title: Seizure control by decanoic acid through direct AMPA receptor inhibition.
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.
authors.affiliation: 1 Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, TW20 0EX, UK.
authors.forename: Pishan
authors.initials: P
authors.lastname: Chang
authors.affiliation: 1 Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, TW20 0EX, UK.
authors.forename: Katrin
authors.initials: K
authors.lastname: Augustin
authors.affiliation: 2 Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, WC1N 3BG, UK.
authors.forename: Kim
authors.initials: K
authors.lastname: Boddum
authors.affiliation: 2 Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, WC1N 3BG, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Williams
authors.affiliation: 2 Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, WC1N 3BG, UK.
authors.forename: Min
authors.initials: M
authors.lastname: Sun
authors.affiliation: 3 School of Biological, Biomedical and Environmental Sciences, University of Hull, Cottingham Road, Hull HU6 7RX, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Terschak
authors.affiliation: 3 School of Biological, Biomedical and Environmental Sciences, University of Hull, Cottingham Road, Hull HU6 7RX, UK.
authors.forename: Jörg D
authors.initials: JD
authors.lastname: Hardege
authors.affiliation: 1 Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, TW20 0EX, UK.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Chen
authors.affiliation: 2 Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, WC1N 3BG, UK m.walker@ucl.ac.uk robin.williams@rhul.ac.uk.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Walker
authors.affiliation: 1 Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, TW20 0EX, UK m.walker@ucl.ac.uk robin.williams@rhul.ac.uk.
authors.forename: Robin S B
authors.initials: RS
authors.lastname: Williams
mesh_terms: D000818:Animals; D003652:Decanoic Acids / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009924:Organ Culture Techniques; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D003652:Decanoic Acids; D018091:Receptors, AMPA; C031071:decanoic acid
keywords: AMPA receptors; decanoic acid; epilepsy; ketogenic diet; seizure control