Screening of conventional anticonvulsants in a genetic mouse model of epilepsy

作者：Nicole A. Hawkins, Lyndsey L. Anderson, Tracy S. Gertler, Linda Laux, Alfred L. George, Jennifer A. Kearney · 发表于：Annals of Clinical and Translational Neurology · 年份：2017 · DOI：10.1002/acn3.413 · 被引用次数：124 · 研究领域：Epilepsy research and treatment、Neuroscience and Neuropharmacology Research、Pharmacological Effects and Toxicity Studies

Abstract Objective Epilepsy is a common neurological disorder that affects 1% of the population. Approximately, 30% of individuals with epilepsy are refractory to treatment, highlighting the need for novel therapies. Conventional anticonvulsant screening relies predominantly on induced seizure models. However, these models may not be etiologically relevant for genetic epilepsies. Mutations in SCN 1A are a common cause of Dravet Syndrome, a severe epileptic encephalopathy. Dravet syndrome typically begins in infancy with seizures provoked by fever and then progresses to include afebrile pleomorphic seizure types. Affected children respond poorly to available anticonvulsants. Scn1a +/− heterozygous knockout mice recapitulate features of Dravet syndrome and provide a potential screening platform to investigate novel therapeutics. In this study, we conducted a screening of conventional anticonvulsants in Scn1a +/− mice to establish assays that most closely correlate with human response data. Methods On the basis of clinical response data from a large, single center, retrospective survey of Dravet syndrome case records, we selected nine drugs for screening in Scn1a +/− mice to determine which phenotypic measures correlate best with human therapeutic response. We evaluated several screening paradigms and incorporated pharmacokinetic monitoring to establish drug exposure levels. Results Scn1a +/− mice exhibited responses to anticonvulsant treatment similar to those observed clinical...