Enhancing the action of serotonin by three different mechanisms prevents spontaneous seizure‐induced mortality in Dravet mice

• DOI: 10.1111/epi.17966
• Publication Date: 2024-04-09T18:57:04Z
• Authors: Jialing Guo; Daniel Min; Emory K. Farrell; Yupeng Zhou; Carl L. Faingold; Joseph F. Cotten; Hua‐Jun Feng
• Keywords: Dravet syndrome; Serotonin reuptake inhibitor; Serotonin Agonist

Abstract Objective Sudden unexpected death in epilepsy (SUDEP) is an underestimated complication of epilepsy. Previous studies have demonstrated that enhancement serotonergic neurotransmission suppresses seizure‐induced sudden evoked seizure models. However, it unclear whether elevated serotonin (5‐HT) function will prevent spontaneous mortality (SSIM), which characteristic human SUDEP. We examined the effects 5‐HT‐enhancing agents act by three different pharmacological mechanisms on SSIM Dravet mice, exhibit a high incidence SUDEP, modeling syndrome. Methods mice both sexes were evaluated for characterization and changes induced enhance 5‐HT‐mediated neurotransmission. Fluoxetine (a selective 5‐HT reuptake inhibitor), fenfluramine releaser agonist), SR 57227 specific 3 receptor or saline (vehicle) was intraperitoneally administered over 8‐day period effect these treatments examined. Results Spontaneous seizures generally progressed from wild running to tonic with without SSIM. at 30 mg/kg, but not 20 5 significantly reduced compared vehicle control. Fenfluramine 1–10 .2 fully protected SSIM, all surviving. Compared control, 10 lowered The drugs independent sex. Significance Our data demonstrate elevating fluoxetine, fenfluramine, reduces eliminates sex‐independent manner. These findings suggest deficits likely play important role pathogenesis fluoxetine are US Food Drug Administration‐approved medications, may potentially SUDEP at‐risk patients.