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. An important feature of SCN1A-derived epilepsy is the high incidence of severe and prolonged early-life FSs and the negative impact these events can have on long-term prognosis. There is increasing evidence from rodent studies, including work from our lab, demonstrating that prolonged early-life FSs result in increased seizure susceptibility and behavioral abnormalities in adulthood. Currently, however, there are no routine clinical interventions that protect against these early-life FSs and the associated long-term adverse consequences. 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 previously demonstrated that Huperzine A (Hup A), a potent, highly specific reversible acetylcholinesterase inhibitor, confers robust protection against induced seizures (6 Hz, MES, PTZ, and hyperthermia) in Scn1a mutant mice. Based on our observations that complex and prolonged early-life FSs result in the exacerbation of seizure and behavioral outcomes in Scn1a mutants during adulthood and our recent findings that Hup A increases resistance to induced seizures, we hypothesize that Hup A would protect against 1) spontaneous seizure generation, and 2) the worsening of seizure and behavioral phenotypes following complex and prolonged early-life FSs.  Results: Preliminary results demonstrate that continuous Hup A administration via osmotic minipumps (8 mg/kg/day) over a two-week period may be efficacious in reducing spontaneous seizure frequency in adult Scn1a+/- mutant mice. We also found that the continuous administration of Hup A resulted in a 50% decrease in AChE activity at 2, 7, and 14 days following administration. We are currently investigating the ability of Hup A administration following prolonged FSs to prevent the worsening of seizure and behavioral phenotypes.  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: This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health [R21NS098776 (AE)] and the Training in Translational Research in Neurology T32 [2T32NS00748016 (JW)].