Abstracts

Rationale: De novo loss-of-function mutations in the voltage-gated sodium channel SCN1A (encoding Nav1.1) are the main cause of Dravet syndrome (DS), a catastrophic early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), refractory afebrile epilepsy, cognitive and behavioral deficits, and a 15-20% mortality rate. SCN1A mutations also lead to genetic epilepsy with febrile seizures plus (GEFS+), which is an inherited disorder characterized by early-life FSs and the development of a wide range of adult epilepsy subtypes. Current antiepileptic drugs (AEDs) often fail to provide adequate protection against the severe seizures and neuropsychiatric comorbidities that occur in patients with SCN1A mutations. Furthermore, almost a third of epilepsy patients do not achieve adequate seizure control, highlighting the urgent need to develop multimodal treatments that can effectively mitigate the broad spectrum of clinical features associated with refractory epilepsies, while minimizing unwanted side effects. Heterozygous Scn1a knockout mice (Scn1a+/-, a model of DS) and heterozygous Scn1a knock-in mice expressing the human SCN1A epilepsy mutation R1648H (Scn1aRH/+, a model of GEFS+) recapitulate many of the clinical features found in patients with DS and GEFS+, and thus provide an important opportunity to develop more efficacious AEDs. Methods: We evaluated the therapeutic potential of Huperzine A (Hup A), a naturally occurring sesquiterpene Lycopodium alkaloid, for the treatment of DS and GEFS+. We previously demonstrated that Hup A (1 mg/kg) conferred robust protection against induced seizures (6 Hz, MES, PTZ). Results: As an extension of this study, we also found significant protection against hyperthermia-induced (febrile) seizures when Hup A was administered to Scn1a mutant mice. Since patients with epilepsy often require chronic treatment, an important element of drug discovery is to determine whether seizure protection can be maintained during long-term use. We found that robust protection against 6 Hz-induced seizures was maintained during daily administration of Hup A in Scn1aRH/+ mutant mice, providing further impetus for the continued evaluation of Hup A as a potential treatment for Scn1a-derived epilepsy. Finally, we also determined the potential pathways by which Hup A provides protection against induced seizures. We are currently investigating the effect of Hup A on the spontaneous seizures that occur in Scn1a mutants. Conclusions: Taken together, this study provides compelling evidence for additional investigation of Hup A as a novel therapeutic strategy in DS and GEFS+, and more broadly, in other forms of refractory epilepsy. Funding: R21NS098776