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

Abstract

Summary 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 anti-seizure drugs, there is a critical need to identify treatments that reduce risk factors for SUDEP. The Kcna1-null mutant mouse lacking the potassium channel Kv1.1alpha subunit model 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, 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.

Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy

“…In the current study, we aimed to determine whether the KD changes PPARγ expression in the brains of epileptic and normal mice; and, if so, whether it contributes to the anti-seizure effects of the KD. Treating epileptic Kv1.1KO mice for two weeks with a KD reduced seizures by ~70% as we have reported previously (Fenoglio-Simeone et al, 2009b; Kim et al 2015; Simeone et al, 2016). KD-treatment increased PPARγ2 in both genotypes resulting in PPARγ2/γ1 ratios that were 2-fold and 6-fold higher for WT and Kv1.1KO brain compared to SD-fed WT mice.…”

“…Seizure severity was scored using a modified Racine scale: 0-normal; 1-myoclonic jerk; 2-side-to-side head movement; 3-forelimb/hindlimb clonus, tail extension, a single rearing event; 4-continuous rearing and falling; 5-severe tonic-clonic seizures. To weigh the incidence and severity of seizures, seizure burden index (SBI) scores were calculated using the equation: SBI = [Σ(σ i γ i )]/ε, where σ indicates the severity; i indicates each stage of seizure (1–5); γ is the frequency; and ε indicates the total number of epochs scored as we have described (Simeone et al, 2014a; Roundtree et al, 2016; Simeone et al, 2016). …”

New insights into the mechanisms of the ketogenic diet

“…Strikingly, KD therapy was found to postpone disease progression, delay the onset of severe seizures and to increase the lifespan of Kcna1-null mice, a model of progressive epilepsy and sudden unexpected death in epilepsy (SUDEP) [45 •• ]. A disease modifying epigenetic mechanism of KD therapy is supported by findings that a predominant increase of DNA methylation is associated with chronic epilepsy in the rat and that KD therapy attenuated seizure progression and ameliorated DNA methylation mediated changes in gene expression [46].…”

Respiratory dysfunction progresses with age in Kcna1‐null mice, a model of sudden unexpected death in epilepsy

“…9,11,12 We have recently demonstrated that seizures progressively become more frequent and severe until the mice die at the early age of postnatal day (P) 42 AE 1.3, 12 although the background strain of the mouse influences the severity of seizures and mortality. 9,10 Kcna1-null (Kcna1 À/À ) mice develop spontaneous recurrent seizures including myoclonic seizures, clonus, and generalized tonicclonic seizures around the third week of their life.…”