title: Therapy for hyperthermia-induced seizures in Scn1a mutant rats.
abstract: OBJECTIVE
  Mutations in the SCN1A gene, which encodes the α1 subunit of voltage-gated sodium channels, cause generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). N1417H-Scn1a mutant rats are considered to be an animal model of human FS+ or GEFS+. To assess the pharmacologic validity of this model, we compared the efficacies of eight different antiepileptic drugs (AEDs) for the treatment of hyperthermia-induced seizures using N1417H-Scn1a mutant rats.
  
  
  METHODS
  AEDs used in this study included valproate, carbamazepine (CBZ), phenobarbital, gabapentin, acetazolamide, diazepam (DZP), topiramate, and potassium bromide (KBr). The effects of these AEDs were evaluated using the hot water model, which is a model of experimental FS. Five-week-old rats were pretreated with each AED and immersed in water at 45°C to induce hyperthermia-induced seizures. The seizure manifestations and video-electroencephalographic recordings were evaluated. Furthermore, the effects of each AED on motor coordination and balance were assessed using the balance-beam test.
  
  
  RESULTS
  KBr significantly reduced seizure durations, and its anticonvulsant effects were comparable to those of DZP. On the other hand, CBZ decreased the seizure threshold. In addition, DZP and not KBr showed significant impairment in motor coordination and balance.
  
  
  CONCLUSIONS
  DZP and KBr showed potent inhibitory effects against hyperthermia-induced seizures in the Scn1a mutant rats, whereas CBZ exhibited adverse effects. These responses to hyperthermia-induced seizures were similar to those in patients with GEFS+ and SMEI. N1417H-Scn1a mutant rats may, therefore, be useful for testing the efficacy of new AEDs against FS in GEFS+ and SMEI patients.
authors.affiliation: Department of Physiology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueshima
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ouchida
authors.forename: Tomoji
authors.initials: T
authors.lastname: Mashimo
authors.forename: Teiichi
authors.initials: T
authors.lastname: Nishiki
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sendo
authors.forename: Tadao
authors.initials: T
authors.lastname: Serikawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Matsui
authors.forename: Iori
authors.initials: I
authors.lastname: Ohmori
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use*; D001965:Bromides / Q000494:pharmacology; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000706:statistics & numerical data; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000503:physiopathology; D004829:Epilepsy, Generalized / Q000235:genetics / Q000503:physiopathology; D005334:Fever / Q000503:physiopathology*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics* / Q000502:physiology*; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D017680:Potassium Compounds / Q000494:pharmacology; D051381:Rats; D011922:Rats, Mutant Strains; D003294:Seizures, Febrile / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control*; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014741:Video Recording
chemical_list: D000927:Anticonvulsants; D001965:Bromides; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D017680:Potassium Compounds; C568242:SCN1A protein, human; C568250:Scn1a protein, rat; D015222:Sodium Channels; C039004:potassium bromide