Abstracts

Rationale: While a powerful anticonvulsant activity has been achieved with various strategies, antiepileptogenic compounds that impinge upon the development of chronic epilepsy are still needed. Eslicarbazepine acetate (ESL) is a once-daily (QD) antiepileptic drug (AED) that is converted extensively to eslicarbazepine (a voltage-gated sodium channel and T-type calcium channel blocker) after oral administration. ESL showed powerful anticonvulsant activity in animal models. We examined if this compound is also antiepileptogenic in the pilocarpine model of epilepsy, in which a single administration of the muscarinic agonist pilocarpine leads to the development of chronic epilepsy, and morphological and synaptic features similar to human temporal lobe epilepsy.Methods: CD-1 male mice were administered pilocarpine (300 mg/kg ip) to develop status epilepticus. Sham animals received injections of saline. After one week of recovery, epileptic mice were administered either vehicle, 150 mg/kg or 300 mg/kg ESL p.o. once-daily for 6 weeks. Non-epileptic sham mice received vehicle. Motor coordination (rotarod and wire test) and spontaneous locomotor behaviour (open field test) were assessed four weeks after the end of ESL treatment. Cortical EEG telemetry monitoring was performed eight weeks after the end of ESL treatment. Twelve weeks after the end of ESL, hippocampal slices were processed for Timm staining and mossy fiber sprouting were scored.Results: EEG monitoring showed that transitory ESL treatment within the epileptogenic period caused a significant decrease in both the frequency (90 and 66% decrease for 150 and 300 mg/kg ESL versus vehicle, respectively) and duration (92 and 74% decrease for 150 and 300 mg/kg ESL as compared to vehicle, respectively) of epileptiform discharges. Conversely, 11% of the trains detected in vehicle-treated mice had a duration over 15 sec and are recognized to correspond to a pathologically epileptiform activity. In addition, vehicle-treated epileptic mice showed a significant motor coordination impairment as compared to sham animals in the rotarod test. Treatment with 150 mg/kg ESL for six weeks resulted in significant less coordination impairment as compared to vehicle-treated mice. Finally, transitory ESL treatment reduced the neuropathological hallmarks of chronic epilepsy. Timm staining of mossy fibers revealed significant mossy fiber sprouting into the inner dentate molecular layer of pilocarpine-injected animals compared with saline-injected controls. ESL treatment resulted in a significant decrease in mossy fiber sprouting.Conclusions: Transitory ESL treatment attenuated both the functional and morphological sequelae of status epilepticus, supporting a possible anti-epileptogenic effect of ESL in the pilocarpine mouse model of chronic epilepsy.