Overexpression of Multiple Drug Resistance Genes in Endothelial Cells from Patients with Refractory Epilepsy

Authors


Address correspondence and reprint requests to Dr. D. Janigro at Cerebrovascular Research, Cleveland Clinic Foundation NB20, 9500 Euclid Avenue/ NB2-137, Cleveland, OH 44195, U.S.A. E-mail: janigrd@ccf.org

Abstract

Summary:  Purpose: It has been suggested that altered drug permeability across the blood–brain barrier (BBB) may be involved in pharmacoresistance to antiepileptic drugs (AEDs). To test this hypothesis further, we measured multiple drug resistance (MDR) gene expression in endothelial cells (ECs) isolated from temporal lobe blood vessels of patients with refractory epilepsy. ECs from umbilical cord or temporal lobe vessels obtained from aneurysm surgeries were used as comparison tissue.

Methods: cDNA arrays were used to determine MDR expression. MDR protein (MRP1) immunocytochemistry and Western blot analysis were used to confirm cDNA array data.

Results: We found overexpression of selected MDR and significantly higher P-glycoprotein levels in “epileptic” versus “control” ECs. Specifically, MDR1, cMRP/MRP2, and MRP5 were upregulated in epileptic tissue, whereas Pgp3/MDR3 levels were comparable to those measured in comparison tissue. The gene encoding cisplatin resistance–associated protein (hCRA-α) also was overexpressed in epileptic tissue. Immunocytochemical analysis revealed that MDR1 immunoreactivity was localized primarily in ECs; MRP1 protein levels also were significantly higher in epileptic tissue.

Conclusions: Complex MDR expression changes may play a role in AEDs pharmacoresistance by altering the permeability of AEDs across the BBB.

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