The Ketogenic Diet and Brain Metabolism of Amino Acids: Relationship to the Anticonvulsant Effect

Abstract

In many epileptic patients, anticonvulsant drugs either fail adequately to control seizures or they cause serious side effects. An important adjunct to pharmacologic therapy is the ketogenic diet, which often improves seizure control, even in patients who respond poorly to medications. The mechanisms that explain the therapeutic effect are incompletely understood. Evidence points to an effect on brain handling of amino acids, especially glutamic acid, the major excitatory neurotransmitter of the central nervous system. The diet may limit the availability of oxaloacetate to the aspartate aminotransferase reaction, an important route of brain glutamate handling. As a result, more glutamate becomes accessible to the glutamate decarboxylase reaction to yield gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter and an important antiseizure agent. In addition, the ketogenic diet appears to favor the synthesis of glutamine, an essential precursor to GABA. This occurs both because ketone body carbon is metabolized to glutamine and because in ketosis there is increased consumption of acetate, which astrocytes in the brain quickly convert to glutamine. The ketogenic diet also may facilitate mechanisms by which the brain exports to blood compounds such as glutamine and alanine, in the process favoring the removal of glutamate carbon and nitrogen.

Heptanoate as a Neural Fuel: Energetic and Neurotransmitter Precursors in Normal and Glucose Transporter I-Deficient (G1D) Brain

“…29 Particularly, GABA C3 and C4 contained a doublet (D3,4) that derives from glutamate labeled in carbons 2,3 and in carbons 1,2 and 3. Although this labeling pattern is consistent with metabolism of [5,6,[7][8][9][10][11][12][13] C 3 ]heptanoate to [1,2,3-13 C 3 ]propionyl-CoA followed by entry into the TCA cycle, the identical pattern could occur as a consequence of carboxylation of [1,2,3-13 C 3 ]pyruvate derived from glucose.…”

“…However, the spectra of glutamate (specifically, the doublet due to J 45 ) demonstrates that pyruvate in the brain was multiply labeled. Therefore, an alternative interpretation of both the 13 C-NMR spectra in Figure 3 and the mass spectrometry observations is simply that 13 The measured 13 C enrichment in plasma glucose shown in Figure 2 fixes the upper limit on the amount of either [2,[3][4][5][6][7][8][9][10][11][12][13] C]pyruvate or [1,2,3-13 C]pyruvate that can be present in the brain (as these are the two labeling patterns that can be metabolized to [1,2-13 C 2 ]acetyl-CoA).…”

“…Mass isotopomers of 13 C-glucose in plasma. Plasma 13 Cglucose was enriched from [5,6,[7][8][9][10][11][12][13] C 3 ]heptanoate in both normal and mutant (glucose transporter type I deficiency, G1D) animal groups. Data were corrected for the natural abundance of 13 C. Glucose was mostly enriched in M þ 2 (Control: 4.63%±1.5%; G1D: 5.28%±1.22%) and M þ 3 (Control: 3.65%±0.86%; G1D: 3.45%±0.69%).…”

“…In this work, we sought to characterize the metabolism of [5,6,7-13 C 3 ]heptanoate in the brain of normal conscious mice and of a transgenic antisense mouse model of G1D that exhibits the common epileptic phenotype typical of the human glucose transporter defect. 14 Administration of heptanoate labeled in this fashion is followed by oxidation of [5,6,7-13 C 3 ]heptanoate or [3,4,[5][6][7][8][9][10][11][12][13] C 3 ]C5-ketone derivatives in the brain without generation of [1,2-13 C 2 ]acetyl-CoA, and, consequently, without enrichment of carbons 4 or 5 of glutamine or glutamate. Using this approach, we demonstrate that plasma glucose becomes enriched with 13 C in the presence of intravenously infused [5,6,7-13 C 3 ]heptanoate as expected, indicating that the understanding of any effects of heptanoate therapy must consider its effects on glucose production.…”

“…In patients with glucose transporter type I deficiency (G1D), ketogenic diet fat (a source only of acetyl-CoA) reduces seizures, but other symptoms persist, providing the motivation for studying heptanoate metabolism. In this work, metabolism of infused [5,6,[7][8][9][10][11][12][13] C 3 ]heptanoate was examined in the normal mouse brain and in G1D by 13 C-nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS). In both groups, plasma glucose was enriched in 13 C, confirming gluconeogenesis from heptanoate.…”