In vitro and in vivo experimental models employed in the discovery and development of antiepileptic drugs for pharmacoresistant epilepsy

Epilepsy is one of the most common chronic, recurrent and progressive neurological diseases. In spite of the large number of antiepileptic drugs currently available for the suppression of seizures, about one-third of patients develop drug-resistant epilepsy, even when they are administered the most appropriate treatment available. Thus, nonclinical models can be valuable tools for the elucidation of the mechanisms underlying the development of pharmacoresistance and also for the development of new therapeutic agents that may be promising therapeutic approaches for this unmet medical need. Up today, several epilepsy and seizure models have been developed, exhibiting similar physiopathological features of human drug-resistant epilepsy; moreover, pharmacological response to antiepileptic drugs clinically available tends to be similar in animal models and humans. Therefore, they should be more intensively used in the preclinical discovery and development of new candidates to antiepileptic drugs. Although useful, in vitro models cannot completely replicate the complexity of a living being and their potential for a systematic use in antiepileptic drug screening is limited. The whole-animal models are the most commonly employed and they can be classified as per se drug-resistant due to an inherent poor drug response or be based on the selection of subgroups of epileptic animals that respond or not to a specific antiepileptic drug. Although more expensive and time-consuming, the latter are chronic models of epilepsy that better exhibit the disease-associated alterations found in human epilepsy. Several antiepileptic drugs in development or already marketed have been already tested and shown to be effective in these models of drug-resistant epilepsy, constituting a new hope for the treatment of drug-resistant epilepsy. This review will provide epilepsy researchers with detailed information on the in vitro and in vivo nonclinical models of interest in drug-resistant epilepsy, which may enable a refined selection of most relevant models for understanding the mechanisms of the disease and developing novel antiepileptic drugs.