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

Neurobiol Dis. 2016 Dec;96:38-46. doi: 10.1016/j.nbd.2016.08.002. Epub 2016 Aug 18.

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.

Keywords: Angelman syndrome; Ketone ester; Metabolism; Motor coordination; Seizure; Synaptic plasticity.

MeSH terms

  • Acoustic Stimulation / adverse effects
  • Action Potentials / drug effects
  • Angelman Syndrome / blood
  • Angelman Syndrome / complications*
  • Animals
  • Conditioning, Psychological / drug effects
  • Disease Models, Animal
  • Esters / blood
  • Esters / pharmacology*
  • Esters / therapeutic use*
  • Excitatory Amino Acid Agonists / toxicity
  • Excitatory Postsynaptic Potentials / drug effects
  • Exploratory Behavior / drug effects*
  • Female
  • Hippocampus / pathology*
  • Kainic Acid / toxicity
  • Ketones / blood
  • Ketones / pharmacology
  • Ketones / therapeutic use
  • Male
  • Maze Learning / drug effects
  • Mice
  • Mice, Transgenic
  • Neuronal Plasticity / drug effects*
  • Psychomotor Performance / drug effects
  • Seizures* / drug therapy
  • Seizures* / etiology
  • Seizures* / pathology
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Esters
  • Excitatory Amino Acid Agonists
  • Ketones
  • Ube3a protein, mouse
  • Ubiquitin-Protein Ligases
  • Kainic Acid