A ketogenic diet protects DBA/1 and Scn1aR1407X/+ mice against seizure-induced respiratory arrest independent of ketosis

Abstract

Patients with uncontrolled epilepsy have a high risk of sudden unexpected death in epilepsy (SUDEP). Seizure-induced respiratory arrest (S-IRA) is thought to be the determining cause of death in many cases of SUDEP. The goal of the present study was to use Scn1aR1407X/+ (Dravet Syndrome, DS) and DBA/1 mice to determine: (1) the effect of a ketogenic diet (KD) on S-IRA and (2) the relationship between serum ketones and the protective effect of a KD. Ketogenic diet treatment significantly decreased spontaneous seizure-induced mortality in DS mice compared to control (8% vs 39%, p = 0.0021). This protective effect was not abolished when ketosis was prevented by supplementing the KD with glucose (10% mortality, p = 0.0007). In DBA/1 mice, the latency to onset of S-IRA due to audiogenic seizures was delayed from 7.6 to 20.8 seconds by a KD on treatment day (TD) 7 compared to control (p < 0.0001), an effect that was reversed on TD14 when mice were crossed over to a control diet on TD7. β-Hydroxybutyrate (BHB) levels were significantly decreased in DBA/1 mice on a KD supplemented with glucose (p = 0.0038), but the protective effect was maintained. Our findings show that a KD decreases SUDEP in DS mice and increases the latency to audiogenic S-IRA in DBA/1 mice. In both mouse models, a KD was protective against S-IRA. This effect may be due in part to specific dietary components rather than generation of ketone bodies.