RT Journal Article
SR Electronic
T1 Synergistic GABA-Enhancing Therapy against Seizures in a Mouse Model of Dravet Syndrome
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 215
OP 224
DO 10.1124/jpet.113.203331
VO 345
IS 2
A1 John C. Oakley
A1 Alvin R. Cho
A1 Christine S. Cheah
A1 Todd Scheuer
A1 William A. Catterall
YR 2013
UL http://jpet.aspetjournals.org/content/345/2/215.abstract
AB 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.