Huperzine A Provides Robust and Sustained Protection against Induced Seizures in Scn1a Mutant Mice.

Jennifer C Wong,Stephen D Collins,Steven Schachter,Andrew Escayg,Stacey B B Dutton

doi:10.3389/fphar.2016.00357

Abstract

De novo loss-of-function mutations in the voltage-gated sodium channel (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 range of adult epilepsy subtypes. Current antiepileptic drugs often fail to protect against the severe seizures and behavioral and cognitive deficits found in patients with SCN1A mutations. To address the need for more efficacious treatments for SCN1A-derived epilepsies, we evaluated the therapeutic potential of Huperzine A, a naturally occurring reversible acetylcholinesterase inhibitor. In CF1 mice, Hup A (0.56 or 1 mg/kg) was found to confer protection against 6 Hz-, pentylenetetrazole (PTZ)-, and maximal electroshock (MES)-induced seizures. Robust protection against 6 Hz-, MES-, and hyperthermia-induced seizures was also achieved following Hup A administration in mouse models of DS (Scn1a+/−) and GEFS+ (Scn1aRH/+). Furthermore, Hup A-mediated seizure protection was sustained during 3 weeks of daily injections in Scn1aRH/+ mutants. Finally, we determined that muscarinic and GABAA receptors play a role in Hup A-mediated seizure protection. These findings indicate that 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.

Highlights

Epilepsy is a common neurological disorder that affects 0.5–1% of the population and is characterized by recurrent seizures that often manifest during childhood
SCN1A mutations lead to genetic epilepsy with febrile seizures plus (GEFS+), which is an inherited disorder characterized by FSs that persist beyond 6 years of age and the development of adult epilepsy (Escayg et al, 2000, 2001)
The administration of Huperzine A (Hup A) was randomized with respect to the order in which each mouse received each dose of Hup A and vehicle

Summary

Introduction

Epilepsy is a common neurological disorder that affects 0.5–1% of the population and is characterized by recurrent seizures that often manifest during childhood. Despite a growing number of available antiepileptic drugs (AEDs), the efficacy of pharmacological intervention for epilepsy has not improved substantially in the last 30 years (Kwan and Brodie, 2006), highlighting the critical need to develop alternative treatments, while minimizing unwanted side effects. Towards this goal, the use of appropriate genetic models of human epilepsy to evaluate potential AEDs might provide a better predictor of clinical efficacy (Loscher and Schmidt, 1994). SCN1A mutations account for at least 80 and 10% of DS and GEFS+ cases, respectively (Claes et al, 2009; Lossin, 2009; Escayg and Goldin, 2010)

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