Role of ABC transporters in pharmacoresistant epilepsy

The diploma thesis summarizes the recent knowledge on the possible role ABC transporters in mechanisms of refractory epilepsy. Approximately 30% of patients with epilepsy are refractory to treatment. An important characteristic of pharmacoresistant epilepsy (PE) is that most patients are at the same time resistant to several antiepileptics (AED) even though these drugs act by different mechanisms. It was suggested that one of the main cause of pharmacoresistance is the decreased drug uptake into the brain mediated by multidrug transporters in the blood-brain barier (BBB). The ABC transporters studied in relation to PE are the following: P-glycoprotein (Pgp, coded by MDR1 gene), some members of the multidrug resistance protein (MRP) family and the breast cancer resistance protein (BCRP). The over-expression of the ABC transporters was demonstrated in capillary endothelial cells of BBB, and astrocytes and neurons of epileptogenic brain tissue. Therefore modulation of ABC efflux transporters of the BBB could be a novel strategy to enhance the penetration of AED into the brain. Coadministration of inhibitors with less toxicity, higher potency and specifity to Pgp together with AED could thus reverse PE and achieve seizure control in epilepsy. The characterization of variations in the MDR1 gene and..