Ketogenic diet, amino acid metabolism, and seizure control

Abstract

The ketogenic diet has been utilized for many years as an adjunctive therapy in the management of epilepsy, especially in those children for whom antiepileptic drugs have not permitted complete relief. The biochemical basis of the dietary effect is unclear. One possibility is that the diet leads to alterations in the metabolism of brain amino acids, most importantly glutamic 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 occurs because of reduced availability of oxaloacetate, the ketoacid precursor to 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 glutamine. The result is increased release from the brain of glutamate, particularly glutamate that had been resident in the synaptic space, in the form of glutamine. These putative adaptations of amino acid metabolism occur as the system evolves from a glucose-based fuel economy to one that utilizes ketone bodies as metabolic substrates. We consider mechanisms by which such changes might lead to the antiepileptic effect.

Neuroprotective and disease-modifying effects of the ketogenic diet

“…Another possible way in which the ketogenic diet may confer neuroprotection is through enhancement of γ-aminobutyric acid (GABA) levels, with a consequent increase in GABAmediated inhibition (Yudkoff et al, 2001). Thus, ketone bodies have been demonstrated to increase the GABA content in rat brain synaptosomes (Erecinska et al, 1996), and, using invivo proton two-dimensional double-quantum spin-echo spectroscopy, the ketogenic diet was associated with elevated levels of GABA in some but not all human subjects studied (Wang et al, 2003).…”

Cerebral Metabolic Adaptation and Ketone Metabolism after Brain Injury

“…After exposure to a volatile convulsant, flurothyl trifluroethyl ether, PND24 mice showed longer latencies to clonic seizures and showed lower mortality rates than PND51 mice (Rho et al, 1999). Although the exact mechanisms for this anti-seizure effect remains unknown, it has been proposed by Yudkoff et al (1997Yudkoff et al ( , 2001Yudkoff et al ( , 2004 that the effects of ketosis on glutamate metabolism may underlie this neuroprotection. The authors hypothesize that the metabolism of ketone bodies pulls oxaloacetate toward citrate production and away from transamination to aspartate.…”

Rapid Adaptation of Rat Brain and Liver Metabolism to a Ketogenic Diet: An Integrated Study Using 1H- and 13C-NMR Spectroscopy

“…neurotransmitter, 33,35,36 compared with Glu, which is an excitatory neurotransmitter. A previous in vitro study showing that the addition of AcetoAc or β-HB protected neurons in culture against Glu cytotoxicity 37 supports our present results.…”