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.

Figure 1

The glutamate-glutamine cycle. Glutamate is released (1 ) from presynaptic terminals into the ECF/synapse, where it stimulates postsynaptic glutamatergic receptors. High-affinity astrocytic transport systems (2 ) quickly remove glutamate from the synapse and convert it to glutamine in the astrocytic glutamine synthetase pathway (3 ). Ammonia diffuses from blood and neurons (4 ) to provide a coreactant for glutamine synthetase. Astrocytes release glutamine (5 ) via specific transport systems. Neurons subsequently take up the glutamine (6 ) via neutral amino acid transporters. Neuronal mitochondria then hydrolyze glutamine to glutamate (7 ), in the process completing the cycle. ECF, extracellular fluid; GABA, gamma-aminobutyric acid; Gln, glutamine; Glu, glutamate; NH₃, ammonia.

Figure 2

The impact of ketone body metabolism on brain handling of glutamate. Under basal conditions, glucose is the sole fuel of brain metabolism (upper half of figure). Glucose is converted to pyruvate via glycolysis, and pyruvate is converted to acetyl-CoA, which enters the tricarboxylic acid cycle. Glutamic acid is formed via transamination of α-ketoglutarate with aspartate. When an individual consumes a ketogenic diet and blood levels of 3-OH-butyrate and acetoacetate increase, the brain will consume these compounds as well as glucose (lower half of figure). Unlike glucose, the metabolism of which yields energy during conversion to pyruvate and lactate via glycolysis, the ketone bodies must be converted to acetyl-CoA, which is metabolized via citrate synthetase (acetyl-CoA + oxaloacetate → citrate + CoA), thereby diminishing the availability of oxaloacetate for transamination of glutamate to aspartate. More glutamate is then available to the glutamate decarboxylase pathway for the synthesis of GABA in GABA-ergic neurons. In addition, in ketosis there is increased blood acetate (or acetylcarnitine). Astrocytes, the major site of acetate consumption, convert this substrate to glutamine, which can be exported to GABA-ergic neurons, which convert this precursor to GABA, the major inhibitory neurotransmitter. The red lettering indicates pathways that are relatively more intense in ketosis, and the blue lettering indicates pathways that become relatively more attenuated.