Epilepsy and the Ketogenic Diet pp 185-199

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The Ketogenic Diet

Interactions With Brain Amino Acid Handling
  • Marc Yudkoff
  • Yevgeny Daikhin
  • Ilana Nissim
  • Itzhak Nissim


The energy requirements of the human brain are enormous. Cerebral oxygen consumption is 35 mL/min/kg or approx 50 mL/min in the adult brain. The rate of wholebody O2 consumption is 250 mL/min, indicating that approx 20% of oxygen utilization is directed toward the needs of the brain, which occupies only 2% of body weight. Virtually no oxygen is stored in the brain, implying that to maintain the integrity of this vital organ, cerebral blood flow (approx 800 mL/min), which constitutes about 15% of cardiac output, must proceed in an uninterrupted manner. If flow is completely shut down, a state of unconsciousness would ensue within 10s.


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  1. 1.
    Siesjo BK. Brain Energy Metabolism. Wiley, New York, 1997.Google Scholar
  2. 2.
    Clarke DD, Sokoloff L. Circulation and energy metabolism of the brain. In: Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD (eds.). Basic Neurochemistry: Molecular, Cellular and Medical Aspects, 6th ed. Lippincott-Raven, Philadelphia, 1999, pp. 637–669.Google Scholar
  3. 3.
    Magistretti PJ, Pellerin L, Rothman DL, Shulman RG. Energy on demand. Science 1999;283:496–497.PubMedCrossRefGoogle Scholar
  4. 4.
    McKenna MC, Tildon JT, Stevenson JH, Boatright R, Huang S. Regulation of energy metabolism in synaptic terminals and cultured rat brain astrocytes: differences revealed using aminooxyacetate. Dev Neurosci 1994;15:320–322.CrossRefGoogle Scholar
  5. 5.
    Yudkoff M, Nelson D, Daikhin Y, Erecinska M. Tricarboxylic acid cycle in rat brain synaptosomes. Fluxes and interactions with aspartate aminotransferase and malate/aspartate shuttle. J Biol Chem 1994;269:27414–27420.PubMedGoogle Scholar
  6. 6.
    Fitzpatrick SM, Cooper AJL, Duffy TE. Use of β-methylene-DL-aspartate to assess the role of aspartate aminotransferase in cerebral oxidative metabolism. J Neurochem 1983;41:1370–1383.PubMedCrossRefGoogle Scholar
  7. 7.
    Yudkoff M, Daikhin Y, Nissim I, Grunstein R, Nissim I. Effect of ketone bodies on astrocyte amino acid metabolism. J Neurochem 1997;69:682–692.PubMedCrossRefGoogle Scholar
  8. 8.
    Yudkoff M, Daikhin M, Nissim I, Lazarow A, Nissim I. Brain amino acid metabolism and ketosis. J Neurosci Res 2001;66:272–281.PubMedCrossRefGoogle Scholar
  9. 9.
    Yudkoff M, Daikhin Y, Nissim I, Lazarow A, Nissim I. Ketogenic diet, amino acid metabolism and seizure control. J Neurosci Res 2001;66:931–940.PubMedCrossRefGoogle Scholar
  10. 10.
    Hertz L, Peng L, Westergaard N, Yudkoff M, Schousboe A. Neuronal-astrocytic interactions in metabolism of transmitter amino acids of the glutamate family. In: Schousboe A, Diemer NH, Kofod H (eds.). Drug Research Related to Neuroactive Amino Acids, Alfred Benzon Symposium 32. Munksgaard, Copenhagen, 1992, pp. 30–48.Google Scholar
  11. 11.
    Gegelashvili G, Schousboe A. Cellular distribution and kinetic properties of high-affinity glutamate transporters. Brain Res Bull 1998;45:233–238.PubMedCrossRefGoogle Scholar
  12. 12.
    Takahashi M, Billups B, Rossi D, Sarantis M, Hamann M, Attwell D. The role of glutamate transporters in glutamate homeostasis in the brain. J Exp Biol 1997;200:401–409.PubMedGoogle Scholar
  13. 13.
    Erecinska M, Silver IA. Metabolism and role of glutamate in mammalian brain. Prog Neurobiol 1990;35:245–296.PubMedCrossRefGoogle Scholar
  14. 14.
    Martinez-Hernandez A, Bell KP, Norenberg MD. Glutamine synthetase: glial localization in brain. Science 1997;195:1356–1358.CrossRefGoogle Scholar
  15. 15.
    Norenberg MD, Martinez-Hernandez A. Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 1979;161:303–310.PubMedCrossRefGoogle Scholar
  16. 16.
