Circadian Effects of Acebutolol Administration in the Scn1b-/- Dravet Syndrome Mouse Model

Abstract

Dravet syndrome (DS) is a severe form of pediatric epilepsy with characterizations of pharmacoresistant seizures and developmental delay. A rarer variant of the DS model is caused by heterozygous loss-of-function mutations in SCN1B, which is essential in regulating sodium channel gating, expression, localization, and the firing of action potentials. Mutations in SCN1B result in severe seizures as well as a higher risk of Sudden Unexpected Death in EPilepsy (SUDEP). Factors underlying SUDEP are poorly understood, although cardiac arrythmias have been implicated. Acebutolol (ACE) is a common beta-blocker used in the treatment of arrhythmias and hypertension. We hypothesized that treating mice with ACE will decrease cardiac arrhythmias and the incidence of SUDEP, prolonging lifespan of Scn1b null mice. Wild-type (WT) and null (KO) mice were given daily injections of 10 mg/kg ACE or saline starting at postnatal day 15 (after typical seizure onset) either during the day (09:00) or at night (21:00). ECG was recorded daily including a baseline and a 20-minute post injection measurement to analyze the long-term and acute effects of treatment. 20 minutes following ACE injection, KO mice displayed a significant reduction in heart rate compared to WT (38% vs. 11%). Interestingly, HR the day prior to death consistently dropped ~50% (average 414 bpm to 193 bpm) in our saline group; this was prevented in KO animals treated with ACE (421 bpm). A modest, but significant, increase in survival curves in our KO animals was observed compared to saline treated mice for those given injections during the day (a 2 day increase in median survival). In addition, in this group, the onset of animal death was delayed. Surprisingly, in the mice injected during the night hours, there was a trend towards a decrease in lifespan. From these findings there is a notable hypersensitivity to ACE in this DS model. Leading up to death, we believe it is possible ACE assisted in decreased cardiovascular deficits that could lead to SUDEP and contributed to the modest increased lifespan. While we are still seeing death in the ACE treated group because of unnoticed, prolonged seizures, or other mechanisms of SUDEP. In addition, our results demonstrate the importance of timing in delivery of drugs targeted at SUDEP. Further work includes testing this hypothesis by adding 24 hour drug delivery or an anti-epileptic drug to see if lifespan is further affected is warranted