The ketogenic diet: Metabolic influences on brain excitability and epilepsy

Trends in Neurosciences

Volumn 36, Issue 1, 2013, Pages 32-40

  Lutas, Andrew ^a   Yellen, Gary ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

Author keywords

Epilepsy; Ketogenic diet; Metabolism; Neuronal excitability; Seizures

Indexed keywords

4 AMINOBUTYRIC ACID; ADENOSINE; ADENOSINE RECEPTOR; ADENOSINE TRIPHOSPHATE SENSITIVE POTASSIUM CHANNEL; BRAIN DERIVED NEUROTROPHIC FACTOR; BRAIN DERIVED NEUROTROPHIC FACTOR RECEPTOR; GLUTAMIC ACID; KETONE BODY; PROTEIN BAD; VESICULAR GLUTAMATE TRANSPORTER 2;

4 AMINOBUTYRIC ACID RELEASE; ANTICONVULSANT ACTIVITY; BRAIN LEVEL; BRAIN METABOLISM; DIET THERAPY; DISEASE PREDISPOSITION; EPILEPSY; GLUCOSE OXIDATION; GLUCOSE UTILIZATION; GLYCOLYSIS; KETOGENIC DIET; MITOCHONDRIAL RESPIRATION; NERVE CELL EXCITABILITY; NEUROPROTECTION; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; SYNAPTIC TRANSMISSION;

ANIMALS; BRAIN; EPILEPSY; HUMANS; KETOGENIC DIET;

EID: 84871718480     PISSN: 01662236     EISSN: 1878108X     Source Type: Journal    
DOI: 10.1016/j.tins.2012.11.005     Document Type: Review

References (98)

