Regional expression of multidrug resistance genes in genetically epilepsy-prone rat brain after a single audiogenic seizure.
OBJECTIVE
The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood-brain barrier. Recent evidence suggests that P-gp-mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR) brain after a single audiogenic seizure.


METHODS
Three groups of adult male GEPRs (n = 5/group) were exposed to a seizure-inducing audiogenic stimulus and killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a stimulus-naïve control. Expression of mdr1a and mdr1b in distinct anatomic brain regions (cortex, midbrain, pons/medulla, hippocampus) was determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in the presence of competitive internal standards.


RESULTS
When compared with control, mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at 24 h after a single audiogenic seizure. Cortical mdr1a expression remained elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla and hippocampus was unchanged. The mdr1b isoform was quantifiable in hippocampus alone and not influenced by seizure activity.


CONCLUSIONS
These findings suggest that acute seizures in the GEPR can induce the expression of mdr genes. The pattern of increased expression appears to follow the anatomic pathway of audiogenic seizures in these animals, with initiation in the midbrain and propagation to the cortex. Further studies are required to investigate the effects of recurrent seizure activity and to characterise mdr expression in other experimental seizure models.
Kwan
Patrick
P
Epilepsy Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland.
Sills
Graeme J
GJ
Butler
Elaine
E
Gant
Timothy W
TW
Meldrum
Brian S
BS
Brodie
Martin J
MJ
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000503:physiopathology; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism; D019450:Genes, MDR; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D008297:Male; D008636:Mesencephalon / Q000503:physiopathology; D051381:Rats; D011922:Rats, Mutant Strains; D012640:Seizures / Q000235:genetics*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3