title: Synergistic GABA-enhancing therapy against seizures in a mouse model of Dravet syndrome.
abstract: Seizures remain uncontrolled in 30% of patients with epilepsy, even with concurrent use of multiple drugs, and uncontrolled seizures result in increased morbidity and mortality. An extreme example is Dravet syndrome (DS), an infantile-onset severe epilepsy caused by heterozygous loss of function mutations in SCN1A, the gene encoding the brain type-I voltage-gated sodium channel NaV1.1. Studies in Scn1a heterozygous knockout mice demonstrate reduced excitability of GABAergic interneurons, suggesting that enhancement of GABA signaling may improve seizure control and comorbidities. We studied the efficacy of two GABA-enhancing drugs, clonazepam and tiagabine, alone and in combination, against thermally evoked myoclonic and generalized tonic-clonic seizures. Clonazepam, a positive allosteric modulator of GABA-A receptors, protected against myoclonic and generalized tonic-clonic seizures. Tiagabine, a presynaptic GABA reuptake inhibitor, was protective against generalized tonic-clonic seizures but only minimally protective against myoclonic seizures and enhanced myoclonic seizure susceptibility at high doses. Combined therapy with clonazepam and tiagabine was synergistic against generalized tonic-clonic seizures but was additive against myoclonic seizures. Toxicity determined by rotorod testing was additive for combination therapy. The synergistic actions of clonazepam and tiagabine gave enhanced seizure protection and reduced toxicity, suggesting that combination therapy may be well tolerated and effective for seizures in DS.
authors: Department of Neurology, University of Washington, Seattle, Washington, USA.
authors: John C
authors: JC
authors: Oakley
authors: Alvin R
authors: AR
authors: Cho
authors: Christine S
authors: CS
authors: Cheah
authors: Todd
authors: T
authors: Scheuer
authors: William A
authors: WA
authors: Catterall
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D002998:Clonazepam / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004831:Epilepsies, Myoclonic / Q000150:complications / Q000188:drug therapy*; D004830:Epilepsy, Tonic-Clonic / Q000188:drug therapy; D005260:Female; D018755:GABA Agonists / Q000627:therapeutic use*; D018757:GABA Modulators / Q000627:therapeutic use; D006358:Hot Temperature; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics; D009557:Nipecotic Acids / Q000627:therapeutic use; D004856:Postural Balance / Q000187:drug effects; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D009435:Synaptic Transmission / Q000187:drug effects; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D000927:Anticonvulsants; D018755:GABA Agonists; D018757:GABA Modulators; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009557:Nipecotic Acids; C568249:Scn1a protein, mouse; D005680:gamma-Aminobutyric Acid; D002998:Clonazepam; D000078308:Tiagabine