1. Kwan P., Brodie M. Early identification of refractory epilepsy. N. Engl. J. Med. 2000, 342:314-319.
2. Neal E., et al. A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia 2009, 50:1109-1126.
3. Peterman M. The ketogenic diet in epilepsy. J. Am. Med. Assoc. 1925, 84:1979-1983.
4. DeVivo D., et al. Chronic ketosis and cerebral metabolism. Ann. Neurol. 1978, 3:331-337.
5. Keith H. Factors influencing experimentally produced convulsions. Arch. Neurol. Psychiatry 1933, 29:148-154.
6. Rho J., et al. Acetoacetate, acetone, and dibenzylamine (a contaminant in l-(+)-beta-hydroxybutyrate) exhibit direct anticonvulsant actions in vivo. Epilepsia 2002, 43:358-361.
7. Likhodii S., et al. Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet. Ann. Neurol. 2003, 54:219-226.
8. Bough K., et al. Path analysis shows that increasing ketogenic ratio, but not beta-hydroxybutyrate, elevates seizure threshold in the rat. Dev. Neurosci. 1999, 21:400-406.
9. Bough K., et al. Higher ketogenic diet ratios confer protection from seizures without neurotoxicity. Epilepsy Res. 2000, 38:15-25.
10. Likhodii S., et al. Dietary fat, ketosis, and seizure resistance in rats on the ketogenic diet. Epilepsia 2000, 41:1400-1410.
11. Dell C., et al. Lipid and fatty acid profiles in rats consuming different high-fat ketogenic diets. Lipids 2001, 36:373-378.
12. Gilbert D., et al. The ketogenic diet: seizure control correlates better with serum beta-hydroxybutyrate than with urine ketones. J. Child Neurol. 2000, 15:787-790.
13. van Delft R., et al. Blood beta-hydroxybutyrate correlates better with seizure reduction due to ketogenic diet than do ketones in the urine. Seizure 2010, 19:36-39.
14. Juge N., et al. Metabolic control of vesicular glutamate transport and release. Neuron 2010, 68:99-211.
15. Thio L., et al. Ketone bodies do not directly alter excitatory or inhibitory hippocampal synaptic transmission. Neurology 2000, 54:325-331.
16. Samoilova M., et al. Chronic in vitro ketosis is neuroprotective but not anti-convulsant. J. Neurochem. 2010, 113:826-861.
17. Yudkoff M., et al. The ketogenic diet and brain metabolism of amino acids: relationship to the anticonvulsant effect. Annu. Rev. Nutr. 2007, 27:415-430.
18. Yudkoff M., et al. Brain amino acid metabolism and ketosis. J. Neurosci. Res. 2001, 66:272-281.
19. Haymond M., et al. Effects of ketosis on glucose flux in children and adults. Am. J. Physiol. 1983, 245:E373-E378.
20. Paul R., et al. Vascular smooth muscle: aerobic glycolysis linked to sodium and potassium transport processes. Science 1979, 206:1414-1416.
21. Mercer R., Dunham P. Membrane-bound ATP fuels the Na/K pump. Studies on membrane-bound glycolytic enzymes on inside-out vesicles from human red cell membranes. J. Gen. Physiol. 1981, 78:547-568.
22. ATP channels in basolateral membrane of Necturus enterocytes. Am. J. Physiol. 1998, 275:C1653-C1659.
23. +-ATPase: evidence for direct coupling of glycolysis to the ATP-hydrolyzing proton pump. J. Biol. Chem. 2001, 276:30407-30413.
24. ++ pumps in human red blood cell ghosts. J. Gen. Physiol. 2009, 134:351-361.
25. Proverbio F., Hoffman J. Membrane compartmentalized ATP and its preferential use by the Na,K-ATPase of human red cell ghosts. J. Gen. Physiol. 1977, 69:605-632.
26. ATP channels in rhythmically active neurons. J. Physiol. 2001, 537:69-81.
27. ATP channel opening in response to action potential firing in mouse dentate granule neurons. J. Neurosci. 2011, 31:8689-8696.
28. + channels. Trends Neurosci. 1998, 21:288-294.
29. ATP channels: hypoglycaemia and hyperglycaemia. Rev. Endocr. Metab. Disord. 2010, 11:157-163.
30. Parton L., et al. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 2007, 449:228-260.
31. ATP channels, is modulated by UCP2, and regulates peripheral glucose homeostasis. Cell Metab. 2010, 12:545-597.
32. ATP channel-forming Kir6.2 subunit and the sulfonylurea receptor SUR1 in rodent brain. FEBS Lett. 1997, 401:59-64.
33. + channel in rat brain. Brain Res. 1998, 814:41-54.
34. Zawar C., et al. Cell-type specific expression of ATP-sensitive potassium channels in the rat hippocampus. J. Physiol. 1999, 514(Pt 2):327-341.
