Ketone Bodies and Brain Glutamate and GABA Metabolism

Abstract

The effects of ketone bodies on brain metabolism of glutamate and GABA were studied in three different systems: synaptosomes, cultured astrocytes and the whole animal. In synaptosomes the addition of either acetoacetate or 3-OH-butyrate was associated with diminished consumption of glutamate via transamination to aspartate and increased formation of labelled GABA from either L-[²H₅-2,3,3,4,4]glutamine or L-[¹⁵N]glutamine. There was no effect of ketone bodies on synaptosomal GABA transamination. An increase of total forebrain GABA and a diminution of aspartate was noted when mice were injected intraperitoneally with 3-OH-butyrate. In cultured astrocytes the addition of acetoacetate to the medium was associated with a significantly enhanced rate of citrate production and with a diminution in the rate of conversion of [¹⁵N]glutamate to [¹⁵N]aspartate. These data are consistent with the hypothesis that the metabolism of ketone bodies to acetyl-CoA results in a diminution of the pool of brain oxaloacetate, which is consumed in the citrate synthetase reaction (oxaloacetate + acetyl-CoA → citrate). As less oxaloacetate is available to the aspartate aminotransferase reaction, thereby lowering the rate of glutamate transamination, more glutamate becomes accessible to the glutamate decarboxylase pathway, thereby favoring the synthesis of GABA.

A preliminary metabolomic analysis of older adults with and without depression

“…However, the production of the ketone beta-hydroxybutyrate could also be from increased lipolysis. Ketone production has also been shown to positively influence the production of GABA (Daikhin and Yudkoff, 1998). We also found changes in concentrations of metabolites such as citrate, glycerol and glycerate and in medium-chain fatty acids, including myristate (C14:0), palmitate (C-16:0), stearate (C-18:0) oleate (C-18:1).…”

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

“…This interaction between metabolism of glucose and that of amino acids suggested to us (23,31,75,(138)(139)(140)(141)(142)) that administration of a ketogenic diet might alter brain handling of neuroactive compounds such as glutamate and GABA. Our rationale was that a dietary regimen that sharply limits carbohydrate intake and obliges a shift in cerebral respiration to fuels other than glucose would have far-reaching implications for the handling of amino acids.…”

“…In addition to these effects, a ketogenic diet alters brain energy metabolism (23,26,31,59,86,99,(138)(139)(140)(141)(142). Ketone bodies may be a more efficient fuel than glucose in terms of energy produced per mole of oxygen consumed (99).…”

The Ketogenic Diet Inhibits Epileptogenesis in EL Mice: A Genetic Model for Idiopathic Epilepsy

“…In KD-fed mice, the glucose consumption may not change, but the glucose oxidative metabolism may be decreased and compensated with ketone body oxidation. On the other hand, recent studies have shown that ketone bodies increased y-aminobutyric acid (GABA) synthesis and decreased aspartate synthesis in purified synaptosomes, cultured astrocytes, and in the whole brain of rats (47). DeVivo et al (36) also reported a decrease in aspartate concentration in the brains of KD-fed rats.…”