title: Efficacy of stiripentol in hyperthermia-induced seizures in a mouse model of Dravet syndrome.
abstract: OBJECTIVE
  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 (Scn1a(RX/+)) 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 Scn1a(RX/+) mice.
  
  
  METHODS
  The seizure-inducing body temperatures in Scn1a(RX/+) 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 Scn1a(RX/+) 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.
  
  
  RESULTS
  The seizure-inducing body temperature was significantly lower in Scn1a(RX/+) 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).
  
  
  CONCLUSIONS
  Scn1a (RX/+) mice have increased susceptibility to hyperthermia-induced seizure in all age groups. STP monotherapy is effective in preventing hyperthermia-induced seizures in Scn1a(RX/+) 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.
authors.affiliation: National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan.
authors.forename: Dezhi
authors.initials: D
authors.lastname: Cao
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ohtani
authors.forename: Ikuo
authors.initials: I
authors.lastname: Ogiwara
authors.forename: Sanae
authors.initials: S
authors.lastname: Ohtani
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamakawa
authors.forename: Yushi
authors.initials: Y
authors.lastname: Inoue
mesh_terms: D000367:Age Factors; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000627:therapeutic use; D000078306:Clobazam; D004148:Dioxolanes / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000188:drug therapy* / Q000209:etiology* / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006979:Hyperthermia, Induced / Q000009:adverse effects*; D051379:Mice; D008822:Mice, Transgenic; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D015222:Sodium Channels / Q000235:genetics
chemical_list: D000927:Anticonvulsants; D004148:Dioxolanes; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568249:Scn1a protein, mouse; D015222:Sodium Channels; D001569:Benzodiazepines; D000078306:Clobazam; C021092:stiripentol