    Cooper AJL, McDonald JM, Gelbard AS, Gledhill RF, Duffy TE. The metabolic fate of 13N-labelled ammonia in rat brain. J Biol Chem 1979;254:4982–4992.PubMedGoogle Scholar
  17. 17.
    Erecinska M, Zaleska MM, Nelson D, Nissim I, Yudkoff M. Neuronal glutamine utilization: glutamine/glutamate homeostasis in synaptosomes. J Neurochem 1990;54:2057–2069.PubMedCrossRefGoogle Scholar
  18. 18.
    Shank RP and Aprison MH. Present status and significance of the glutamine cycle in neural tissues. Life Sci 1977;28:837–842.CrossRefGoogle Scholar
  19. 19.
    Grill V, Björkhem M, Gutniak M, Lindqvist M. Brain uptake and release of amino acids in nondiabetic and insulin-dependent diabetic subjects: important role of glutamine release for nitrogen balance. Metabolism 1992;41:28–32.PubMedCrossRefGoogle Scholar
  20. 20.
    Smith QR, Momma S, Aoyagi M, Rapoport SI. Kinetics of neutral amino acid transport across the blood-brain barrier. J Neurochem 1987;49:1651–1658.PubMedCrossRefGoogle Scholar
  21. 21.
    Bixel MG, Hutson SM, Hamprecht B. Cellular distribution of branched-chain amino acid aminotransferase isoenzymes among rat brain glial cells in culture. J Histochem Cytochem 1997;45:685–694.PubMedCrossRefGoogle Scholar
  22. 22.
    Hutson SM, Wallin R, Hall TR. Identification of mitochondrial branched chain aminotransferase and its isoforms in rat tissues. J Biol Chem 1992;267:15681–15686.PubMedGoogle Scholar
  23. 23.
    Yudkoff M, Daikhin Y, Lin Z-P, Nissim I, Stern J, Pleasure D, Nissim I. Interrelationships of leucine and glutamate in cultured astrocytes. J Neurochem 1994;62:1192–1202.PubMedCrossRefGoogle Scholar
  24. 24.
    Yudkoff M, Daikhin Y. Nelson D, Nissim I, Erecinska M. Neuronal metabolism of branched-chain amino acids: flux through the aminotransferase pathway in synaptosomes. J Neurochem 1996;66:2136–2145.PubMedCrossRefGoogle Scholar
  25. 25.
    Kanamori K. Ross BD. Kondrat RW. Rate of glutamate synthesis from leucine in rat brain measured in vivo by 15N NMR. J Neurochem 1998;70:1304–1315.PubMedCrossRefGoogle Scholar
  26. 26.
    Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GF. Brain metabolism during fasting. J Clin Invest 1967;46:1589–1595.PubMedCrossRefGoogle Scholar
  27. 27.
    Gjedde A, Crone C. Induction processes in blood-brain transfer of ketone bodies during starvation. Am J Physiol 1975;229:1165–1169.PubMedGoogle Scholar
  28. 28.
    Tildon JT, Roeder LM. Transport of 3-hydroxy[3-14C]butyrate by dissociated cells from rat brain. Am J Physiol 1998;255:C133–C139.Google Scholar
  29. 29.
    Leino RL, Gerhart DZ, Duelli R, Enerson BE, Drewes LR. Diet-induced ketosis increases monocarboxylate transporter (MCT1) levels in rat brain. Neurochem Int 2001;38:519–527.PubMedCrossRefGoogle Scholar
  30. 30.
    Pierre K, Magistretti PJ, Pellerin L. MCT2 is a major neuronal monocarboxylate transporter in the adult mouse brain. J Cereb Blood Flow Metab 2002;22:586–595.PubMedCrossRefGoogle Scholar
  31. 31.
    Koper JW, Lopes-Cardozo M, Van Golde LM. Preferential utilizationof ketone bodies for the synthesis of myelin cholesterol in vivo. Biochim Biophys Acta 1981;666:411–417.PubMedCrossRefGoogle Scholar
  32. 32.
    Lopes-Cardozo M, Koper JW, Klein W, Van Golde LM. Acetoacetate is a cholesterogenic precursor for myelinating rat brain and spinal cord. Incorporation of label from [3-14C]acetoacetate, [14C]glucose and 3H2O. Biochim Biophys Acta 1984;794:350–352.PubMedCrossRefGoogle Scholar
  33. 33.
    Gerhart DZ, Enerson BE, Zhdankina OY, Leino RL, Drewes LR. Expression of monocarboxylate transporter MCT1 by brain endothelium and glia in adult and suckling rats. Am J Physiol 1997;273:E207–E213.PubMedGoogle Scholar
  34. 34.
