Abstracts

RATIONALE: Hippocampal sclerosis (HC) is one of the commonest causes of refractory epilepsy. Over-expression of the drug transporter P-glycoprotein (P-gp) confers chemoresistance in certain cancers. P-gp extrudes a wide range of xenobiotics from cells and is present in cerebral capillaries where it contributes to the integrity of the blood-brain barrier. It is encoded by the MDR1 gene in man and the mdr1a and 1b isoforms in rodents. We hypothesise that over-expression of the MDR1 gene may play a role in the pathophysiology of refractory epilepsy secondary to HC by limiting antiepileptic drug (AED) access to the epileptic focus. METHODS: Regional mdr1 gene expression was determined in the brains of Sprague-Dawley rats using quantitative reverse transcriptase-polymerase chain reaction. The effects of physical injury and experimental seizures on the expression of mdr1 were determined in rat brain cortex damaged by focal laser application and in the brains of genetically epilepsy-prone rats (GEPRs) and amygdala-kindled rats, respectively. A range of single-dose AEDs were administered to mdr1a knockout mice, which lack cerebrovascular P-gp, and their brain levels measured. Temporal lobe tissues resected from patients with refractory epilepsy due to HC were examined for the extent of MDR1 gene expression. RESULTS: The hippocampus of Sprague-Dawley rats expressed both mdr1 isoforms, while other brain regions expressed mdr1a only. Mdr1a expression was higher in the region of a cortical laser lesion, compared with the contralateral hemisphere. The profile of mdr1 expression in audiogenically stimulated GEPRs differed from that in unstimulated controls. Phenytoin, carbamazepine and topiramate reached higher levels in the brains of mdr1a knock-out mice than in wild-type mice (p<0.05), suggesting they are substrates for P-gp. Finally, significant MDR1 expression was observed in resected tissues from patients with HC. Data from kindled rat brains will be presented. CONCLUSIONS: MDR gene expression may be relevant to the pharmacoresistance of HC. This mechanism may also play a role in other aetiologies of refractory epilepsy.