35. ATP channels in the mechanism of the ketogenic diet. Epilepsia 2008, 49(Suppl. 8):80-82.
36. ATP channels. J. Neurosci. 2007, 27:3618-3643.
37. Depaulis A., et al. Endogenous control of epilepsy: the nigral inhibitory system. Prog. Neurobiol. 1994, 42:33-52.
38. ATP channels in inspiratory brainstem neurones and their hypoxic activation: involvement of metabotropic receptors, G-proteins and cytoskeleton. Brain Res. 2000, 853:60-67.
39. Li D-P., et al. Adenosine inhibits paraventricular pre-sympathetic neurons through ATP-dependent potassium channels. J. Neurochem. 2010, 113:530-542.
40. ATP channels. J. Neurosci. 2010, 30:3886-3981.
41. Phillis J., Wu P. The role of adenosine and its nucleotides in central synaptic transmission. Prog. Neurobiol. 1981, 16:187-239.
42. Masino S., Geiger J. Are purines mediators of the anticonvulsant/neuroprotective effects of ketogenic diets?. Trends Neurosci. 2008, 31:273-281.
43. Fedele D., et al. Astrogliosis in epilepsy leads to overexpression of adenosine kinase, resulting in seizure aggravation. Brain 2005, 128:2383-2395.
44. 1 receptors. J. Clin. Invest. 2011, 121:2679-2762.
45. Huttenlocher P. Ketonemia and seizures: metabolic and anticonvulsant effects of two ketogenic diets in childhood epilepsy. Pediatr. Res. 1976, 10:536-540.
46. Pfeifer H., Thiele E. Low-glycemic-index treatment: a liberalized ketogenic diet for treatment of intractable epilepsy. Neurology 2005, 65:1810-1812.
47. Chipuk J., et al. The BCL-2 family reunion. Mol. Cell 2010, 37:299-310.
48. Danial N.N. BAD: undertaker by night, candyman by day. Oncogene 2008, 27(Suppl. 1):S53-S70.
49. ATP channel activity confers resistance to epileptic seizures. Neuron 2012, 74:719-749.
50. Brenner R., et al. BK channel beta4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures. Nat. Neurosci. 2005, 8:1752-1759.
51. Coulter D. Chronic epileptogenic cellular alterations in the limbic system after status epilepticus. Epilepsia 1999, 40(Suppl. 1):S23-S33. discussion S40-S41.
52. Heinemann U., et al. The dentate gyrus as a regulated gate for the propagation of epileptiform activity. Epilepsy Res. Suppl. 1992, 7:273-280.
53. Hsu D. The dentate gyrus as a filter or gate: a look back and a look ahead. Prog. Brain Res. 2007, 163:601-613.
54. Nakada H., Wick A. The effect of 2-deoxyglucose on the metabolism of glucose, fructose, and galactose by rat diaphragm. J. Biol. Chem. 1956, 222:671-676.
55. Wick A., et al. Localization of the primary metabolic block produced by 2-deoxyglucose. J. Biol. Chem. 1957, 224:963-969.
56. Garriga-Canut M., et al. 2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure. Nat. Neurosci. 2006, 9:1382-1389.
57. He X-P., et al. Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model. Neuron 2004, 43:31-42.
58. McNamara J.O., Scharfman H.E. Temporal lobe epilepsy and the BDNF receptor, TrkB. Epilepsia 2010, 51:46.
59. Hu X-L., et al. Neuron-restrictive silencer factor is not required for the antiepileptic effect of the ketogenic diet. Epilepsia 2011, 52:1609-1625.
60. Kelleher J., et al. Energy metabolism in hypoxic astrocytes: protective mechanism of fructose-1,6-bisphosphate. Neurochem. Res. 1995, 20:785-792.
61. Lian X-Y., et al. Fructose-1,6-bisphosphate has anticonvulsant activity in models of acute seizures in adult rats. J. Neurosci. 2007, 27:12007-12018.
62. Stringer J., Xu K. Possible mechanisms for the anticonvulsant activity of fructose-1,6-diphosphate. Epilepsia 2008, 49(Suppl. 8):101-103.
63. Kim D.Y., et al. Ketone bodies are protective against oxidative stress in neocortical neurons. J. Neurochem. 2007, 101:1316-1326.
64. Maalouf M., et al. Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience 2007, 145:256-264.
65. Jarrett S., et al. The ketogenic diet increases mitochondrial glutathione levels. J. Neurochem. 2008, 106:1044-1051.
66. Kim D.Y., et al. Ketones prevent synaptic dysfunction induced by mitochondrial respiratory complex inhibitors. J. Neurochem. 2010, 114:130-141.
67. Sullivan P., et al. The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann. Neurol. 2004, 55:576-656.
68. Noebels J., et al. Jasper's Basic Mechanisms of the Epilepsies 2012, National Center for Biotechnology Information Bookshelf. 4th edn.
