Ketone ester supplementation attenuates seizure activity, and improves behavior and hippocampal synaptic plasticity in an Angelman syndrome mouse model

Abstract

Angelman syndrome (AS) is a rare genetic and neurological disorder presenting with seizures, developmental delay, ataxia, and lack of speech. Previous studies have indicated that oxidative stress-dependent metabolic dysfunction may underlie the phenotypic deficits reported in the AS mouse model. While the ketogenic diet (KD) has been used to protect against oxidative stress and has successfully treated refractory epilepsy in AS case studies, issues arise due to its strict adherence requirements, in addition to selective eating habits and weight issues reported in patients with AS. We hypothesized that ketone ester supplementation would mimic the KD as an anticonvulsant and improve the behavioral and synaptic plasticity deficits in vivo. AS mice were supplemented R,S-1,3-butanediol acetoacetate diester (KE) ad libitum for eight weeks. KE administration improved motor coordination, learning and memory, and synaptic plasticity in AS mice. The KE was also anticonvulsant and altered brain amino acid metabolism in AS treated animals. Our findings suggest that KE supplementation produces sustained ketosis and ameliorates many phenotypes in the AS mouse model, and should be investigated further for future clinical use.

Exogenous Ketone Supplements Reduce Anxiety-Related Behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk Rats

“…Thus, theoretically, as ketone supplementation may generate similar changes in brain neurotransmitter systems as KD by means of ketosis (Figures 1–3), chronic and sub-chronic ketone supplementation-provoked anxiolytic effects may be evoked by means of glutamatergic and/or GABAergic as well as adenosinergic system in SPD and WAG/Rij rats. Indeed, a recent study supports the effect of ketone esters increasing the brain GABA/Glutamate ratio in an animal model of Angelman’s syndrome (Ciarlone et al, 2016). However, our knowledge is not sufficient at present to explain the mechanism(s), by which ketone supplementation exerts its anti-anxiety effects.…”

Delta rhythmicity is a reliable EEG biomarker in Angelman syndrome: a parallel mouse and human analysis

“…Loss-of-function mutations in the maternal copy of the imprinted UBE3A gene cause AS [2, 3], while maternal duplications in the same region (15q11-13) are linked to autism [4–6]. Recent work has identified multiple approaches with preclinical therapeutic potential for AS: antisense oligonucleotides and topoisomerase inhibitors have the potential to unsilence paternal UBE3A and re-express UBE3A protein; gene therapy provides a direct method of expressing UBE3A ; mechanism-based approaches downstream of UBE3A include GABA A agonists (THIP/gaboxadol) and modulation of αCaMKII; other approaches include altering diet [7–12]. Many of these approaches are in the pipeline for upcoming clinical trials.…”

Use of the Ketogenic Diet to Treat Intractable Epilepsy in Mitochondrial Disorders

“…Research interest is also centred around the possibility of replacing the strict diet with its challenging adherence rules with supplements, like a “ketogenic pill”. Ketone esters given orally were effective anticonvulsants in mouse models of Angelmans and in pentylenetetrazole-model of seizures [64,65]. In addition, in Sada et al, lactate dehydrogensae (LDH) inhibition was seen to be effective in suppressing seizures.…”