Abstracts

Rationale: Despite the development of new compounds, more than 30% of patients with epilepsy are still resistant to antiepileptic drugs (AEDs). Pharmaceutical industry clearly needs new preclinical strategies to improve AED discovery and development. Accordingly, chronic animal models of epilepsy that are resistant to one or several AEDs appear of great interest. Mesiotemporal lobe epilepsy (MTLE) is the most common form of epilepsy that is refractory to antiepileptic drugs (AEDs) and several strategies are being developed to better treat this syndrome. To this aim, the development of new animal models with similar features of MTLE is mandatory. Methods: During the past ten years, a chronic model of MTLE in adult mice has emerged where spontaneous recurrent focal seizures with mild behavioural expression are observed. In this model, a unilateral injection of kainate (KA) into the dorsal hippocampus induces ipsilateral cell loss in CA1, CA3 and hilus areas, as well as gliosis, sprouting of mossy fibres and a progressive dispersion of the granule cells of the dentate gyrus. In addition, spontaneous recurrent hippocampal paroxysmal discharges (HPD) develop during the first 3 weeks post KA and then remain stable and stereotyped for the whole life of the animals. These HPDs occur spontaneously about 45 times per hour when the animals are in a state of quiet wakefulness, generally last 15-20 sec and are associated with behavioural arrest and/or mild motor automatisms. Results: By using this MTLE mouse model, SynapCell has developed a broad range of preclinical solutions to better identify promising drug candidates targeting partial drug-resistant epilepsies. First, the in vivo screening protocol allows testing of small libraries of compounds and relies on quantitative EEG evaluation of the efficacy of new AEDs on highly recurrent HPDs, using a latin-square protocol on a limited number of MTLE mice. Then, promising drug candidates can be further studied for their dose-response effects with acute treatments, their efficacy over time with chronic protocols as well as their efficacy when co-administered with other AEDs in add-on protocols. Finally, this model also allows the assessment of disease modifying potential of compounds on the appearance of chronic seizures during the epileptogenic period. Conclusions: Altogether, this chronic model of MTLE reproduces some of the behavioral, electroclinical and histopathological features of human MTLE and represents a unique tool to identify new AEDs that could be efficient in drug-resistant MTLE patients.