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

D Cao, H Ohtani, I Ogiwara, S Ohtani, Y Takahashi… - …, 2012 - Wiley Online Library
D Cao, H Ohtani, I Ogiwara, S Ohtani, Y Takahashi, K Yamakawa, Y Inoue
Epilepsia, 2012Wiley Online Library
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 …
Summary
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, 3–5 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 5–10 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.
Wiley Online Library