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Keywords:

  • anaplerosis;
  • NMR spectroscopy;
  • status epilepticus;
  • 13C isotope;
  • seizures;
  • medium chain triglyceride

Abstract

Thumbnail image of graphical 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.