    Dombrowski GJ Jr, Swiatek KR, Chao K-L. Lactate, 3-hydroxybutyrate and glucose as substrates for early postnatal rat brain. Neurochem Res 1989;14:667–675.PubMedCrossRefGoogle Scholar
  35. 35.
    Nehlig A, Pereira de Vasconcelos A. Glucose and ketone body utilization by the brain of neonatal rats. Prog Neurobiol 1993;40:163–221.PubMedCrossRefGoogle Scholar
  36. 36.
    Fukao T, Song XQ, Mitchell GA, Yamaguchi S, Sukegawa K, Orii T, Kondo N. Enzymes of ketone body utilization in human tissues: protein and messenger RNA levels of succinyl-coenzyme A (CoA):3-ketoacid CoA transferase and mitochondrial and cytosolic acetoacetyl-CoA thiolases. Pediatr Res 1997;42:498–502.PubMedCrossRefGoogle Scholar
  37. 37.
    Berl S, Takagaki G, Clarke DD, Waelsch H. Metabolic compartments in vivo. Ammonia and glutamic acid metabolism in brain and liver. J Biol Chem 1962;237:2562–2569.PubMedGoogle Scholar
  38. 38.
    Cerdan S, Kunnecke B, Seelig J. Cerebral metabolism of [1,2-13C2]acetate as detected by in vivo and in vitro 13C NMR. J Biol Chem 1990;265:12916–12926.PubMedGoogle Scholar
  39. 39.
    Waniewski RA, Martin DL. Preferential utilization of acetate by astrocytes is attributable to transport. J Neurosci 1998;18:5225–5233.PubMedGoogle Scholar
  40. 40.
    Booth RFG, Clark JB. A rapid method for the preparation of relatively pure, metabolically competent synaptosomes from rat brain. Biochem J 1978;176:365–370.PubMedGoogle Scholar
  41. 41.
    Ratnakumari L, Murthy CRK. Activities of pyruvate dehydrogenase, enzymes of citric acid cycle, and aminotransferases in the subcellular fractions of cerebral cortex in normal and hyperammonemic rats. Neurochem Res 1989;14:221–228.PubMedCrossRefGoogle Scholar
  42. 42.
    Erecinska M, Dagani E Relationships between the neuronal sodium/potassium pump and energy metabolism. Effects of K+, Na+ and adenosine triphosphate in isolated brain synaptosomes. J Gen Physiol 1990;95:591–616.PubMedCrossRefGoogle Scholar
  43. 43.
    Erecinska M, Nelson D, Daikhin Y, Yudkoff M. Regulation of GABA level in rat brain synaptosomes: fluxes through enzymes of the GABA shunt and effects of glutamate, calcium, and ketone bodies. J Neurochem 1996;67:2325–2334.PubMedCrossRefGoogle Scholar
  44. 44.
    Mason GF, Gruetter R, Rothman DL, Bchar KL, Shulman RG, Novotny EJ. Simultaneous determination of the rates of the TCA cycle, glucose utilization, alpha-ketoglutarate/glutamate exchange, and glutamine synthesis in human brain by NMR. J Cereb Blood Flow Metab 1995;15:12–25.PubMedCrossRefGoogle Scholar
  45. 45.
    DeVivo DC, Leckie MP, Ferrendelli JS, McDougal DB Jr. Chronic ketosis and cerebral metabolism. Ann Neurol 1978;3:331–337.CrossRefGoogle Scholar
  46. 46.
    Thurston JH, Hauhart RE, Schiro JA. Beta-hydroxybutyrate reverses insulin-induced hypoglycemic coma in suckling-weanling mice despite low blood and brain glucose levels. Metab Brain Dis 1986;1:63–82.PubMedCrossRefGoogle Scholar
  47. 47.
    DeDeyn PP, Marescau B, MacDonald RL. Epilepsy and the GABA-hypothesis: a brief review and some samples. Acta Neurol Belg 1990;90:65–81.Google Scholar
  48. 48.
    Olsen RW, Avoli M. GABA andepileptogenesis. Epilepsia 1997;38:399–407.PubMedCrossRefGoogle Scholar
  49. 49.
    Loscher W, Swark WS. Evidence for impaired GABAergic activity in the substantia nigra of amygdaloid kindled rats. Brain Res 1985;339:146–150.PubMedCrossRefGoogle Scholar
  50. 50.
    Lasley SM, Yan QS. Diminished potassium-stimulated GABA release in vivo in genetically epilepsyprone rats. Neurosci Lett 1994;175:145–148.PubMedCrossRefGoogle Scholar
  51. 51.
