title: Huperzine A Provides Robust and Sustained Protection against Induced Seizures inScn1aMutant Mice.
abstract: De novoloss-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.SCN1Amutations 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 withSCN1Amutations. To address the need for more efficacious treatments forSCN1A-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 inScn1aRH/+mutants. Finally, we determined that muscarinic and GABAAreceptors 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.
authors: Department of Human Genetics, Emory University Atlanta, GA, USA.
authors: Jennifer C
authors: JC
authors: Wong
authors: Department of Human Genetics, Emory UniversityAtlanta, GA, USA; Department of Biology, Agnes Scott CollegeAtlanta, GA, USA.
authors: Stacey B B
authors: SB
authors: Dutton
authors: Biscayne Pharmaceuticals Miami, FL, USA.
authors: Stephen D
authors: SD
authors: Collins
authors: Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, and Massachusetts General Hospital Boston, MA, USA.
authors: Steven
authors: S
authors: Schachter
authors: Department of Human Genetics, Emory University Atlanta, GA, USA.
authors: Andrew
authors: A
authors: Escayg
keywords: Dravet syndrome; Scn1a; genetic epilepsy with febrile seizures plus; huperzine A; seizure