Introduction: Around 30% of patients with epilepsy suffer from drug-resistant seizures. Drug-resistant seizures may have significant consequences such as sudden death in epilepsy, injuries, memory disturbances, and childhood learning and developmental problems. Available antiepileptic drugs (AEDs) work via numerous mechanisms - mainly through inhibition of voltage-operated Na+ and/or Ca2+ channels, excitation of K+ channels, enhancement of GABA-mediated inhibition and/or blockade of glutamate-produced excitation. However, the discovery and development of novel brain targets may improve the future pharmacological management of epilepsy and hence is of pivotal importance.
Areas covered: This article examines novel drug targets such as brain multidrug efflux transporters and inflammatory pathways; it progresses to discuss possible strategies for the management of drug-resistant seizures. Reduction of the consequences of blood brain barrier dysfunction and enhancement of anti-oxidative defense are discussed.
Expert opinion: Novel drug targets comprise brain multidrug efflux transporters, TGF-β, Nrf2-ARE or m-TOR signaling and inflammatory pathways. Gene therapy and antagomirs seem the most promising targets. Epileptic foci may be significantly suppressed by viral-vector-mediated gene transfer, leading to an increased in situ concentration of inhibitory factors (for instance, galanin). Also, antagomirs offer a promising possibility of seizure inhibition by silencing micro-RNAs involved in epileptogenesis and possibly in seizure generation.
Keywords: Antiepileptic drugs; antagomirs; epilepsy; epileptogenesis; gene therapy; inflammatory pathways; multidrug efflux transporters; pharmacoresistance; seizures.