Abstracts

Overexpression of drug transporters has been shown in epileptogenic brain material and might play a role in the development of pharmacoresistance. However, it is not known whether overexpression is due to an initial insult, or evolves more gradually because of recurrent spontaneous seizures. In the present study, we investigated the expression of the multidrug transporters MRP1 and MRP2 during epileptogenesis in a rat model for temporal lobe epilepsy. Using immunocytochemistry, we examined protein expression in relation to the occurrence of a status epilepticus (SE) and the progression of recurrent seizure activity later in life in rats that were continuously EEG monitored. MRP1 and MRP2 were transiently upregulated in glial cells within the hippocampus 1 day and 1 week after SE. On the contrary, MRP1 and MRP2 were persistently overexpressed in chronic epileptic rats, especially in glial cells that surrounded blood vessels in ventral parts of the brain (piriform, perirhinal and entorhinal cortex). Overexpression of these drugtransporters was related to the occurrence of SE, since rats that were stimulated but had not exhibited SE were similar to control rats. Increased expression was most evident in rats with a high seizure frequency and less prominent in rats that had occasional seizures. The present results indicate that MRP proteins are not only induced by the SE itself but that they are also upregulated in the chronic epileptic phase, although at more restricted brain regions. Whether this might contribute to reduction of the extracellular drug concentration in these regions, leading to drug-refractoriness is presently under investigation. (Supported by Epilepsy Clinics Foundation Heemstede (Lopes da Silva fellowship).)