The ketogenic diet and brain metabolism of amino acids: relationship to the anticonvulsant effect.
In many epileptic patients, anticonvulsant drugs either fail adequately to control seizures or they cause serious side effects. An important adjunct to pharmacologic therapy is the ketogenic diet, which often improves seizure control, even in patients who respond poorly to medications. The mechanisms that explain the therapeutic effect are incompletely understood. Evidence points to an effect on brain handling of amino acids, especially glutamic acid, the major excitatory neurotransmitter of the central nervous system. The diet may limit the availability of oxaloacetate to the aspartate aminotransferase reaction, an important route of brain glutamate handling. As a result, more glutamate becomes accessible to the glutamate decarboxylase reaction to yield gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter and an important antiseizure agent. In addition, the ketogenic diet appears to favor the synthesis of glutamine, an essential precursor to GABA. This occurs both because ketone body carbon is metabolized to glutamine and because in ketosis there is increased consumption of acetate, which astrocytes in the brain quickly convert to glutamine. The ketogenic diet also may facilitate mechanisms by which the brain exports to blood compounds such as glutamine and alanine, in the process favoring the removal of glutamate carbon and nitrogen.
Yudkoff
Marc
M
Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. yudkoff@email.chop.edu
Daikhin
Yevgeny
Y
Melø
Torun Margareta
TM
Nissim
Ilana
I
Sonnewald
Ursula
U
Nissim
Itzhak
I
D000596:Amino Acids / Q000378:metabolism*; D000927:Anticonvulsants / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism*; D003131:Combined Modality Therapy; D004032:Diet; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007657:Ketone Bodies / Q000378:metabolism*; D007662:Ketosis / Q000378:metabolism*; D012640:Seizures / Q000178:diet therapy / Q000188:drug therapy / Q000378:metabolism*; D016896:Treatment Outcome
D000596:Amino Acids; D000927:Anticonvulsants; D007657:Ketone Bodies; D018698:Glutamic Acid