Mechanisms of drug resistance in epilepsy: relevance for antiepileptic drug discovery

Background: Epilepsy, the most common chronic neurological pathology, is symptomatically treated by present antiepileptic drugs (AEDs) in about two-thirds of the cases. Unfortunately, this proportion has not been significantly reduced despite the introduction of several new-generation AEDs. Objective: This review challenges the utility of the paradigm of the excitation–inhibition imbalance for AED discovery and review mechanisms, presumed to be involved in drug-resistant epilepsy, with the purpose of discussing their relevance as targets for future AED discovery. Conclusion: Considering epilepsy as a mere imbalance between excitation and inhibition seems incapable of providing any proper basis for enabling future AED discovery to combat drug-resistant epilepsy as it oversimplifies a complex pathology, yet insufficiently understood. Two current hypotheses on the mechanisms of drug resistance in epilepsy highlight the roles of increased activity of blood–brain barrier multidrug transporter proteins and of alterations in the drug targets rendering them drug-insensitive. Both mechanisms are relevant but seem insufficient to account for the complexity of brain changes involved in drug-resistant epilepsy. Recent studies of drug-resistant epilepsy have revealed the involvement of inflammation processes, functional glia changes and altered intercellular communication related to gap junctions. This provides further, albeit not exhaustive, examples of targets to consider for future AED discovery. A successful strategy aimed at overcoming resistance to AEDs necessitates an integrated vision encompassing the basic features of intractable epilepsies.