Abstracts

Upregulation of members of the ATP-binding cassette (ABC) transporter protein superfamily has been implicated as a potentially important factor in the development of refractory epilepsy. To date, brain overexpression of P-glycoprotein, multidrug resistance-associated protein 1 (MRP1) and MRP2 has been documented in refractory epilepsy. Recently, another member of the ABC superfamily named mitoxantrone resistance protein (MXR, encoded by [italic]ABCG2[/italic]), has been detected in cerebral capillary endothelial cells. However, the role of MXR in refractory epilepsy is unknown. To further elucidate the role of MXR in refractory epilepsy, we examined the distribution and expression of MXR in resection specimens from patients with medically refractory temporal lobe epilepsy (TLE). A total of 43 brain specimens from 17 consecutive patients surgically treated for medically refractory TLE were analyzed in these studies. A combination of immunohistochemistry (IHC) and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to examine the distribution and expression level of MXR protein and ABCG2 mRNA. Expression at the protein and RNA levels in the lesional tissue was compared with expression in the histologically normal adjacent tissue. Fifteen patients had mesial temporal sclerosis (MTS) and two patients had focal cortical dysplasia (FCD). IHC was performed in 4 specimens from patients with FCD and in 12 specimens from patients with MTS. In FCD cases, MXR expression was noted in neurons and reactive astrocytes in both lesional and histologically normal adjacent tissues. However, the immunoreactivity was more abundant and more intense in the lesional tissue. In MTS cases, MXR immunoreactivity was observed in neurons and glial cells in gliotic hippocampus. Strong MXR immunoreactivity was detected in blood vessels but not in neurons or glial cells in the lateral temporal cortex. qRT-PCR was performed in 27 specimens from patients with MTS. There was a 1.6-fold increase in ABCG2 mRNA in the hippocampus compared to that in the lateral temporal cortex. Our findings suggest that upregulation of MXR/ABCG2 is widespread in human epileptic brain. This supports a potential role of MXR in the cellular mechanisms underlying drug resistance. (Supported by The National Epifellows Foundation, NIH M01-RR00079, and NIH U01-GM61390.)