title: Seizure control by derivatives of medium chain fatty acids associated with the ketogenic diet show novel branching-point structure for enhanced potency.
abstract: The medium chain triglyceride (MCT) ketogenic diet is a major treatment of drug-resistant epilepsy but is problematic, particularly in adults, because of poor tolerability. Branched derivatives of octanoic acid (OA), a medium chain fat provided in the diet have been suggested as potential new treatments for drug-resistant epilepsy, but the structural basis of this functionality has not been determined. Here we investigate structural variants of branched medium chain fatty acids as new seizure-control treatments. We initially employ a series of methyl-branched OA derivatives, and using the GABAA receptor antagonist pentylenetetrazol to induce seizure-like activity in rat hippocampal slices, we show a strong, branch-point-specific activity that improves upon the related epilepsy treatment valproic acid. Using low magnesium conditions to induce glutamate excitotoxicity in rat primary hippocampal neuronal cultures for the assessment of neuroprotection, we also show a structural dependence identical to that for seizure control, suggesting a related mechanism of action for these compounds in both seizure control and neuroprotection. In contrast, the effect of these compounds on histone deacetylase (HDAC) inhibition, associated with teratogenicity, shows no correlation with therapeutic efficacy. Furthermore, small structural modifications of the starting compounds provide active compounds without HDAC inhibitory effects. Finally, using multiple in vivo seizure models, we identify potent lead candidates for the treatment of epilepsy. This study therefore identifies a novel family of fatty acids, related to the MCT ketogenic diet, that show promise as new treatments for epilepsy control and possibly other MCT ketogenic diet-responding conditions, such as Alzheimer disease.
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, United Kingdom (P.C., A.M.E.Z., J.P.M., R.S.B.W.); Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, United Kingdom (A.J.C., J.S.); and Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, United Kingdom (S.W., M.C.-J., M.C.W.).
authors.forename: Pishan
authors.initials: P
authors.lastname: Chang
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, United Kingdom (P.C., A.M.E.Z., J.P.M., R.S.B.W.); Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, United Kingdom (A.J.C., J.S.); and Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, United Kingdom (S.W., M.C.-J., M.C.W.).
authors.forename: Alexandra M E
authors.initials: AM
authors.lastname: Zuckermann
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, United Kingdom (P.C., A.M.E.Z., J.P.M., R.S.B.W.); Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, United Kingdom (A.J.C., J.S.); and Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, United Kingdom (S.W., M.C.-J., M.C.W.).
authors.forename: Sophie
authors.initials: S
authors.lastname: Williams
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, United Kingdom (P.C., A.M.E.Z., J.P.M., R.S.B.W.); Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, United Kingdom (A.J.C., J.S.); and Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, United Kingdom (S.W., M.C.-J., M.C.W.).
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Close
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, United Kingdom (P.C., A.M.E.Z., J.P.M., R.S.B.W.); Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, United Kingdom (A.J.C., J.S.); and Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, United Kingdom (S.W., M.C.-J., M.C.W.).
authors.forename: Marife
authors.initials: M
authors.lastname: Cano-Jaimez
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, United Kingdom (P.C., A.M.E.Z., J.P.M., R.S.B.W.); Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, United Kingdom (A.J.C., J.S.); and Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, United Kingdom (S.W., M.C.-J., M.C.W.).
authors.forename: James P
authors.initials: JP
authors.lastname: McEvoy
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, United Kingdom (P.C., A.M.E.Z., J.P.M., R.S.B.W.); Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, United Kingdom (A.J.C., J.S.); and Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, United Kingdom (S.W., M.C.-J., M.C.W.).
authors.forename: John
authors.initials: J
authors.lastname: Spencer
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, United Kingdom (P.C., A.M.E.Z., J.P.M., R.S.B.W.); Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, United Kingdom (A.J.C., J.S.); and Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, United Kingdom (S.W., M.C.-J., M.C.W.) robin.williams@rhul.ac.uk m.walker@ucl.ac.uk.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Walker
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, United Kingdom (P.C., A.M.E.Z., J.P.M., R.S.B.W.); Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, United Kingdom (A.J.C., J.S.); and Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, United Kingdom (S.W., M.C.-J., M.C.W.) robin.williams@rhul.ac.uk m.walker@ucl.ac.uk.
authors.forename: Robin S B
authors.initials: RS
authors.lastname: Williams
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002210:Caprylates / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D055423:Diet, Ketogenic; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000378:metabolism; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010433:Pentylenetetrazole / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000178:diet therapy / Q000188:drug therapy* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D002210:Caprylates; D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; D006655:Histone Deacetylases; D008274:Magnesium; C031492:octanoic acid; D010433:Pentylenetetrazole