Stiripentol prevents lethal audiogenic seizures in two mouse strains, relevant for SUDEP prevention

Sudden Unexpected Death in Epilepsy (SUDEP) represents a severe outcome for individuals with epilepsy, with an estimated prevalence of 1 per 1000 patients. Stiripentol (STP, Diacomit©) is an antiseizure medication approved for Dravet syndrome, a rare developmental and epileptic encephalopathy with a high mortality rate (15 per 1000), wherein SUDEP accounts for approximately two-thirds of the cases. In this study, we aim to evaluate the effects of STP on lethal seizures using two preclinical models of SUDEP based on audiogenic seizures: a novel SUDEP model, the lethal audiogenic seizure (LAGS+) mouse line issued from a genetic selection, and the DBA/2JRj inbred mouse strain. The latter one was employed to perform a pharmacokinetic/pharmacodynamic (PK/PD) assessment. In both models, STP dose-dependently prevented tonic-clonic seizures and associated mortality when audiogenic seizures were induced 30 min after systemic administration of STP. The LAGS+ model required higher doses of STP to achieve seizure suppression compared to the DBA/2JRj model where a median dose of 75 mg/kg i.p. STP prevented tonic seizures between 30 min and 4 h post-administration, and conferred protection against mortality for up to 2 h. Efficacy was associated with elevated STP levels in plasma and brain tissues 1-hour post-administration, with a brain-to-plasma concentration ratio of approximately 1:4. These findings suggest that STP exerts direct effects in preventing seizures and SUDEP in the two preclinical models studied. The observed plasma and brain concentrations of STP are compatible with the involvement of multiple mechanisms in its protective effects against seizures and SUDEP.