Rationale:
Sudden Unexpected death in epilepsy (SUDEP) is dramatic outcome for epileptic patients, with a prevalence of 1 per 1000. Stiripentol (STP, Diacomit
©) is an antiseizure medication indicated for Dravet syndrome, a rare developmental and epileptic encephalopathy with high mortality rate (15 per 1000), in which SUDEP accounts for about 2/3. The audiogenic seizure as a model for SUDEP is widely used, as it relies on the non-invasive induction of a potentially lethal convulsion. Here, we used a new genetic mouse model of SUDEP to evaluate the efficacy of STP to reduce lethal audiogenic seizures. Precisely the new model allows to dissociate an indirect anti-lethal effect by reducing convulsive activity from a direct anti-lethal effect by inhibiting the lethality that follows a tonic seizure.Methods:
Our laboratory has recently developed the LAGS+ line (for letal audiogenic seizure) to study SUDEP, based on a directional genetic selection on phenotypic criteria. This selected line shows lethal hyper-sensitivity to audiogenic stimulation following presentation of a white noise sound stimulus at over 110 dB. Directional selection was initiated from a four-way cross derived from the audiogenic prone strains DBA/1J, DBA/2J, BALB/cJ and 129/SvTer. After nine generations of selection, LAGS+ mice showed a 99% rate of tonic seizures associated with a 99% lethality rate, corresponding to a 98% efficacy. Here, male and female LAGS+ mice at S9 generation received a single dose of STP (from 0 to 1000 mg/kg i.p.) 30 min before audiogenic stimulation. Each mouse was evaluated once, during a maximum of 60 sec, and the following patterns were scored: wild running, clonic seizures, tonic-clonic seizures, non-lethal tonic seizures, lethal tonic seizures.
Results:
Regarding an indirect effect on lethality (or a reduction of the seizure susceptibility), STP has shown an anti-seizure effect from the dose of 100 mg/kg. This effect increased in a dose-dependent manner until the maximum dose of 1000 mg/kg, at which no mice had seizures. Regarding a direct effect on lethality (or an inhibition of the lethality in tonic seizures), we have observed that STP can reduce the lethality following a tonic seizure, when doses are ranged between 100 and 200 mg/kg. In comparison, LAGS+ mice treated with vehicle all died from a tonic seizure.
Conclusions:
The major advantage of our new mouse model to study SUDEP lies on its robustness in presenting a lethal tonic seizure ( >99%) following audiogenic stimulation. Here, STP has shown that, depending on the dose range, it can reduce the lethality of tonic seizures, and at higher doses, exhibits anticonvulsant effects. Surprisingly, we did not observe any inhibition of lethality following tonic seizures at higher doses ( > 200 mg/kg). This result suggests that the direct and indirect effects of STP against lethality represent two independent mechanisms and making STP a suitable drug to prevent SUDEP. To our knowledge, this is the first time that a direct effect against mortality has been observed with an anti-epileptic drug.
Funding: Biocodex