title: Is the interaction between fatty acids and tryptophan responsible for the efficacy of a ketogenic diet in epilepsy? The new hypothesis of action.
abstract: The effects of a ketogenic diet in controlling seizure activity have been proven in many studies, although its mechanism of action remains elusive in many regards. We hypothesize that the ketogenic diet may exert its antiepileptic effects by influencing tryptophan (TRP) metabolism. The aim of this study was to investigate the influence of octanoic and decanoic fatty acids (FAs), the main components in the MCT diet (medium-chain triglyceride diet, a subtype of the ketogenic diet), on the metabolism of TRP, the activity of the kynurenic pathway and the concentrations of monoamines and amino acids, including branched-chain amino acids (BCAA) and aromatic amino acids (AAA) in rats. The acute effects of FA on the sedation index and hippocampal electrical after-discharge threshold were also assessed. We observed that intragastric administration of FA increased the brain levels of TRP and the central and peripheral concentrations of kynurenic acid (KYNA), as well as caused significant changes in the brain and plasma concentrations of BCAA and AAA. We found that the administration of FA clearly increased the seizure threshold and induced sedation. Furthermore, we have demonstrated that blocking TRP passage into the brain abolished these effects of FA but had no similar effect on the formation of ketone bodies. Given that FAs are major components of a ketogenic diet, it is suggested that the anticonvulsant effects of a ketogenic diet may be at least partly dependent on changes in TRP metabolism. We also propose a more general hypothesis concerning the intracellular mechanism of the ketogenic diet.
authors.affiliation: Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland; Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland. Electronic address: piomac@yahoo.com.
authors.forename: P
authors.initials: P
authors.lastname: Maciejak
authors.affiliation: Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Szyndler
authors.affiliation: Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland.
authors.forename: D
authors.initials: D
authors.lastname: Turzyńska
authors.affiliation: Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Sobolewska
authors.affiliation: Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Kołosowska
authors.affiliation: Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland.
authors.forename: P
authors.initials: P
authors.lastname: Krząścik
authors.affiliation: Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland; Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Płaźnik
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D055423:Diet, Ketogenic; D004827:Epilepsy / Q000178:diet therapy* / Q000378:metabolism*; D005227:Fatty Acids / Q000008:administration & dosage / Q000378:metabolism*; D006993:Hypnotics and Sedatives / Q000008:administration & dosage; D058542:Implantable Neurostimulators; D007657:Ketone Bodies / Q000378:metabolism; D007736:Kynurenic Acid / Q000378:metabolism; D008297:Male; D008959:Models, Neurological; D017208:Rats, Wistar; D016896:Treatment Outcome; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D006993:Hypnotics and Sedatives; D007657:Ketone Bodies; D014364:Tryptophan; D007736:Kynurenic Acid
keywords: NAD(+)/NADH ratio; ketogenic diet; kynurenic acid; octanoic and decanoic fatty acids; seizure activity; tryptophan