69. Bough K., et al. Calorie restriction and ketogenic diet diminish neuronal excitability in rat dentate gyrus in vivo. Epilepsia 2003, 44:752-760.
70. McDaniel S.S., et al. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia 2011, 52:e7-e11.
71. Wilder R.M. The effects of ketonemia on the course of epilepsy. Mayo Clin. Proc. 1921, 2:307-308.
72. Conklin H.W. Cause and treatment of epilepsy. J. Am. Osteopath. Assoc. 1922, 26:11-14.
73. Bailey E.E., et al. The use of diet in the treatment of epilepsy. Epilepsy Behav. 2005, 6:4-8.
74. Pong A., et al. Glucose transporter type I deficiency syndrome: epilepsy phenotypes and outcomes. Epilepsia 2012, 53:1503-1510.
75. Kossoff E., et al. Efficacy of the Atkins diet as therapy for intractable epilepsy. Neurology 2003, 61:1789-1791.
76. Kossoff E., et al. A modified Atkins diet is effective for the treatment of intractable pediatric epilepsy. Epilepsia 2006, 47:421-424.
77. Kossoff E., et al. A prospective study of the modified Atkins diet for intractable epilepsy in adults. Epilepsia 2008, 49:316-319.
78. Muzykewicz D., et al. Efficacy, safety, and tolerability of the low glycemic index treatment in pediatric epilepsy. Epilepsia 2009, 50:1118-1126.
79. Attwell D., Laughlin S. An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow Metab. 2001, 21:1133-1178.
80. Howarth C., et al. Updated energy budgets for neural computation in the neocortex and cerebellum. J. Cereb. Blood Flow Metab. 2012, 32:1222-1232.
81. Ivannikov M., et al. Calcium clearance and its energy requirements in cerebellar neurons. Cell Calcium 2010, 47:507-520.
82. 2+ uptake in smooth muscle plasma membrane vesicles by an endogenous glycolytic cascade. FASEB J. 1989, 3:2298-2301.
83. James J., et al. Linkage of aerobic glycolysis to sodium-potassium transport in rat skeletal muscle. Implications for increased muscle lactate production in sepsis. J. Clin. Invest. 1996, 98:2388-2397.
84. Pellerin L., et al. Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia 2007, 55:1251-1262.
85. Hu Y., Wilson G. A temporary local energy pool coupled to neuronal activity: fluctuations of extracellular lactate levels in rat brain monitored with rapid-response enzyme-based sensor. J. Neurochem. 1997, 69:1484-1490.
86. Schurr A. Lactate: the ultimate cerebral oxidative energy substrate?. J. Cereb. Blood Flow Metab. 2006, 26:142-152.
87. Gallagher C., et al. The human brain utilizes lactate via the tricarboxylic acid cycle: a 13C-labelled microdialysis and high-resolution nuclear magnetic resonance study. Brain 2009, 132:2839-2849.
88. van Hall G., et al. Blood lactate is an important energy source for the human brain. J. Cereb. Blood Flow Metab. 2009, 29:1121-1129.
89. Boumezbeur F., et al. The contribution of blood lactate to brain energy metabolism in humans measured by dynamic 13C nuclear magnetic resonance spectroscopy. J. Neurosci. 2010, 30:13983-13991.
90. Ivanov A., et al. Lactate effectively covers energy demands during neuronal network activity in neonatal hippocampal slices. Front. Neuroenergetics 2011, 3:2.
91. Bough K., et al. An anticonvulsant profile of the ketogenic diet in the rat. Epilepsy Res. 2002, 50:313-325.
92. Samala R., et al. Anticonvulsant profile of a balanced ketogenic diet in acute mouse seizure models. Epilepsy Res. 2008, 81:119-127.
93. Owen O., et al. Brain metabolism during fasting. J. Clin. Invest. 1967, 46:1589-1595.
94. Ruderman N., et al. Regulation of glucose and ketone-body metabolism in brain of anaesthetized rats. Biochem. J. 1974, 138:1-10.
95. Zhang Y., et al. Contribution of brain glucose and ketone bodies to oxidative metabolism. Adv. Exp. Med. Biol. 2013, 765:365-370.
96. Hájos N., et al. Maintaining network activity in submerged hippocampal slices: importance of oxygen supply. Eur. J. Neurosci. 2009, 29:319-327.
97. Tantama M., et al. Optogenetic reporters: Fluorescent protein-based genetically encoded indicators of signaling and metabolism in the brain. Prog. Brain Res. 2012, 196:235-263.
98. Guzmán M., Blázquez C. Is there an astrocyte-neuron ketone body shuttle?. Trends Endocrinol. Metab. 2001, 12:169-173.