{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T04:56:54Z","timestamp":1788238614397,"version":"build-2803163510"},"reference-count":65,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T00:00:00Z","timestamp":1703203200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012739","name":"Zogenix","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012739","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006978","name":"University of California Berkeley","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006978","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>In patients with Dravet syndrome (DS), fenfluramine reduced convulsive seizure frequency and provided clinical benefit in nonseizure endpoints (e.g., executive function, survival). In zebrafish mutant <jats:italic>scn1<\/jats:italic> DS models, chronic fenfluramine treatment preserved neuronal cytoarchitecture prior to seizure onset and prevented gliosis; here, we extend these findings to a mammalian model of DS (<jats:italic>Scn1a<\/jats:italic><jats:sup><jats:italic>+\/\u2212<\/jats:italic><\/jats:sup> mice) by evaluating the effects of fenfluramine on neuroinflammation (degenerated myelin, activated microglia) and survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>Scn1a<\/jats:italic><jats:sup><jats:italic>+\/\u2212<\/jats:italic><\/jats:sup> DS mice were treated subcutaneously once daily with fenfluramine (15\u2009mg\/kg) or vehicle from postnatal day (PND) 7 until 35\u201037. Sagittal brain sections were processed for immunohistochemistry using antibodies to degraded myelin basic protein (D\u2010MBP) for degenerated myelin, or CD11b for activated (inflammatory) microglia; sections were scored semi\u2010quantitatively. Apoptotic nuclei were quantified by TUNEL assay. Statistical significance was evaluated by 1\u2010way ANOVA with post\u2010hoc Dunnett's test (D\u2010MBP, CD11b, and TUNEL) or Logrank Mantel\u2010Cox (survival).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Quantitation of D\u2010MBP immunostaining per 0.1\u2009mm<jats:sup>2<\/jats:sup> unit area of the parietal cortex and hippocampus CA3 yielded significantly higher spheroidal and punctate myelin debris counts in vehicle\u2010treated DS mice than in wild\u2010type mice. Fenfluramine treatment in DS mice significantly reduced these counts. Activated CD11b\u2009+\u2009microglia were more abundant in DS mouse corpus callosum and hippocampus than in wild\u2010type controls. Fenfluramine treatment of DS mice resulted in significantly fewer activated CD11b\u2009+\u2009microglia than vehicle\u2010treated DS mice in these brain regions. TUNEL staining in corpus callosum was increased in DS mice relative to wild\u2010type controls. Fenfluramine treatment in DS mice lowered TUNEL staining relative to vehicle\u2010treated DS mice. By PND 35\u201037, 55% of control DS mice had died, compared with 24% of DS mice receiving fenfluramine treatment (<jats:italic>P<\/jats:italic>\u2009=\u20090.0291).<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>This is the first report of anti\u2010neuroinflammation and pro\u2010survival after fenfluramine treatment in a mammalian DS model. These results corroborate prior data in humans and animal models and suggest important pharmacological activities for fenfluramine beyond seizure reduction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Plain Language Summary<\/jats:title><jats:p>Dravet syndrome is a severe epilepsy disorder that impairs learning and causes premature death. Clinical studies in patients with Dravet syndrome show that fenfluramine reduces convulsive seizures. Additional studies suggest that fenfluramine may have benefits beyond seizures, including promoting survival and improving control over emotions and behavior. Our study is the first to use a Dravet mouse model to investigate nonseizure outcomes of fenfluramine. Results showed that fenfluramine treatment of Dravet mice reduced neuroinflammation significantly more than saline treatment. Fenfluramine\u2010treated Dravet mice also lived longer than saline\u2010treated mice. These results support clinical observations that fenfluramine may have benefits beyond seizures.<\/jats:p><\/jats:sec>","DOI":"10.1002\/epi4.12873","type":"journal-article","created":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T07:45:46Z","timestamp":1701243946000},"page":"300-313","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Fenfluramine increases survival and reduces markers of neurodegeneration in a mouse model of Dravet syndrome"],"prefix":"10.1002","volume":"9","author":[{"given":"John","family":"Cha","sequence":"first","affiliation":[{"name":"University of California San Francisco  San Francisco California USA"},{"name":"Zogenix, Inc. (now a part of UCB)  Emeryville California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Filatov","sequence":"additional","affiliation":[{"name":"Zogenix, Inc. 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