Ketogenic Diet And Amino Acid Transport

The foregoing discussion involved changes in the metabolism of glutamate and related compounds that appear to occur consequent to ketosis. It also appears that significant alterations of amino acid transport occur in the ketotic brain and that these adaptations may contribute to the anticonvulsant effect. We have found, for example, that the entry of leucine into brain is greatly increased in ketotic mice (8). The uptake from blood to brain of leucine and other large neutral amino acids is mediated via the l-transporter system, which functions primarily as an amino acid exchanger (81,82). Although the affinity of the transporter for glutamine is not especially high (83), the abundance of glutamine in brain favors the utilization of glutamine for facilitating neutral amino acid uptake (84). Glutamine would be formed in astrocytes from glutamate that had been transported from the synaptic cleft (see Fig. 7).

In ketosis the brain/blood ratio for leucine is increased and that for glutamine is unchanged relative to control (Yudkoff et al., unpublished data), a factor that would favor leucine entry into brain via exchange for glutamine. An important consequence of

Fig. 7. Putative effects of ketosis on brain amino acid transport. The uptake of leucine into brain, which is increased in the ketotic mouse, may occur via exchange for internal glutamine. Glutamine, in turn, is formed from intrasynaptic glutamate that is taken up by astrocytes, the major site in brain of the glutamine synthetase pathway. Release of glutamate by epileptic brain is probably increased, and the development of more rapid large neutral amino acid-glutamine exchange affords the system with a more efficient capacity for the removal of glutamate from the extracellular fluid (ECF).

Fig. 7. Putative effects of ketosis on brain amino acid transport. The uptake of leucine into brain, which is increased in the ketotic mouse, may occur via exchange for internal glutamine. Glutamine, in turn, is formed from intrasynaptic glutamate that is taken up by astrocytes, the major site in brain of the glutamine synthetase pathway. Release of glutamate by epileptic brain is probably increased, and the development of more rapid large neutral amino acid-glutamine exchange affords the system with a more efficient capacity for the removal of glutamate from the extracellular fluid (ECF).

this adaptation might be an enhanced capacity to dispose of glutamate that had been released into the synaptic cleft. In effect, the brain would "detoxify" extracellular glutamate not simply by swiftly removing it from the synapse into astrocytes and then converting it to glutamine, but by exporting the latter into the blood rather than exporting it back to neurons (Fig. 2). This "loss" of glutamine would quickly be compensated by the transamination of the newly imported leucine (Fig. 7). However, during periods of enhanced glutamate release from neurons, a phenomenon that characterizes seizure activity, the system would have at its disposal a new mechanism for the removal of external glutamate.

A highly ordered array of amino acid transporters mediate the exchange of glutamate, glutamine, and related compounds between neurons, astrocytes, and capillaries (82). It is likely that the ketogenic diet, which, as we have seen, induces fundamental alterations in the metabolism of brain amino acids, and also changes the function of these tissue-specific amino acid transport systems. We cannot know a priori that these presumed adaptations will give rise to an anticonvulsant effect, although the accepted clinical efficacy of the ketogenic diet affords a rationale for future experimentation to test the hypothesis that ketosis-induced changes in the function of amino acid transporters enable the ability of the brain to contain seizures by favoring novel mechanisms for the removal of glutamic acid.

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