Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy.
OBJECTIVE
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.
Dombrowski
S M
SM
Department of Neurological Surgery, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Desai
S Y
SY
Marroni
M
M
Cucullo
L
L
Goodrich
K
K
Bingaman
W
W
Mayberg
M R
MR
Bengez
L
L
Janigro
D
D
D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D010597:Pharmacogenetics; D013702:Temporal Lobe / Q000098:blood supply
D000927:Anticonvulsants; D027425:ATP-Binding Cassette, Sub-Family C Proteins