Brain / cytology
  • Cell Line, Transformed
  • Endothelial Cells / drug effects*
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Pregnane X Receptor
  • Rats
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Steroid / metabolism*
  • Transcription Factors / metabolism*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anticonvulsants
  • Multidrug Resistance-Associated Proteins
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Transcription Factors
  • constitutive androstane receptor