Searching for the ideal antiepileptogenic agent in experimental models: single treatment versus combinatorial treatment strategies

Abstract

A major unmet medical need is the lack of treatments to prevent (or modify) epilepsy in patients at risk, for example, after epileptogenic brain insults such as traumatic brain injury, stroke, or prolonged acute symptomatic seizures like complex febrile seizures or status epilepticus. Typically, following such brain insults there is a seizure-free interval ("latent period"), lasting months to years before the onset of spontaneous recurrent epileptic seizures. The latent period after a brain insult offers a window of opportunity in which an appropriate treatment may prevent or modify the epileptogenic process induced by a brain insult. A similar latent period occurs in patients with epileptogenic gene mutations. Studies using animal models of epilepsy have led to a greater understanding of the factors underlying epileptogenesis and have provided significant insight into potential targets by which the development of epilepsy may be prevented or modified. This review focuses largely on some of the most common animal models of epileptogenesis and their potential utility for evaluating proposed antiepileptogenic therapies and identifying useful biomarkers. The authors also describe some of the limitations of using animal models in the search for therapies that move beyond the symptomatic treatment of epilepsy. Promising results of previous studies designed to evaluate antiepileptogenesis and the role of monotherapy versus polytherapy approaches are also discussed. Recent data from both models of genetic and acquired epilepsies strongly indicate that it is possible to prevent or modify epileptogenesis, and, hopefully, such promising results can ultimately be translated into the clinic.

Fig. 1

Important models of epileptogenesis. Please note that the models shown are not exclusive, but represent rather examples of models that have been used in the past for studying epileptogenesis. Not all of these models have been used as yet for studying drug effects on epileptogenesis. SE = status epilepticus; TBI = traumatic brain injury; MAM = methylazoxymethanol acetate; GAERS = Genetic Absence Epileptic Rat of Strasbourg; GEPR = genetically epilepsy-prone rat; BNFC = benign familial neonatal convulsions; KV = voltage-gated Kv potassium channels; WAG/Rij = Wistar Albino Glaxo/Rij

Fig. 2

Concepts and model parameters in studying drug effects on epileptogenesis. EEG = electroencephalography