Abstracts

Rationale: Prevention of premature mortality due to sudden unexpected death in epilepsy (SUDEP) is a major goal in epilepsy. Most of the witnessed clinical cases reported generalized seizures leading to respiratory and cardiac failure leading to SUDEP. The DBA/1 mouse model of SUDEP exhibits generalized tonic-clonic seizures resulting in S-IRA, which leads to cardiac arrest and death. We previously found that several selective serotonin (5-HT) reuptake inhibitors prevent S-IRA in DBA mice. However, not all the drugs that enhance the activation of 5-HT receptors effectively block S-IRA in DBA mice. Therefore, the present study investigated if ±fenfluramine (FFA), which augments 5-HT release, alters susceptibility to seizure and S-IRA in DBA/1mice. Methods: DBA/1 mice (21-30 days old) were primed by being subjected to audiogenic seizures and S-IRA with 3-4 seizures (once daily), using an electrical bell. Mice that consistently showed S-IRA susceptibility on 3 consecutive tests and were resuscitated with a rodent respirator were studied. At least 24h after priming, the mice received either FFA (5-40 mg/kg) or saline (vehicle) intraperitoneally and were tested for susceptibility to seizures and S-IRA. Seizure behaviors were recorded on videotape, quantified, and compared statistically (Chi-Square Test; significance set at p Results: We characterized the dose-response relationship for FFA against seizures and S-IRA in DBA/1 mice by testing susceptibility at 30 min, 12 and 24h, and then at 24h intervals. Mice that received 10 (n=11) and 15 mg/kg (n=9) of FFA showed significantly (p 50 value of FFA against seizure susceptibility at 30 min was 21.4 mg/kg. A more detailed study of the time course of effect was done using 5 (n=9), 10 (n=10), 15 (n=10) and 20 mg/kg (n=9) doses of FFA at 8h intervals over a 24h period. We found that 15 mg/kg showed a significantly reduced seizure severity (p Conclusions: FFA was effective in blocking S-IRA and seizures in DBA/1 mice in a dose- and time-dependent manner. Blockade of S-IRA by FFA was long-lasting unlike that of all other 5-HT-enhancing drugs previously tested. Our studies are the first to show the efficacy of FFA in a mammalian model of SUDEP. Thus, FFA may prove effective in the prophylaxis of SUDEP in addition to improving seizure control. This finding may be clinically important in light of the recent success with FFA in treatment of Dravet Syndrome patients who have a high risk of SUDEP (Ceulemans et al., Epilepsia, 2016).  Funding: This research is supported by a grant from Zogenix Inc.