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Seizure control by decanoic acid through direct AMPA receptor inhibition

Williams, Robin S. B.; Chang, Pishan; Augustin, Katrin; Boddum, Kim; Williams, Sophie; Sun, Min; Terschak, John A.; Hardege, Jörg D.; Chen, Philip E.; Walker, Matthew C.; Williams, Robin S.B.

Authors

Robin S. B. Williams

Pishan Chang

Katrin Augustin

Kim Boddum

Sophie Williams

Min Sun

John A. Terschak

Philip E. Chen

Matthew C. Walker

Robin S.B. Williams



Abstract

The medium chain triglyceride ketogenic diet is an established treatment for drug-resistant epilepsy that increases plasma levels of decanoic acid and ketones. Recently, decanoic acid has been shown to provide seizure control in vivo, yet its mechanism of action remains unclear. Here we show that decanoic acid, but not the ketones β-hydroxybutryate or acetone, shows antiseizure activity in two acute ex vivo rat hippocampal slice models of epileptiform activity. To search for a mechanism of decanoic acid, we show it has a strong inhibitory effect on excitatory, but not inhibitory, neurotransmission in hippocampal slices. Using heterologous expression of excitatory ionotropic glutamate receptor AMPA subunits in Xenopus oocytes, we 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. Together our 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.

Journal Article Type Article
Publication Date Feb 1, 2016
Journal Brain
Print ISSN 1460-2156
Electronic ISSN 1460-2156
Publisher Oxford University Press (OUP)
Peer Reviewed Peer Reviewed
Volume 139
Issue 2
Pages 431-443
APA6 Citation Chang, P., Augustin, K., Boddum, K., Williams, S., Sun, M., Terschak, J. A., …Williams, R. S. (2016). Seizure control by decanoic acid through direct AMPA receptor inhibition. Brain, 139(2), 431-443. https://doi.org/10.1093/brain/awv325
DOI https://doi.org/10.1093/brain/awv325
Keywords AMPA receptors, Decanoic acid, Epilepsy, Ketogenic diet, Seizure control
Publisher URL http://brain.oxfordjournals.org/content/139/2/431
Additional Information This is a copy of an open access article published in Brain, 2015, v.139 issue 2.

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Copyright Statement
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.





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