Molecular and cellular mechanisms of pharmacoresistance in epilepsy

Epilepsy is a common and devastating neurological disorder. In many patients with epilepsy, seizures are well-controlled with currently available anti-epileptic drugs (AEDs), but a substantial (∼30%) proportion of patients continue to have seizures despite carefully optimized drug treatment. Two concepts have been put forward to explain the development of pharmacoresistance. The transporter hypothesis contends that the expression or function of multidrug transporters in the brain is augmented, leading to impaired access of AEDs to CNS targets. The target hypothesis holds that epilepsy-related changes in the properties of the drug targets themselves may result in reduced drug sensitivity. Recent studies have started to dissect the molecular underpinnings of both transporter- and target-mediated mechanisms of pharmacoresistance in human and experimental epilepsy. An emerging understanding of these underlying molecular and cellular mechanisms is likely to provide important impetus for the development of new pharmacological treatment strategies.