Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epileps

Hadera, Mussie G., Smeland, Olav B., McDonald, Tanya S., Tan, Kah Ni, Sonnewald, Ursula and Borges, Karin (2014) Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epileps. Journal of Neurochemistry, 129 1: 107-119. doi:10.1111/jnc.12610


Author Hadera, Mussie G.
Smeland, Olav B.
McDonald, Tanya S.
Tan, Kah Ni
Sonnewald, Ursula
Borges, Karin
Title Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epileps
Journal name Journal of Neurochemistry   Check publisher's open access policy
ISSN 0022-3042
1471-4159
Publication date 2014-04-01
Year available 2013
Sub-type Article (original research)
DOI 10.1111/jnc.12610
Volume 129
Issue 1
Start page 107
End page 119
Total pages 13
Place of publication Chichester, West Sussex, United Kingdom
Publisher Wiley-Blackwell
Language eng
Formatted abstract
Triheptanoin, the triglyceride of heptanoate, is anticonvulsant in various epilepsy models. It is thought to improve energy metabolism in the epileptic brain by re-filling the tricarboxylic acid (TCA) cycle with C4-intermediates (anaplerosis). Here, we injected mice with [1,2-13C]glucose 3.5–4 weeks after pilocarpine-induced status epilepticus (SE) fed either a control or triheptanoin diet. Amounts of metabolites and incorporations of 13C were determined in extracts of cerebral cortices and hippocampal formation and enzyme activity and mRNA expression were quantified. The percentage enrichment with two 13C atoms in malate, citrate, succinate, and GABA was reduced in hippocampal formation of control-fed SE compared with control mice. Except for succinate, these reductions were not found in triheptanoin-fed SE mice, indicating that triheptanoin prevented a decrease of TCA cycle capacity. Compared to those on control diet, triheptanoin-fed SE mice showed few changes in most other metabolite levels and their 13C labeling. Reduced pyruvate carboxylase mRNA and enzyme activity in forebrains and decreased [2,3-13C]aspartate amounts in cortex suggest a pyruvate carboxylation independent source of C-4 TCA cycle intermediates. Most likely anaplerosis was kept unchanged by carboxylation of propionyl-CoA derived from heptanoate. Further studies are proposed to fully understand triheptanoin's effects on neuroglial metabolism and interaction.

In the hippocampal formation (HF) of a mouse epilepsy model, formation of citrate, GABA, succinate, fumarate, and malate from 13C-labeled glucose is reduced. Triheptanoin, the triglyceride of heptanoate, inhibits pyruvate carboxylase activity (PC, green arrow), but restores some of these metabolite levels (red arrows). The refilling of the TCA cycle via carboxylation of propionyl-CoA is likely to contribute to triheptanoin's anticonvulsant effects.
Keyword Anaplerosis
NMR spectroscopy
Status epilepticus
13C isotope
Seizures
Medium chain triglyceride
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print: 2 December 2013.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Biomedical Sciences Publications
 
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Created: Wed, 22 Jan 2014, 20:13:10 EST by Ms Joanne Biles on behalf of School of Biomedical Sciences