Significance of MDR1 and multiple drug resistance in refractory human epileptic brain.
BACKGROUND
The multiple drug resistance protein (MDR1/P-glycoprotein) is overexpressed in glia and blood-brain barrier (BBB) endothelium in drug refractory human epileptic tissue. Since various antiepileptic drugs (AEDs) can act as substrates for MDR1, the enhanced expression/function of this protein may increase their active extrusion from the brain, resulting in decreased responsiveness to AEDs.


METHODS
Human drug resistant epileptic brain tissues were collected after surgical resection. Astrocyte cell cultures were established from these tissues, and commercially available normal human astrocytes were used as controls. Uptake of fluorescent doxorubicin and radioactive-labeled Phenytoin was measured in the two cell populations, and the effect of MDR1 blockers was evaluated. Frozen human epileptic brain tissue slices were double immunostained to locate MDR1 in neurons and glia. Other slices were exposed to toxic concentrations of Phenytoin to study cell viability in the presence or absence of a specific MDR1 blocker.


RESULTS
MDR1 was overexpressed in blood vessels, astrocytes and neurons in human epileptic drug-resistant brain. In addition, MDR1-mediated cellular drug extrusion was increased in human 'epileptic' astrocytes compared to 'normal' ones. Concomitantly, cell viability in the presence of cytotoxic compounds was increased.


CONCLUSIONS
Overexpression of MDR1 in different cell types in drug-resistant epileptic human brain leads to functional alterations, not all of which are linked to drug pharmacokinetics. In particular, the modulation of glioneuronal MDR1 function in epileptic brain in the presence of toxic concentrations of xenobiotics may constitute a novel cytoprotective mechanism.
Marchi
Nicola
N
Cerebrovascular Research Center, The Cleveland Clinic, Cleveland, OH 44195, USA. marchi@marionegri.it <marchi@marionegri.it>
Hallene
Kerri L
KL
Kight
Kelly M
KM
Cucullo
Luca
L
Moddel
Gabriel
G
Bingaman
William
W
Dini
Gabriele
G
Vezzani
Annamaria
A
Janigro
Damir
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D000927:Anticonvulsants / Q000378:metabolism / Q000627:therapeutic use; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D004317:Doxorubicin / Q000378:metabolism; D018432:Drug Resistance, Multiple; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D010672:Phenytoin / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000927:Anticonvulsants; D010672:Phenytoin; D004317:Doxorubicin