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

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 [1,2-13 C]glucose 3.5-4 weeks after pilocarpine-induced status epilepticus (SE) fed either a control or triheptanoin diet. Amounts of metabolites and incorporations of 13 C were determined in extracts of cerebral cortices and hippocampal formation and enzyme activity and mRNA expression were quantified. The percentage enrichment with two 13 C 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 13 C labeling. Reduced pyruvate carboxylase mRNA and enzyme activity in forebrains and decreased [2,3-13 C]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.

Anaplerotic treatment of long-chain fat oxidation disorders with triheptanoin: Review of 15years Experience

“…A recent retrospective chart review study of 20 of these same patients concluded that extension of the TH diet for three years reduced days required in hospital for clinical complications. [29] Recent animal studies with TH report significant benefit for serious complications such as correction of ventricular hypertrophy and pressure overload in rats [30], relief of ischemic stroke [31] and reduced seizures [32]. These observations indicate that an unrecognized energy deficiency exists in broad areas of disease and may also benefit from TH and carnitine therapy in humans.…”

Physiological bases of the K+ and the glutamate/GABA hypotheses of epilepsy

“…In the pilocarpine rat model of epilepsy, NKA activity has been shown to be reduced in the acute period but substantially increased in the chronic period (Fernandes et al, 1996; Reime Kinjo et al, 2007). In the same model, it has been recently reported that glucose metabolism and the expression of some enzymes involved in energy metabolism are both decreased in the long-term (Araujo et al, 2014; Hadera et al, 2013). No clear-cut relation has been observed between ATP levels and K + -induced epileptiform activity in epileptogenic rat hippocampus (Marichich and Nasello, 1973).…”

How does the ketogenic diet induce anti-seizure effects?

“…These actions may contribute to anti-seizure effects. In this regard, the anaplerotic substrate triheptanoin has been shown to raise seizure thresholds in mouse seizure models, and to help restore levels of TCA intermediates [58,59]. Further, replenishment of the TCA cycle may counter seizure-induced energy failure and augment inhibitory neurotransmission [60].…”