Decanoic acid, not ketones, behind therapeutic effect of MCT ketogenic diet

The medium chain triglyceride(MCT) ketogenic diet is an established treatment for drug-resistant epilepsy that increases plasma levels of decanoic acid and ketones. The general assumption is that the diet’s antiepileptic effect is due to ketone production.However there is a poor correlation between serum ketones and seizure control.

Recently decanoic acid within the MCT ketogenic diet has been shown to block seizures among people with epilepsy to a greater extent than medications currently used to treat the condition. Besides decanoic acid may even have fewer side effects.Indeed, in vitro, decanoic acid is more potent than valproic acid [a branched chain fatty acid isomer of octanoic acid],a common antiepileptic drug.

However the therapeutic mechanism of the MCT ketogenic diet remains unclear. In research published online in Brain, a team of researchers at the Royal Holloway University of London and University College London, has shown that a major constituent of the MCT ketogenic diet, decanoic acid, but not the ketones β-hydroxybutryate or acetone, exhibits antiseizure activity in two acute ex vivo rat hippocampal slice models of epileptiform activity.

Using heterologous expression of excitatory ionotropic glutamate receptor AMPA subunits in Xenopus oocytes, they show that this effect is through direct AMPA receptor inhibition, a target shared by a recently introduced epilepsy treatment perampanel.

Decanoic acid acts as a non-competitive antagonist at therapeutically relevant concentrations, in a voltage- and subunit-dependent manner, and this is sufficient to explain its antiseizure effects. This inhibitory effect is likely to be caused by binding to sites on the M3 helix of the AMPA-GluA2 transmembrane domain; independent from the binding site of perampanel.

These results indicate that the direct inhibition of excitatory neurotransmission by decanoic acid in the brain contributes to the anti-convulsant effect of the medium chain triglyceride ketogenic diet. According to Prof Robin Williams at Royal Holloway University, the possibility that mechanism of action of the ketogenic diet is related to the fat in the diet rather than the ketones will lead to the development of improved diets and suggests that the ketogenic diet should be renamed simply as the "MCT diet".

It is important to note, however, that there may be circumstances where ketones do play a greater role in seizure control such as in Glut1 deficiency, the ketones from the ketogenic diet providing the brain with an alternative energy source. In addition the ketogenic diet in the longer term may modify metabolic and gene expression, which could have important disease-modifying effects.

Citation

Chang P, Augustin K, Boddum K, Williams S, Sun M, Terschak JA, Hardege JD, Chen PE, Walker MC, Williams RS (2015) Seizure control by decanoic acid through direct AMPA receptor inhibition. BRAIN 2015. DOI: http://dx.doi.org/10.1093/brain/awv325 First published online: 25 November 2015

cover photo: courtesy The Charlie Foundation for ketogenic therapies