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

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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 determineMDRexpression. 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,andMRP5were upregulated in epileptic tissue, whereasPgp3/MDR3levels 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 thatMDR1immunoreactivity 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.