STRATEGIES FOR THE DEVELOPMENT OF DRUGS FOR PHARMACORESISTANT EPILEPSIES

Presently, most strategies for development of antiepileptic drugs (AED s) center around seizure models that are known to respond to presently marketed AEDs. These strategies do not take into account that epileps y can be a progressive disease. Moreover, region-specific aspects of e pileptogenesis are rarely considered when new AEDs are developed. Seiz ures in the temporal lobe are often difficult to treat. Animal studies on various seizure models in the hippocampus and the entorhinal corte x (EC) suggest that these structures do not a priori produce seizures that are difficult to treat. However, seizure-like events in the EC te nd to progress to a state of status epilepticus-like activity that can not be suppressed by presently marketed AEDs. Loss of gamma-aminobutyr ic acid (GABA)ergic neurotransmission and increased excitatory synapti c coupling seem to cooperate for induction of this state. Epilepsy ind uced alterations in the interaction between the EC and the hippocampus may lead to alterations that facilitate precipitation of seizures. Be cause of the recurrent interaction between the hippocampus and the EC, these seizures may reach an intensity that is no longer controllable by presently available AEDs. Ontogenetic alterations of the circuitry between the EC and the hippocampus, seizure-induced stabilization of s ynaptic connections overexpressed during ontogenesis, seizure-induced lesions and subsequent rearrangements of internal cell properties, and synaptic arrangements and kindling-like alterations of nerve cell and glial behavior may all be involved in the generation of a neuronal ag gregate whose balance between inhibitory and excitatory processes beco mes readily disturbed. Strategies for the development of AEDs treating such seizures should suppress hyperactivity and prevent progression o f epileptogenesis. AEDs directed against seizures may be effective if they can be given in sufficient concentrations to suppress very intens e local seizures.