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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037915-04
Application #
6394000
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Fureman, Brandy E
Project Start
1998-06-01
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
4
Fiscal Year
2001
Total Cost
$269,029
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Li, Changhong; Nissim, Itzhak; Chen, Pan et al. (2008) Elimination of KATP channels in mouse islets results in elevated [U-13C]glucose metabolism, glutaminolysis, and pyruvate cycling but a decreased gamma-aminobutyric acid shunt. J Biol Chem 283:17238-49
Li, Changhong; Matter, Andrea; Kelly, Andrea et al. (2006) Effects of a GTP-insensitive mutation of glutamate dehydrogenase on insulin secretion in transgenic mice. J Biol Chem 281:15064-72
Yudkoff, Marc; Daikhin, Yevgeny; Nissim, Ilana et al. (2006) Short-term fasting, seizure control and brain amino acid metabolism. Neurochem Int 48:650-6
Yudkoff, Marc; Daikhin, Yevgeny; Nissim, Ilana et al. (2005) Brain amino acid requirements and toxicity: the example of leucine. J Nutr 135:1531S-8S
Yudkoff, Marc; Daikhin, Yevgeny; Nissim, Ilana et al. (2005) Response of brain amino acid metabolism to ketosis. Neurochem Int 47:119-28
Li, Changhong; Buettger, Carol; Kwagh, Jae et al. (2004) A signaling role of glutamine in insulin secretion. J Biol Chem 279:13393-401
Yudkoff, Marc; Daikhin, Yevgeny; Nissim, Ilana et al. (2004) Ketogenic diet, brain glutamate metabolism and seizure control. Prostaglandins Leukot Essent Fatty Acids 70:277-85
Yudkoff, Marc; Daikhin, Yevgeny; Nissim, Ilana et al. (2003) Metabolism of brain amino acids following pentylenetetrazole treatment. Epilepsy Res 53:151-62
Li, Changhong; Najafi, Habiba; Daikhin, Yevgeny et al. (2003) Regulation of leucine-stimulated insulin secretion and glutamine metabolism in isolated rat islets. J Biol Chem 278:2853-8
Yudkoff, M; Daikhin, Y; Nissim, I et al. (2000) Acidosis and astrocyte amino acid metabolism. Neurochem Int 36:329-39

Showing the most recent 10 out of 13 publications