Huperzine A Provides Robust and Sustained Protection against Induced Seizures in Scn1a Mutant MiceReportar como inadecuado




Huperzine A Provides Robust and Sustained Protection against Induced Seizures in Scn1a Mutant Mice - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal Title:

Frontiers in Pharmacology

Volume:

Volume 7

Publisher:

Frontiers Media | 2016-10-17

Type of Work:

Article | Final Publisher PDF

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.

Subjects: Biology, Genetics - Biology, Neuroscience - Research Funding: This work was supported by the National Institute of Neurological Disorders and Stroke NINDS of the National Institutes of Health R01NS072221, R21NS098776 AE and the Training in Translational Research in Neurology T32 2T32NS00748016 JW.

Keywords: huperzine A - Scn1a - Dravet syndrome - genetic epilepsy with febrile seizures plus - seizure -



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

Fuente: https://open.library.emory.edu/



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