potassium-bromide and Epilepsies--Myoclonic

Topics: Adolescent; Anticonvulsants; Bromides; Child; Child, Preschool; Drug Evaluation; Drug Therapy, Combination; Epilepsies, Myoclonic; Epilepsies, Partial; Epilepsy, Tonic-Clonic; Humans; Male; Potassium Compounds; Retrospective Studies; Treatment Outcome

Dravet syndrome is a catastrophic pediatric epilepsy with severe intellectual disability, impaired social development and persistent drug-resistant seizures. One of its primary monogenic causes are mutations in Nav1.1 (SCN1A), a voltage-gated sodium channel. Here we characterize zebrafish Nav1.1 (scn1Lab) mutants originally identified in a chemical mutagenesis screen. Mutants exhibit spontaneous abnormal electrographic activity, hyperactivity and convulsive behaviours. Although scn1Lab expression is reduced, microarray analysis is remarkable for the small fraction of differentially expressed genes (~3%) and lack of compensatory expression changes in other scn subunits. Ketogenic diet, diazepam, valproate, potassium bromide and stiripentol attenuate mutant seizure activity; seven other antiepileptic drugs have no effect. A phenotype-based screen of 320 compounds identifies a US Food and Drug Administration-approved compound (clemizole) that inhibits convulsive behaviours and electrographic seizures. This approach represents a new direction in modelling pediatric epilepsy and could be used to identify novel therapeutics for any monogenic epilepsy disorder.

Topics: Animals; Anticonvulsants; Benzimidazoles; Bromides; Diazepam; Dioxolanes; Drug Evaluation, Preclinical; Epilepsies, Myoclonic; Gene Expression Profiling; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Potassium Compounds; Seizures; Valproic Acid; Voltage-Gated Sodium Channel beta-1 Subunit; Zebrafish; Zebrafish Proteins

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.. 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.. 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.. 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.

Topics: Animals; Anticonvulsants; Bromides; Disease Models, Animal; Electroencephalography; Epilepsies, Myoclonic; Epilepsy, Generalized; Fever; Humans; Male; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Potassium Compounds; Rats; Rats, Mutant Strains; Seizures, Febrile; Sodium Channels; Video Recording