Abstracts

Rationale: Genetic factors play an important role in the etiology of epilepsy, and the neuronal voltage-gated sodium channels (VGSCs) have emerged as an important family of epilepsy genes. In particular, de novo loss-of-function mutations in the VGSC 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 anti-epilepsy drugs 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. In the proposed studies, we will test the hypothesis that Huperzine A (Hup A), a naturally occurring sesquiterpene Lycopodium alkaloid, will be efficacious in the treatment of DS and GEFS+. This hypothesis is based on the biological properties of Hup A, its demonstrated clinical safety, tolerability, and ability to improve cognitive function.Methods: We first generated a dose response curve in wild-type (WT) CF1 male mice (N = 12/dose) utilizing the 6 Hz seizure induction paradigm (44mA) with a modified Racine scale: 0, no abnormal behavior; 1, staring, unresponsive for ³ 5 seconds; 2, forelimb clonus; 3, rearing and falling. We found that a dose of 1 mg/kg Hup A provided the maximum seizure protection in the CF1 WT mice. Therefore, we tested this dose of Hup A in 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+).Results: Hup A (1 mg/kg) provided robust protection against 6 Hz-induced seizures in both mouse lines (N = 8-12/group). We are also evaluating the ability of Hup A to protect these mouse lines against seizures induced by the maximal electroshock seizure (MES) paradigm.Conclusions: In summary, Hup A might provide a novel therapeutic strategy for increasing seizure resistance in DS and GEFS+, and more broadly, in other forms of refractory epilepsy. Future directions include evaluating the therapeutic potential of Hup A in protecting against spontaneous seizures, using a mouse model of mesial temporal lobe epilepsy.