Abstracts

Rationale: The incidence of sudden unexpected death in epilepsy (SUDEP) is more than twenty-fold higher in patients with epilepsy than that of death in the general population. Previous studies have demonstrated that enhanced serotonin (5-HT) function prevents seizure-induced respiratory arrest in provoked seizure models. However, it is unclear whether increased 5-HT neurotransmission alleviates seizure-induced mortality in spontaneous seizure (epilepsy) models. The present study investigated the effect of fluoxetine, a selective serotonin reuptake inhibitor, on spontaneous seizure-induced mortality in the Dravet mouse, a rodent model that closely mimics human Dravet syndrome, a type of epilepsy with a high rate of SUDEP.

Methods: Dravet mice are susceptible to hyperthermia-evoked seizures and spontaneous seizures and exhibit a high rate of SUDEP.  Hyperthermia-primed Dravet mice were used in the study.  Fluoxetine or vehicle (saline) was intraperitoneally (i.p.) injected twice daily for seven days, and the effect of fluoxetine or vehicle on spontaneous seizure-induced mortality was examined. Data were plotted using a Kaplan-Meier survival curve. Statistical comparison between the fluoxetine treatment group and the control group was performed using the log-rank (Mantel-Cox) test.

Results: Systematic administration (i.p.) of fluoxetine at 30 mg/kg (n = 12) significantly reduced spontaneous seizure-induced mortality as compared with vehicle control (n = 21) in Dravet mice (p < 0.01).  However, compared with vehicle control, fluoxetine at 20 mg/kg (n = 19) (p = 0.0587) or 5 mg/kg (n = 10) did not significantly alter spontaneous seizure-induced mortality in Dravet mice.