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• W3109587470 abstract "Summary Objective Dravet syndrome (DS) is a rare, but catastrophic genetic epilepsy, with 80% of patients with carrying a mutation in the SCN1A gene. Currently, no anti-seizure drug (ASD) exists that adequately controls seizures. Patients with DS often present clinically with a febrile seizure and generalized tonic-clonic seizures that continue throughout life. To facilitate the development of ASDs for DS, the contract site of the NINDS Epilepsy Therapy Screening Program (ETSP) has evaluated a mouse model of DS using the conditional knock-in Scn1a A1783V/WT mouse. Methods Survival rates and temperature thresholds for Scn1a A1783V/WT were determined. Prototype ASDs were administered via intraperitoneal injections at the time-to-peak effect, which was previously determined, prior to the induction of hyperthermia-induced seizures. Protection was determined if ASDs significantly increased the temperature at which Scn1a A1783V/WT mice seized. Results Approximately 50% of Scn1a A1783V/WT survive to adulthood and all have hyperthermia-induce seizures. The results suggest that hyperthermia-induced seizures in this model of DS are highly refractory to a battery of ASDs. Exceptions were clobazam, tiagabine, and the combination of clobazam and valproic acid with add-on stiripentol, which elevated seizure thresholds Significance Overall, the data demonstrate the proposed model for DS is suitable for screening novel compounds for the ability to block hyperthermia-induced seizures and heterozygous mice can be evaluated repeatedly over the course of several weeks, allowing for higher throughput screening. Key Points Scn1a A1783V/WT mice have a 50% survival rate and all have hyperthermia-induced seizures. Common DS treatments such as CLB and combinatorial therapy of CLB, VPA, and STP increase temperature thresholds in Scn1a A1783V/WT mice. Sodium channel blockers, such as CBZ and LTG, decrease temperature thresholds of Scn1a A1783V/WT mice as predicted. S cn1a A1783V/WT mice are highly pharmacoresitant to common ASDs The Scn1a A1783V/WT may be a useful preclinical drug screening platform for the treatment of DS." @default.
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• W3109587470 date "2020-12-02" @default.
• W3109587470 modified "2023-09-26" @default.
• W3109587470 title "Development of an Antiseizure Drug Screening Platform for Dravet Syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program" @default.
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• W3109587470 doi "https://doi.org/10.1101/2020.12.01.406470" @default.
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