Journal
EPILEPSIA
Volume 42, Issue 12, Pages 1501-1506Publisher
BLACKWELL PUBLISHING INC
DOI: 10.1046/j.1528-1157.2001.12301.x
Keywords
antiepileptic drug levels; pharmacokinetics; blood-brain barrier; cDNA arrays; pharmacogenomics
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Funding
- NHLBI NIH HHS [2RO1 HL51614] Funding Source: Medline
- NINDS NIH HHS [R01 NS38195] Funding Source: Medline
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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-alpha) 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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