Abstracts

Rationale: The DBA/1 mouse model of sudden unexpected death in epilepsy (SUDEP) exhibits chronic susceptibility to seizure-induced cardio-respiratory death (S-ICRD). The only effective preventative therapy for sudden death in DBA/1 mice is fluoxetine, a selective serotonin (5-HT) re-uptake inhibitor (SSRI), which blocks death without blocking seizures or reducing seizure severity (Faingold et al., Epilepsy Behav., 2011). SSRIs have been shown retrospectively to reduce respiratory depression in certain types of epilepsy patients (Bateman et al., Epilepsia, 2010). Several SSRIs are currently available, but it is not clear if all of these agents are effective in blocking S-ICRD and, if so, whether there is a selectivity of effects on S-ICRD vs. anticonvulsant effects in DBA/1 mice. The present study evaluated the effects of two other SSRIs, sertraline and fluvoxamine, as well as a selective 5HT₇ agonist (AS-19) to determine if these agents are effective and/or selective in blocking S-ICRD since 5-HT₇ receptors are involved in spinal control of respiration. Methods: DBA/1 mice (8-22g, 24-65 days old) were evaluated for susceptibility to audiogenic S-ICRD, using an electrical bell (122 dB SPL). Behaviors were recorded on video, and seizure parameters were quantified visually off-line. Mice that exhibited S-ICRD were resuscitated using a rodent respirator. At least 24 hr later mice exhibiting seizure-induced S-ICRD were given sertraline (4-80 mg/kg, i.p.), fluvoxamine (30-80 mg/kg) or AS-19 (10-60 mg/kg) and tested for S-ICRD after drug. Results: S-ICRD was significantly reduced (p <0.05, Wilcoxon signed rank test) by sertraline 30 min after administration (>40 mg/kg), but the mice remained susceptible to audiogenic seizure at the same time. Fluvoxamine also significantly reduced S-ICRD (p <0.05), 30 min after the drug (>60 mg/kg), and the mice remained susceptible to seizures at the same time. Return to S-ICRD was observed 24 hr after drug with each SSRI. Although seizure susceptibility remained after fluvoxamine and sertraline, seizure severity was reduced, as indicated by the significantly reduced incidence of tonic seizures (p <0.05) at the doses that blocked S-ICRD. This lack of selectivity for blocking S-ICRD contrasts with relative selectivity of fluoxetine, which significantly reduced S-ICRD at doses that did not significantly reduce tonic seizures. The 5-HT₇ agonist was not effective in blocking S-ICRD in DBA/1 mice, and, in higher doses, was toxic and pro-convulsant. Conclusions: Since the 5-HT₇ agonist was ineffective in blocking S-ICRD, this suggests that this 5-HT receptor subtype and actions at the spinal level do not contribute importantly to the ability of SSRIs to block S-ICRD. The relative selectivity of fluoxetine to block S-ICRD without affecting seizure severity contrasts with the effects of sertraline and fluvoxamine and may have clinical implications for the potential prevention of SUDEP in patients that should be evaluated. (Support: EAM at SIUSM and Citizens United to Cure Epilepsy)