Seizure control by decanoic acid through direct AMPA receptor inhibition.

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

doi:10.1093/brain/awv325

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.

Highlights

The medium chain triglyceride (MCT) ketogenic diet was first identified as a treatment for refractory epilepsy in 1971 (Huttenlocher et al, 1971)
It has been established that decanoic acid has antiseizure effects at clinically relevant concentrations in vitro and in vivo (Chang et al, 2013; Wlaz et al, 2015) but octanoic acid does not, and with previous in vivo pharmacokinetic data indicating that decanoic acid penetrates the blood–brain barrier (Oldendorf, 1973), these data suggest that decanoic acid directly contributes to the therapeutic effect of the MCT ketogenic diet
In vitro, decanoic acid is more potent than valproic acid [a branched chain fatty acid isomer of octanoic acid, that is commonly used in the treatment of epilepsy (Chang et al, 2013), and which has been shown to act on phosphoinositide signalling in seizure control (Xu et al, 2007; Chang et al, 2012, 2014a)]

Summary

Introduction

The medium chain triglyceride (MCT) ketogenic diet was first identified as a treatment for refractory epilepsy in 1971 (Huttenlocher et al, 1971). In vitro, decanoic acid is more potent than valproic acid [a branched chain fatty acid isomer of octanoic acid, that is commonly used in the treatment of epilepsy (Chang et al, 2013), and which has been shown to act on phosphoinositide signalling in seizure control (Xu et al, 2007; Chang et al, 2012, 2014a)]. It is unclear if ketones or decanoic acid provide direct, acute antiseizure effects during administration of an MCT diet, and by what mechanism.

Methods

Results

Conclusion