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

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

JOURNAL=Frontiers in Pharmacology

VOLUME=7

YEAR=2016

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2016.00357

DOI=10.3389/fphar.2016.00357

ISSN=1663-9812

ABSTRACT=<p><italic>De novo</italic> loss-of-function mutations in the voltage-gated sodium channel (VGSC) <italic>SCN1A</italic> (encoding Na<sub>v</sub>1.1) 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. <italic>SCN1A</italic> 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 <italic>SCN1A</italic> mutations. To address the need for more efficacious treatments for <italic>SCN1A</italic>-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 (<italic>Scn1a</italic><sup>+/−</sup>) and GEFS+ (<italic>Scn1a</italic><sup>RH/+</sup>). Furthermore, Hup A-mediated seizure protection was sustained during 3 weeks of daily injections in <italic>Scn1a</italic><sup>RH/+</sup> mutants. Finally, we determined that muscarinic and GABA<sub>A</sub> 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.</p>