In human
epilepsy, pharmacoresistance to
antiepileptic drug therapy is a major problem affecting a substantial fraction of patients. Many of the currently available
antiepileptic drugs target
voltage-gated sodium channels, leading to a rate-dependent suppression of neuronal discharge. A loss of use-dependent block has emerged as a potential cellular mechanism of pharmacoresistance for
anticonvulsants acting on
voltage-gated sodium channels. There is a need both for compounds that overcome this resistance mechanism and for novel drugs that inhibit the process of epileptogenesis. We show that
eslicarbazepine acetate, a once-daily
antiepileptic drug, may constitute a candidate compound that addresses both issues.
Eslicarbazepine acetate is converted extensively to
eslicarbazepine after
oral administration. We have first tested using patch-clamp recording in human and rat hippocampal slices if
eslicarbazepine, the major active metabolite of
eslicarbazepine acetate, shows maintained activity in chronically epileptic tissue. We show that
eslicarbazepine exhibits maintained use-dependent blocking effects both in human and experimental
epilepsy with significant add-on effects to
carbamazepine in human
epilepsy. Second, we show that
eslicarbazepine acetate also inhibits Cav3.2 T-type Ca(2+) channels, which have been shown to be key mediators of epileptogenesis. We then examined if transitory administration of
eslicarbazepine acetate (once daily for 6 weeks, 150 mg/kg or 300 mg/kg) after induction of
epilepsy in mice has an effect on the development of chronic
seizures and neuropathological correlates of chronic
epilepsy. We found that
eslicarbazepine acetate exhibits strong antiepileptogenic effects in experimental
epilepsy. EEG monitoring showed that transitory
eslicarbazepine acetate treatment resulted in a significant decrease in seizure activity at the chronic state, 8 weeks after the end of treatment. Moreover,
eslicarbazepine acetate treatment resulted in a significant decrease in mossy fibre sprouting into the inner molecular layer of
pilocarpine-injected mice, as detected by Timm staining. In addition, epileptic animals treated with 150 mg/kg, but not those that received 300 mg/kg
eslicarbazepine acetate showed an attenuated neuronal loss. These results indicate that
eslicarbazepine potentially overcomes a cellular resistance mechanism to conventional
antiepileptic drugs and at the same time constitutes a potent antiepileptogenic agent.