Fenfluramine, a Serotonin Releaser, Prevents Spontaneous Seizure-induced Mortality in Dravet Mice
Abstract number :
3.052
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2022
Submission ID :
2204832
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:26 AM
Authors :
Hua-Jun Feng, PhD – Massachusetts General Hospital and Harvard Medical School; Jialing Guo, MD, PhD – Massachusetts General Hospital and Harvard Medical School
Rationale: Sudden unexpected death in epilepsy (SUDEP) accounts for up to 17% of deaths in patients with epilepsy and ranks second in years of potential life lost among common neurological disorders. Previous studies have demonstrated that augmenting serotonergic (5-HT) neurotransmission suppresses seizure-induced respiratory arrest in provoked seizure models. However, it remains unknown if enhancing 5-HT function prevents spontaneous seizure-induced mortality, a condition that closely mimics SUDEP in patients. In the present study, we evaluated the effect of fenfluramine, a drug that increases 5-HT release in the brain, on spontaneous seizure-induced mortality in Dravet mice.
Methods: The Dravet mouse recapitulates the salient feature of human Dravet syndrome, including spontaneous seizures, hyperthermia-evoked seizures, and a high rate of SUDEP. The seizures induced by hyperthermia are similar to spontaneous seizures in Dravet mice. Hyperthermia-primed Dravet mice were systematically administered fenfluramine or saline (vehicle) twice daily for seven days. The effect of fenfluramine or vehicle on spontaneous seizure-induced mortality was plotted using a Kaplan Meier survival curve. Statistical difference in spontaneous seizure-induced mortality between the fenfluramine treatment group and the control group was compared using the log-rank (Mantel-Cox) test.
Results: Fenfluramine at 1 mg/kg (n = 10) significantly reduced spontaneous seizure-induced mortality as compared with vehicle control (n = 19) in Dravet mice (p < 0.05). As compared with vehicle control, fenfluramine at 5 mg/kg (n = 13) (p < 0.01) or 10 mg/kg (n = 10) (p < 0.05) also significantly suppressed spontaneous seizure-induced mortality. Interestingly, fenfluramine at 1, 5 and 10 mg/kg fully protected Dravet mice from spontaneous seizure-induced mortality, with all the mice survived the treatment course in each group. However, fenfluramine at 0.2 mg/kg (n = 12) did not significantly reduce spontaneous seizure-induced mortality as compared with vehicle control.
Basic Mechanisms