Efficacy of stiripentol in hyperthermia-induced seizures in a mouse model of Dravet syndrome

Purpose: We previously reported a mutant mouse carrying a severe myoclonic epilepsy in infancy (SMEI) mutation in Scn1a. In this study, we examined the susceptibility to hyperthermia-induced seizures of heterozygous Scn1a mutant mice (Scn1aRX/+) and wild-type (Scn1a+/+) mice. Then we assessed the efficacy of stiripentol (STP) monotherapy versus STP and clobazam (CLB) combination therapy to prevent hyperthermia-induced seizures in Scn1aRX/+ mice. Methods: The seizure-inducing body temperatures in Scn1aRX/+ mice and age-matched Scn1a+/+ mice were compared in three age groups (1 month, 35 months, > 6 months). Then STP, CLB, or STP + CLB was administered intraperitoneally to Scn1aRX/+ mice of two age groups (p1M, aged 1 month; p5M, aged 510 months). The efficacy of medications was assessed by comparing the seizure-inducing body temperature and the duration of seizures. Key Findings: The seizure-inducing body temperature was significantly lower in Scn1aRX/+ than in Scn1a+/+ mice for all age groups (p < 0.01). The seizure-inducing body temperature was significantly elevated after administration of STP in p1M (p < 0.05) but not in p5M (p > 0.05), and it was significantly elevated after administration of CLB in both age groups (p < 0.05). The seizure-inducing body temperature was significantly higher after administration of STP + CLB than after administration of CLB in p5M (p < 0.05). Significance: Scn1a RX/+ mice have increased susceptibility to hyperthermia-induced seizure in all age groups. STP monotherapy is effective in preventing hyperthermia-induced seizures in Scn1aRX/+ mice aged 1 month, but not in those aged 5 months and older. When used in combination therapy with CLB, STP inhibits the metabolism of CLB and probably synergistically enhances the anticonvulsant effect in mice aged 1 month.