    Gould EM, Curto KA, Craig CR, Fleming WW, Taylor DA. The role of GABA-A receptors in the subsensitivity of Purkinje neurons to GABA in genetic epilepsy prone rats. Brain Res 1995:698:62–68.PubMedCrossRefGoogle Scholar
  52. 52.
    Hovanics GE, DeLorey TM, Firestone LL, Quinlan JJ, Handforth A, Harrison NL, Krasowski MD, Rick CE, Korpi ER, Makela R, Brilliant MH, Hagiwara N, Ferguson C, Snyder K, Olsen RW. Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc Natl Acad Sci U S A 1997;94:4143–4148.CrossRefGoogle Scholar
  53. 53.
    White HS. Clinical significance of animal seizure models and mechanism of action studies of potential antiepileptic drugs. Epilepsia 1997;38 (Suppl 1):S9–S17.PubMedCrossRefGoogle Scholar
  54. 54.
    Meldrum BS. Update on the mechanism of action of antiepileptic drugs. Epilepsia 1996;37 (Suppl 6):S4–S11.PubMedCrossRefGoogle Scholar
  55. 55.
    Petroff OA, Rothman D, Behar KL, Mattson RH. Low brain GABA level is associated with poor seizure control. Ann Neurol 1996;40:908–911.PubMedCrossRefGoogle Scholar
  56. 56.
    Storm-Mathisen J, Leknes AK, Bore AT, Vaaland JL, Edminson P, Haug FM, Ottersen OP. First visualization of glutamate and GABA in neurones by immunocytochemistry. Nature 1983;301:517–520.PubMedCrossRefGoogle Scholar
  57. 57.
    Storm-Mathisen J, Ottersen OP. Antibodies against amino acid neurotrnasmitters. In: Paunula P, Paivarinta H, Soinila S (eds.). Neurohistochemistry: Modem Methods and Applications. Liss, New York, 1986, pp. 107–136.Google Scholar
  58. 58.
    Patel AJ. Balazs R, Richter D. Contribution of the GABA bypath to glucose oxidation, and the development of compartmentation in the brain. Nature 1970;226:1160–1161.PubMedCrossRefGoogle Scholar
  59. 59.
    Patel AJ, Johnson AL, Balazs R. Metabolic compartmentation of glutamate associated with the formation of y-aminobutyrate. J Neurochem 1974;23:1271–1279.PubMedCrossRefGoogle Scholar
  60. 60.
    Battaglioli G, Martin DL. Stimulation of synaptosomal γ -aminobutyric acid synthesis by glutamate and glutamine. J Neurochem 1990;54:1179–1187.PubMedCrossRefGoogle Scholar
  61. 61.
    Paulsen RE, Fonnum F. Role of glial cells for the basal and Ca2+-dependent K+-evoked release of transmitter amino acids investigated by microdialysis. J Neurochem 1989;52:1823–1829.PubMedCrossRefGoogle Scholar
  62. 62.
    Wu J-Y. Purification, characterization and kinetic studies of GAD and GABA-T from mouse brain. In: Roberts E, Chase TN, Tower DB (eds.). GABA in Nervous System Function. Raven, New York, 1976, pp. 7–55.Google Scholar
  63. 63.
    Porter TG, Martin DL. Stability and activation of glutamate apodecarboxylase from pig brain. J Neurochem 1988;51:1886–1891.PubMedCrossRefGoogle Scholar
  64. 64.
    Sonnewald U, Westergaard N, Schousboe A, Svendsen JS, Unsgard G, Petersen SB. Direct demonstration by [13C]NMR spectroscopy that glutamine from astrocytes is a precursor for GABA synthesis in neurons. Neurochem Int 1993;22:19–29.PubMedCrossRefGoogle Scholar
  65. 65.
    DeVivo DC, Malas KL, Leckie MP. Starvation and seizures: observations on the electroconvulsive threshold and cerebral metabolism of the starved adult rat. Arch Neurol 1975;32:755–760.CrossRefGoogle Scholar
  66. 66.
    Pan JW, Bebin EM, Chu WJ, Hetherington HP. Ketosis and epilepsy: 31P spectroscopic imaging at 4.1T. Epilepsia 1999;40:703–707.PubMedCrossRefGoogle Scholar
  67. 67.
    Al-Mudallal AS, LaManna JC, Lust WD, Harik SI. Diet-induced ketosis does not cause cerebral acidosis. Epilepsia 1996;37:258–261.PubMedCrossRefGoogle Scholar
  68. 68.
