Ketogenic diet, amino acid metabolism, and seizure control

The ketogenic diet has been utilized for many years as an adjunctive therap y in the management of epilepsy, especially in those children for whom anti epileptic drugs have not permitted complete relief. The biochemical basis o f the dietary effect is unclear. One possibility is that the diet leads to alterations in the metabolism of brain amino acids, most importantly glutam ic acid, the major excitatory neurotransmitter. In this review, we explore the theme. We present evidence that ketosis can lead to the following: 1) a diminution in the rate of glutamate transamination to aspartate that occur s because of reduced availability of oxaloacetate, the ketoacid precursor t o aspartate; 2) enhanced conversion of glutamate to GABA; and 3) increased uptake of neutral amino acids into the brain. Transport of these compounds involves an uptake system that exchanges the neutral amino acid for glutami ne. The result is increased release from the brain of glutamate, particular ly glutamate that had been resident in the synaptic space, in the form of g lutamine. These putative adaptations of amino acid metabolism occur as the system evolves from a glucose-based fuel economy to one that utilizes keton e bodies as metabolic substrates. We consider mechanisms by which such chan ges might lead to the antiepileptic effect. (C) 2001 Wiley-Liss, Inc.