Ketogenic diet treatment increases longevity in Kcna1-null mice, a model of sudden unexpected death in epilepsy

Abstract

Individuals with poorly controlled epilepsy have a higher risk for sudden unexpected death in epilepsy (SUDEP). With approximately one third of people with epilepsy not achieving adequate seizure control with current antiseizure drugs, there is a critical need to identify treatments that reduce risk factors for SUDEP. The Kcna1-null mutant mouse models risk factors and terminal events associated with SUDEP. In the current study, we demonstrate the progressive nature of epilepsy and sudden death in this model (mean age of mortality (± SEM), postnatal day [P] 42.8 ± 1.3) and tested the hypothesis that long-term treatment with the ketogenic diet (KD) will prolong the life of Kcna1-null mice. We found that the KD postpones disease progression by delaying the onset of severe seizures and increases the lifespan of these mutant mice by 47%. Future studies are needed to determine the mechanisms underlying the KD effects on longevity.

Keywords: Disease progression; Kv1.1 knockout; Mortality; Seizures; Survival.

Figure 1. KD treatment delays seizure progression in Kcna1-null mice

(A) The increase in seizure number after P30 in control SD-treated control Kcna1-null mice (Ctl, red) is attenuated in KD-treated mice (KD, blue). Data are plotted as the mean ± SEM. ⁺⁺Differs from Ctl P25–29, p < 0.005, ⁺⁺⁺p < 0.001, ⁺⁺⁺⁺p < 0.0001. *** Differs from Ctl within age group, p < 0.001. (B) Ratio of mild to severe seizures are plotted and analyzed within age groups, *p < 0.05, ***p < 0.0001. (C) Onset of severe generalized tonic clonic (GTC) seizures increases prior to sudden death for both Ctl and KD-treated groups (Mann-Whitney t test, *p < 0.05) (n=4–7 for each group at each time point).

Figure 2. Ketogenic Diet increases longevity of Kcna1-null mice

(A) SD-treated control epileptic mice that were a part of this longevity study (Ctl; n = 22, red lines) exhibited the same survival curve as retrospective analyses of the Kcna1-null mice of the entire colony (n = 90, Ctl, entire colony, black lines). KD treatment significantly increased the survival of in Kcna1-null mice (KD; n = 10; p < 0.0001, blue lines). (B) Cumulative probability of death curves also demonstrated the rightward shift of the population as a whole in KD animals. Data points were fit with a cumulative Gaussian nonlinear regression and Goodness of Fit R square ranged from 0.91–0.98. (C and D) Measurements of blood BHB and glucose levels at baseline (~P22), during treatment (P32-P39) and prior to death. Final measurements were taken between P35-P49 for SD-treated Kcna1-null (Ctl, red) mice, between P50-P70 for KD-treated Kcna1-null mice (KD, blue), and between P50-P70 for SD-treated wild type (WT, black) mice (n = 5–9 for each group at each time point), **p < 0.001; ****p < 0.0001 vs. baseline measurements.