Abstracts

Rationale: The incidence of sudden unexpected death in epilepsy (SUDEP) is 1.4 per 1000 patient-years, accounting for up to 17% of deaths in patients with epilepsy. Previous studies observed that enhancing serotonin (5-HT) neurotransmission by activating 5-HT3 receptors suppresses seizure-induced respiratory arrest in provoked seizure models. However, it remains unknown if activating 5-HT3 receptors also prevents seizure-induced mortality in spontaneous seizure models. The present study investigated the effect of SR 57227, a potent and selective 5-HT3 receptor agonist, on spontaneous seizure-induced mortality in Dravet mice, an animal model of human Dravet syndrome.

Methods: The Dravet mouse has been shown to closely mimic human Dravet syndrome, which exhibits spontaneous seizures, hyperthermia-evoked seizures, and a high rate of SUDEP. Hyperthermia-evoked seizures in Dravet mice are behaviorally similar to spontaneous seizures. Hyperthermia-primed Dravet mice were intraperitoneally (i.p.) administered SR 57227 or saline (vehicle) twice daily for seven days. The effect of SR 57227 or vehicle on spontaneous seizure-induced mortality was analyzed using a Kaplan Meier survival curve. Statistical comparison of spontaneous seizure-induced mortality between the SR 57227 treatment group and the control group was carried out using the log-rank (Mantel-Cox) test.

Results: As compared with vehicle (saline) control (n = 22), i.p. injection of SR 57227 at 20 mg/kg (n = 9) significantly reduced spontaneous seizure-induced mortality in Dravet mice (p < 0.05). However, SR 57227 at 10 mg/kg (n = 10) or 5 mg/kg (n = 9) did not significantly alter spontaneous seizure-induced mortality as compared with vehicle control in Dravet mice.