February 7, 2019

Fenfluramine, a Serotonin-Releasing Drug, Prevents Seizure-Induced Respiratory Arrest and is Anticonvulsant in the DBA/1 Mouse Model of SUDEP

OBJECTIVE: Prevention of sudden unexpected death in epilepsy (SUDEP) is a critical goal for epilepsy therapy. The DBA/1 mouse model of SUDEP exhibits an elevated susceptibility to seizure-induced death in response to electroconvulsive shock, hyperthermia, convulsant drug, and acoustic stimulation. The serotonin hypothesis of SUDEP is based on findings that treatments which modify serotonergic function significantly alter susceptibility to seizure-induced sudden death in several epilepsy models, including DBA/1 mice. Serotonergic abnormalities have also recently been observed in human SUDEP. 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 SUDEP. Therefore, we investigated the effects of fenfluramine on seizures and seizure-induced respiratory arrest (S-IRA) in DBA/1 mice.

METHODS: The dose and time course of the effects of fenfluramine (i.p.) on audiogenic seizures (Sz) induced by an electric bell in DBA/1 mice were determined. Videos of Sz-induced behaviors were recorded for analysis. Statistical significance (P < 0.05) was evaluated using the chi-square test.

RESULTS: Sixteen hours after administration of 15 mg/kg of fenfluramine, a high incidence of selective block of S-IRA susceptibility (P < 0.001) occurred in DBA/1 mice without blocking any convulsive behavior. Thirty minutes after 20-40 mg/kg of fenfluramine, significant reductions of seizure incidence and severity, as well as S-IRA susceptibility occurred, which were long-lasting (less than or equal to 48 hours). The median effective dose (ED50 ) of fenfluramine for significantly reducing Sz at 30 minutes was 21 mg/kg.

SIGNIFICANCE: This study presents the first evidence for the effectiveness of fenfluramine in reducing seizure incidence, severity, and seizure-induced respiratory arrest susceptibility in a mammalian SUDEP model. The ability of fenfluramine to block seizure-induced respiratory arrest selectively suggests the potential usefulness of fenfluramine in prophylaxis of SUDEP. These results further confirm and extend the serotonin hypothesis of SUDEP.

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