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.

1. The anticonvulsant effects of docosahexaenoic acid in rodents

“…"Ketosis" is an elevation of the ketone breakdown products of fat metabolism -acetoacetate, beta-hydroxybutyrate and acetone (Hartman et al, 2007). In 1921, Wilder, the originator of the ketogenic diet, hypothesized that a high fat diet -which also creates ketosis -could produce the same effects as fasting (Stafstrom et al, 2008).…”

“…One of these is the "ketone hypothesis" -the hypothesis that the ketone bodies have direct anticonvulsant properties (Hartman et al, 2007). There is some support for this hypothesis.…”

“…The mechanism of action of this diet has yet to be solved, although many possible mechanisms of action have been suggested Hartman et al, 2007).…”

The Ketogenic Diet: Proposed Mechanisms of Action

“…Finally, it must be noted that brain levels of GABA have been measured in animals on a ketogenic diet, and widespread elevations have not been found, although studies are continuing and there is a possibility that there may be regional changes occurring in discrete areas. 4,11 …”

“…A more complete discussion of these and the other hypotheses can be found in a useful book, entitled Epilepsy and the Ketogenic Diet, 3 and in a useful review article, entitled The Neuropharmacology of the Ketogenic Diet. 4 …”