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Seizure control by ketogenic diet-associated medium chain fatty acids.

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'.
PMID
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Authors

Mayor MeshTerms

Diet, Ketogenic

Keywords
Journal Title neuropharmacology
Publication Year Start




 
PMID- 23177536
OWN - NLM
STAT- MEDLINE
DCOM- 20130906
LR  - 20171116
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Linking)
VI  - 69
DP  - 2013 Jun
TI  - Seizure control by ketogenic diet-associated medium chain fatty acids.
PG  - 105-14
LID - 10.1016/j.neuropharm.2012.11.004 [doi]
LID - S0028-3908(12)00538-2 [pii]
AB  - 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'.
CI  - Copyright (c) 2012 Elsevier Ltd. All rights reserved.
FAU - Chang, Pishan
AU  - Chang P
AD  - Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway
      University of London, Egham, TW20 0EX, UK.
FAU - Terbach, Nicole
AU  - Terbach N
FAU - Plant, Nick
AU  - Plant N
FAU - Chen, Philip E
AU  - Chen PE
FAU - Walker, Matthew C
AU  - Walker MC
FAU - Williams, Robin S B
AU  - Williams RS
LA  - eng
GR  - G0900775/1/National Centre for the Replacement, Refinement and Reduction of
      Animals in Research/United Kingdom
GR  - 082640/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121120
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (4-methyloctanoic acid)
RN  - 0 (Anticonvulsants)
RN  - 0 (Caprylates)
RN  - 0 (Convulsants)
RN  - 0 (Fatty Acids)
RN  - 0 (Hypnotics and Sedatives)
RN  - 0 (Pheromones)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - 97SEH7577T (pelargonic acid)
RN  - EC 3.5.1.98 (Histone Deacetylases)
RN  - WM5Z385K7T (Pentylenetetrazole)
SB  - IM
MH  - Animals
MH  - Anticonvulsants/therapeutic use
MH  - Caprylates/pharmacology
MH  - Cell Line
MH  - Chemical and Drug Induced Liver Injury/pathology
MH  - Convulsants
MH  - *Diet, Ketogenic
MH  - Dose-Response Relationship, Drug
MH  - Drug Resistance
MH  - Fatty Acids/pharmacology/*therapeutic use
MH  - Histone Deacetylases/metabolism
MH  - Humans
MH  - Hypnotics and Sedatives/pharmacology
MH  - Male
MH  - Pentylenetetrazole
MH  - Pheromones/pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Seizures/chemically induced/*diet therapy/physiopathology
MH  - Status Epilepticus/drug therapy/physiopathology
MH  - Valproic Acid/therapeutic use
PMC - PMC3625124
OID - NLM: PMC3625124
EDAT- 2012/11/28 06:00
MHDA- 2013/09/07 06:00
CRDT- 2012/11/27 06:00
PHST- 2012/08/09 00:00 [received]
PHST- 2012/10/31 00:00 [revised]
PHST- 2012/11/02 00:00 [accepted]
PHST- 2012/11/27 06:00 [entrez]
PHST- 2012/11/28 06:00 [pubmed]
PHST- 2013/09/07 06:00 [medline]
AID - S0028-3908(12)00538-2 [pii]
AID - 10.1016/j.neuropharm.2012.11.004 [doi]
PST - ppublish
SO  - Neuropharmacology. 2013 Jun;69:105-14. doi: 10.1016/j.neuropharm.2012.11.004.
      Epub 2012 Nov 20.