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

Abstract

<i>De novo</i> loss-of-function mutations in the voltage-gated sodium channel (VGSC) <i>SCN1A</i> (encoding Na_v1.1) 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. <i>SCN1A</i> 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 <i>SCN1A</i> mutations. To address the need for more efficacious treatments for <i>SCN1A</i>-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 (<i>Scn1a</i>^+/-) and GEFS+ (<i>Scn1a</i>^RH/+). Furthermore, Hup A-mediated seizure protection was sustained during 3 weeks of daily injections in <i>Scn1a</i>^RH/+ mutants. Finally, we determined that muscarinic and GABA_A 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.