Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is the major cause of deaths in patients with epilepsy. Studies in humans and animal models of SUDEP indicate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death after generalized seizures. Enhancing brain serotonin (5-HT) levels by clinically used medications, such as selective 5-HT reuptake inhibitors (SSRIs) or 5-hydroxytryptophan (5-HTP), a chemical precursor for 5-HT synthesis, reduces S-IRA in DBA/1 mice. However, use of other clinically used medications to prevent S-IRA is scarcely reported. In the current study, we evaluated the effect of atomoxetine, a norepinephrine reuptake inhibitor and a medication clinically used to treat attention deficit and hyperactivity disorder (ADHD), on the incidence of S-IRA in DBA/1 mice. Methods: Consistent susceptibility to generalized audiogenic seizures (AGSz) followed by S-IRA in DBA/1 mice was established by applying acoustic stimulation once daily for 3-4 days starting at postnatal day 26-28 (primed DBA/1 mice). Nonprimed DBA/1 mice were never exposed to the acoustic stimulation. S-IRA was evoked by either acoustic stimulation using an electrical bell (96 dB SPL) in primed DBA/1 mice or systemic administration of pentylenetetrazole (PTZ, 75 mg/kg, i.p.) in nonprimed DBA/1 mice. For acoustic stimulation method, S-IRA was always confirmed 24 hr prior to experiment. Atomoxetine or vehicle (saline) was administered i.p. 2 hr before acoustic stimulation or PTZ injection, and the effect of atomoxetine (vehicle) on S-IRA was examined and digitally recorded for offline analysis. Results: The rate of S-IRA evoked by acoustic stimulation was significantly reduced by atomoxetine at 10 mg/kg (54.5%, n = 11; p < 0.05) and 15 mg/kg (10%, n = 10; p < 0.01) as compared with vehicle control (100%, n = 7) in primed DBA/1 mice. Atomoxetine treatment did not block the susceptibility of primed DBA/1 mice to AGSz. As compared with the rate of S-IRA evoked by PTZ in vehicle treatment (100%, n = 6), atomoxetine at 10 mg/kg (28.6%, n = 7; p < 0.05) and 15 mg/kg (28.6%, n = 7; p < 0.05) significantly reduced S-IRA evoked by PTZ. Conclusions: These data suggest that enhancing norepinephrine levels significantly suppresses S-IRA in DBA/1 mice. As a medication used to treat brain disorders such as ADHD, atomoxetine has the merit as a potential therapy for SUDEP. Funding: Supported by R03NS078591, CURE (Citizens United for Research in Epilepsy) foundation grant and fund from the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital to HJF