Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome

Abstract

Dravet syndrome, an epileptic encephalopathy affecting children, largely results from heterozygous loss-of-function mutations in the brain voltage-gated sodium channel gene SCN1A. Heterozygous Scn1a knockout (Scn1a +/−) mice recapitulate the severe epilepsy phenotype of Dravet syndrome and are an accepted animal model. Because clinical observations suggest conventional sodium channel blocking antiepileptic drugs may worsen the disease, we predicted the phenotype of Scn1a +/− mice would be exacerbated by GS967, a potent, unconventional sodium channel blocker. Unexpectedly, GS967 significantly improved survival of Scn1a +/− mice and suppressed spontaneous seizures. By contrast, lamotrigine exacerbated the seizure phenotype. Electrophysiological recordings of acutely dissociated neurons revealed that chronic GS967-treatment had no impact on evoked action potential firing frequency of interneurons, but did suppress aberrant spontaneous firing of pyramidal neurons and was associated with significantly lower sodium current density. Lamotrigine had no effects on neuronal excitability of either neuron subtype. Additionally, chronically GS967-treated Scn1a +/− mice exhibited normalized pyramidal neuron sodium current density and reduced hippocampal NaV1.6 protein levels, whereas lamotrigine treatment had no effect on either pyramidal neuron sodium current or hippocampal NaV1.6 levels. Our findings demonstrate unexpected efficacy of a novel sodium channel blocker in Dravet syndrome and suggest a potential mechanism involving a secondary change in NaV1.6.

The novel sodium channel modulator GS‐458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy

“…The estimated dose was 1.5 mg/kg/d based on average daily consumption of 190 g of chow/kg of body weight (http://www.researchdiets.com/resource-center-page/typical-food-intake). Previous studies showed that chronic treatment with this dose resulted in GS967 plasma and brain concentrations of 1.0 ± 0.08 and 1.7 ± 0.1 μmol·L –1 , respectively . Chronic treatment with GS967 at 1.5 mg/kg/d did not cause overt adverse neurobehavioral or sedating effects in WT C3HeB/FeJ at 5‐7 weeks of treatment (Figure ).…”

“…Vehicle control mice were administered either vegetable oil or 0.5% methyl cellulose in water. For chronic administration studies, mice were fed Purina 5001 rodent chow compounded with GS967 (8 mg/kg of chow; Research Diets, New Brunswick, NJ, USA) . The estimated dose was 1.5 mg/kg/d based on average daily consumption of 190 g of chow/kg of body weight (http://www.researchdiets.com/resource-center-page/typical-food-intake).…”

“…The estimated dose was 1.5 mg/kg/d based on average consumption of 190 g of chow per kg of body weight. Previous studies established that this dose results in plasma levels of ~1 μmol·L –1 . Survival was monitored up to 9 months of age by performing census checks 3‐4 days per week.…”

Novel Quantitative Analyses of Spontaneous Synaptic Events in Cortical Pyramidal Cells Reveal Subtle Parvalbumin-Expressing Interneuron Dysfunction in a Knock-In Mouse Model of Alzheimer’s Disease

“…Since PV INs are essential for generating gamma oscillations and for suppressing hypersynchronous network activity, an impairment in PV IN function shared among different mouse models of AD and present during the initial stages of the disease may have highly relevant clinical and therapeutic consequences. The development of specific Na + channel modulators is an obvious start in this direction (Anderson et al, 2017; Frederiksen et al, 2017). …”

Modulation of Abnormal Sodium Channel Currents in Heart and Brain: Hope for SUDEP Prevention and Seizure Reduction

“…Interestingly, two recent papers have highlighted the antiepileptic effects of two drugs known to inhibit cardiac sodium channels (18,19). Ranolazine, a specific inhibitor of persistent sodium currents and an FDA-approved drug for angina pectoris, reduced seizure frequency by approximately 50% in the gain of function Scn2a Q54 mouse, however GS967, a novel compound with greater inhibition of persistent sodium currents, decreased seizure frequency by more than 90% and increased survival, in addition to preventing neuron loss in the dentate hilus and suppressing mossy fiber sprouting in the dentate gyrus (18).…”