The neuropharmacology of the ketogenic diet

Abstract

The ketogenic diet is a valuable therapeutic approach for epilepsy, one in which most clinical experience has been with children. Although the mechanism by which the diet protects against seizures is unknown, there is evidence that it causes effects on intermediary metabolism that influence the dynamics of the major inhibitory and excitatory neurotransmitter systems in brain. The pattern of protection of the ketogenic diet in animal models of seizures is distinct from that of other anticonvulsants, suggesting that it has a unique mechanism of action. During consumption of the ketogenic diet, marked alterations in brain energy metabolism occur, with ketone bodies partly replacing glucose as fuel. Whether these metabolic changes contribute to acute seizure protection is unclear; however, the ketone body acetone has anticonvulsant activity and could play a role in the seizure protection afforded by the diet. In addition to acute seizure protection, the ketogenic diet provides protection against the development of spontaneous recurrent seizures in models of chronic epilepsy, and it has neuroprotective properties in diverse models of neurodegenerative disease.

Figure 1

Alterations in intermediary metabolism during the high-fat, low-carbohydrate ketogenic diet that lead to the formation of ketone bodies. The ketogenic diet provides high levels of long chain fatty acids and is deficient in carbohydrates so that glucose availability is severely limited. The demand to maintain serum glucose causes oxaloacetate to be shunted from the Krebs cycle to the pathway for gluconeogenesis, a multistep process that is the reverse of glycolysis. As a result of diminished oxaloacetate, the Krebs cycle has reduced capacity to handle the high levels of acetyl-CoA generated from fat. Instead, acetyl-CoA is converted to the ketone body acetoacetate which spontaneously degrades to acetone. Acetoacetate also is converted enzymatically to β-hydroxybutyrate in a reversible reaction catalyzed by the NADH-dependent mitochondrial enzyme β-hydroxybutyrate dehydrogenase. Ketone bodies represent alternative energy substrates for the brain. Not all Krebs cycle intermediates are shown in the schematic. Abbreviations: CAT, carnitine-acylcarnitine translocase; LCFA, long chain fatty acids; MCT, monocarboxylic acid transporter.

Figure 2

Alterations in the metabolism of excitatory amino acids and γ-aminobutyric acid (GABA) during the high-fat, low-carbohydrate ketogenic diet. Metabolism of acetyl-CoA generated from fats leads to high consumption of oxaloacetate (see Fig. 1). L-Aspartate, a nonessential amino acid, is formed by the transamination of oxaloacetate with an amino group from glutamate. Reduced availability of oxaloacetate along with robust availability of α-ketoglutarate from high activity of the first part of the Krebs cycle leads to low aspartate levels. It has been hypothesized that more glutamate is thus accessible to glutamic acid decarboxylase for production of GABA [33]. Not all Krebs cycle intermediates are shown in the schematic.