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The <jats:styled-content style=\"fixed-case\">DBA<\/jats:styled-content>\/1 mouse model of <jats:styled-content style=\"fixed-case\">SUDEP<\/jats:styled-content> exhibits an elevated susceptibility to seizure\u2010induced death in response to electroconvulsive shock, hyperthermia, convulsant drug, and acoustic stimulation. The serotonin hypothesis of <jats:styled-content style=\"fixed-case\">SUDEP<\/jats:styled-content> is based on findings that treatments which modify serotonergic function significantly alter susceptibility to seizure\u2010induced sudden death in several epilepsy models, including <jats:styled-content style=\"fixed-case\">DBA<\/jats:styled-content>\/1 mice. Serotonergic abnormalities have also recently been observed in human <jats:styled-content style=\"fixed-case\">SUDEP<\/jats:styled-content>. Fenfluramine is a drug that enhances serotonin release in the brain. Recent studies have found that the addition of fenfluramine improved seizure control in patients with Dravet syndrome, which has a high incidence of <jats:styled-content style=\"fixed-case\">SUDEP<\/jats:styled-content>. Therefore, we investigated the effects of fenfluramine on seizures and seizure\u2010induced respiratory arrest (S\u2010<jats:styled-content style=\"fixed-case\">IRA<\/jats:styled-content>) in <jats:styled-content style=\"fixed-case\">DBA<\/jats:styled-content>\/1 mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The dose and time course of the effects of fenfluramine (i.p.) on audiogenic seizures (Sz) induced by an electric bell in <jats:styled-content style=\"fixed-case\">DBA<\/jats:styled-content>\/1 mice were determined. Videos of Sz\u2010induced behaviors were recorded for analysis. Statistical significance (<jats:italic>P\u00a0<\/jats:italic>&lt;<jats:italic>\u00a0<\/jats:italic>0.05) was evaluated using the chi\u2010square test.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sixteen hours after administration of 15\u00a0mg\/kg of fenfluramine, a high incidence of selective block of S\u2010<jats:styled-content style=\"fixed-case\">IRA<\/jats:styled-content> susceptibility (<jats:italic>P\u00a0<\/jats:italic>&lt;<jats:italic>\u00a0<\/jats:italic>0.001) occurred in <jats:styled-content style=\"fixed-case\">DBA<\/jats:styled-content>\/1 mice without blocking any convulsive behavior. Thirty minutes after 20\u201040\u00a0mg\/kg of fenfluramine, significant reductions of seizure incidence and severity, as well as S\u2010<jats:styled-content style=\"fixed-case\">IRA<\/jats:styled-content> susceptibility occurred, which were long\u2010lasting (\u226548\u00a0hours). The median effective dose (<jats:styled-content style=\"fixed-case\">ED<\/jats:styled-content><jats:sub>50<\/jats:sub>) of fenfluramine for significantly reducing Sz at 30\u00a0minutes was 21\u00a0mg\/kg.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>This study presents the first evidence for the effectiveness of fenfluramine in reducing seizure incidence, severity, and S\u2010<jats:styled-content style=\"fixed-case\">IRA<\/jats:styled-content> susceptibility in a mammalian <jats:styled-content style=\"fixed-case\">SUDEP<\/jats:styled-content> model. The ability of fenfluramine to block S\u2010<jats:styled-content style=\"fixed-case\">IRA<\/jats:styled-content> selectively suggests the potential usefulness of fenfluramine in prophylaxis of <jats:styled-content style=\"fixed-case\">SUDEP<\/jats:styled-content>. These results further confirm and extend the serotonin hypothesis of <jats:styled-content style=\"fixed-case\">SUDEP<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.14658","type":"journal-article","created":{"date-parts":[[2019,2,5]],"date-time":"2019-02-05T11:11:27Z","timestamp":1549365087000},"page":"485-494","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Fenfluramine, a serotonin\u2010releasing drug, prevents seizure\u2010induced respiratory arrest and is anticonvulsant in the <scp>DBA<\/scp>\/1 mouse model of <scp>SUDEP<\/scp>"],"prefix":"10.1111","volume":"60","author":[{"given":"Srinivasan","family":"Tupal","sequence":"first","affiliation":[{"name":"Department of Pharmacology Southern Illinois University School of Medicine Springfield Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl 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