The ketogenic diet is often used to control seizures in children who are resistant to antiepileptic drugs. The mode of action is totally unknown. The PI hypothesizes, based on their preliminary data, that one reason the ketone bodies (3-OH-butyrate and acetoacetate) are so effective in controlling seizures is that they increase the brain concentration of GABA (gamma amino butyric acid), a major inhibitory neurotransmitter, and lower the concentration of aspartate, an excitatory compound. Ketone bodies bring about these changes because they sharply reduce the rate of transamination of glutamate to aspartate. As a result, more glutamate becomes available for the synthesis of GABA. In astrocytes, more glutamate becomes available to the glutamine synthetase pathway. This results in increased synthesis of glutamine, a highly effective precursor to GABA. They propose to test this hypothesis by developing a rat model of the ketogenic diet. The model involves the prolonged (from weeks to months) feeding of rat pups with either an artificial rat milk or an isocaloric amount of a high fat (ketogenic diet). They will use stable isotopes, e.g., 15N and 13C to measure rates of glutamate metabolism to GABA, aspartate and glutamine. Mass spectrometry is used as an analytical tool with which to measure stable isotopic abundance in amino acids and tricarboxylic acid cycle intermediates. The three specific aims are: (1) To test the above hypothesis; (2) To characterize the ketogenic diet: Is high fat feeding necessary, or could ketone bodies alone be fed? How rapidly do amino acid changes develop? How sustained are they? Are changes more pronounced in less mature animals?; and (3) To determine whether the ketogenic diet can ameliorate seizures in a standard rat model of epilepsy, and whether this therapeutic effect is associated with changes of amino acid levels that mimic those noted in control animals.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurological Sciences Subcommittee 1 (NLS)
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Fureman, Brandy E
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Children's Hospital of Philadelphia
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