| Title: | Seizure control by ketogenic diet-associated medium chain fatty acids |
| Author(s): | Chang P; Terbach N; Plant N; Chen PE; Walker MC; Williams RS; |
| Address: | "Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, TW20 0EX, UK" |
| DOI: | 10.1016/j.neuropharm.2012.11.004 |
| ISSN/ISBN: | 1873-7064 (Electronic) 0028-3908 (Print) 0028-3908 (Linking) |
| Abstract: | "The medium chain triglyceride (MCT) ketogenic diet is used extensively for treating refractory childhood epilepsy. This diet increases the plasma levels of medium straight chain fatty acids. A role for these and related fatty acids in seizure control has not been established. We compared the potency of an established epilepsy treatment, Valproate (VPA), with a range of MCT diet-associated fatty acids (and related branched compounds), using in vitro seizure and in vivo epilepsy models, and assessed side effect potential in vitro for one aspect of teratogenicity, for liver toxicology and in vivo for sedation, and for a neuroprotective effect. We identify specific medium chain fatty acids (both prescribed in the MCT diet, and related compounds branched on the fourth carbon) that provide significantly enhanced in vitro seizure control compared to VPA. The activity of these compounds on seizure control is independent of histone deacetylase inhibitory activity (associated with the teratogenicity of VPA), and does not correlate with liver cell toxicity. In vivo, these compounds were more potent in epilepsy control (perforant pathway stimulation induced status epilepticus), showed less sedation and enhanced neuroprotection compared to VPA. Our data therefore implicates medium chain fatty acids in the mechanism of the MCT ketogenic diet, and highlights a related new family of compounds that are more potent than VPA in seizure control with a reduced potential for side effects. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'" |
| Keywords: | "Animals Anticonvulsants/therapeutic use Caprylates/pharmacology Cell Line Chemical and Drug Induced Liver Injury/pathology Convulsants *Diet, Ketogenic Dose-Response Relationship, Drug Drug Resistance Fatty Acids/pharmacology/*therapeutic use Histone Deac;" |
| Notes: | "MedlineChang, Pishan Terbach, Nicole Plant, Nick Chen, Philip E Walker, Matthew C Williams, Robin S B eng G0900775/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom 082640/WT_/Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov't England 2012/11/28 Neuropharmacology. 2013 Jun; 69:105-14. doi: 10.1016/j.neuropharm.2012.11.004. Epub 2012 Nov 20" |