    Novotny EJ Jr, Chen J, Rothman DL. Alterations in cerebral metabolism with the ketogenic diet. Epilepsia 1997;38 (Suppl 8):S147.Google Scholar
  69. 69.
    Erecinska M, Zaleska MM, Nissim I, Nelson D, Dagani F, Yudkoff M. Glucose and synaptosomal glucose metabolism: studies with [15N]glutamate. J Neurochem 1988;51:892–902.PubMedCrossRefGoogle Scholar
  70. 70.
    McKenna MC, Tildon JT, Stevenson JH, Boatright R, Huang S. Regulation of energy metabolism in synaptic terminals and cultured rat brain astrocytes: differences revealed using aminooxyacetate. Dev Neurosci 1993;15:320–329.PubMedCrossRefGoogle Scholar
  71. 71.
    Peng L, Hertz L. Potassium-induced stimulation of oxidative metabolism of glucose in cultures of intact cerebellar granule cells but not in corresponding cells with dendritic degeneration. Brain Res 1993;629:331–334.PubMedCrossRefGoogle Scholar
  72. 72.
    Waagepetersen HS, Sonnewald U, Larsson OM, Schousboe A. Compartmentation of TCA cycle metabolism in cultured neocortical neurons revealed by 13C MR spectroscopy. Neurochem Int 2000;36:349–358.PubMedCrossRefGoogle Scholar
  73. 73.
    Do KQ, Klancnik J, Gahwiler BH, et al. Release of EAA: animal studies and epileptic foci studies in humans. In: Meldrum BS, Moroni F, Simon RP (eds.). Excitatory Amino Acids. Press, New York, 1991, pp. 677–685.Google Scholar
  74. 74.
    Carlson H, Ronne-Engstrum E, Ungerstedt U, Hillered L. Seizure-related elevations of extracellular amino acids in human focal epilepsy. Neurosci Lett 1992;140:30–32.PubMedCrossRefGoogle Scholar
  75. 75.
    Flavin HJ, Wieraszko A, Seyfried TN. Enhanced aspartate release from hippocampal slices of epileptic (EL) mice. J Neurochem 1991;56:1007–1001.PubMedCrossRefGoogle Scholar
  76. 76.
    Millan MH, Chapman AG, Meldrum BS. Extracellular amino acid levels in hippocampus during pilocarpine-induced seizures. Epilepsy Res 1993;14:139–148.PubMedCrossRefGoogle Scholar
  77. 77.
    Raiteri M, Marchi M, Costi A, Volpe G. Endogenous aspartate release in the rat hippocampus inhibited by M2 “cardiac” muscarinic receptors. Eur J Pharmacol 1990;177:181–187.PubMedCrossRefGoogle Scholar
  78. 78.
    Martin D, Bustos GA, Bowe MA, Bray SD, Nadler JV. Autoreceptor regulation of glutamate and aspartate release from slices of the hippocampal CA1 area. J Neurochem 1991;56:1647–1655.PubMedCrossRefGoogle Scholar
  79. 79.
    Fleck MW, Henze DA, Barrionuevo G, Palmer AM. Aspartate and glutamate mediate excitatory synaptic transmission in area CA1 of the hippocampus. J Neurosci 1993;13:3944–3955.PubMedGoogle Scholar
  80. 80.
    Meldrum BS. The role of glutamate in epilepsy and other CNS disorders. Neurology 1994;44:S14–S23.PubMedGoogle Scholar
  81. 81.
    Boado RJ, Li JY, Nagaya M, Zhang C, Pardridge WM. Selective expression of the large neutral amino acid transporter at the blood-brain barrier. Proc Natl Acad Sci U S A 1999;96:12079–12084.PubMedCrossRefGoogle Scholar
  82. 82.
    Broer S, Brookes N. Transfer of glutamine between astrocytes and neurons. J Neurochem 2001;77:705–719.PubMedCrossRefGoogle Scholar
  83. 83.
    Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T, Cha SH, Matsuo H, Fukushima J, Fukasawa Y, Tani Y, Taketani Y, Uchino H, Kim, JY, Inatomi J, Okayasu I, Miyamoto K, Takeda E, Goya T, Endou H. Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochim Biophys Acta 2001;1514:291–302.PubMedCrossRefGoogle Scholar
  84. 84.
    Huang Y, Zielke HR, Tildon JT, Zielke CL, Baab PJ. Elevation of amino acids in the interstitial space of the rat brain following infusion of large neutral amino and keto acids by microdialysis: leucine infusion. Dev Neurosci 1996;18:415–419.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Marc Yudkoff
  • Yevgeny Daikhin
  • Ilana Nissim
  • Itzhak Nissim

There are no affiliations available

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