Abstracts

P-glycoprotein (P-gp), encoded by [italic]ABCB1[/italic] ([italic]MDR1[/italic]), is the most extensively studied transporter associated with drug resistance in epilepsy. The first study in this line of work demonstrated that 7 of 13 brain specimens from the lateral temporal cortex (LTC) in patients with mesial temporal lobe epilepsy (MTLE) had ABCB1 mRNA levels more than 10 times greater than those in normal brain as determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Subsequent studies focused on immunohistochemical detection of P-gp and found that immunoreactivity of P-gp was confined to the neurons and glial cells in the lesional tissues, e.g. the hippocampus in patients with MTLE, but not in the histologically normal adjacent tissues. To date, the quantitative relationship between P-gp/ABCB1 mRNA expression in lesional and histologically normal adjacent tissue has not been reported. To address this issue, we systematically examined the expression patterns of P-gp and ABCB1 mRNA in the hippocampus and LTC from patients with medically refractory MTLE. A total of 39 brain specimens collected from 15 patients with the diagnosis of medically refractory MTLE were analyzed. A combination of immunohistochemistry (IHC) and qRT-PCR was used to determine the distribution and level of expression of P-gp and ABCB1 mRNA. Expression at the protein and RNA levels in the hippocampus was compared with expression in the LTC. All patients had pathologically confirmed hippocampal sclerosis. IHC was performed in 12 specimens (6 from hippocampus and 6 from LTC). P-gp was detected primarily in the endothelial cells in both hippocampus and LTC. Neuronal expression of P-gp was observed in only a small percentage of samples and only in the hippocampus. qRT-PCR was performed in 27 specimens (14 from hippocampus and 13 from LTC). The analysis revealed a 1.5 fold increase in ABCB1 mRNA in the hippocampus compared to that in the LTC. Our findings suggest that upregulation of P-gp is largely confined to capillary endothelial cells and is widespread but more abundant in the region of epileptogenic focus. The high expression of P-gp in capillary endothelial cells is consistent with the role of this membrane transporter in limiting anticonvulsant access to the brain. (Supported by The National Epifellows Foundation, NIH M01-RR00079, and NIH U01-GM61390.)