Ketone bodies in epilepsy

Journal of Neurochemistry

Volumn 121, Issue 1, 2012, Pages 28-35

  McNally, Melanie A ^a   Hartman, Adam L ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

hydroxybutyrate; acetoacetate; acetone; epilepsy; ketogenic diet; seizure

Indexed keywords

3 HYDROXYBUTYRIC ACID; 4 AMINOBUTYRIC ACID; 4 AMINOBUTYRIC ACID A RECEPTOR; ACETOACETIC ACID; ACETONE; ADENOSINE TRIPHOSPHATE SENSITIVE POTASSIUM CHANNEL; KETONE BODY; VESICULAR GLUTAMATE TRANSPORTER;

ANTICONVULSANT ACTIVITY; ANTIOXIDANT ACTIVITY; CITRIC ACID CYCLE; DRUG MECHANISM; ELECTRON TRANSPORT; EPILEPSY; FATTY ACID METABOLISM; GABAERGIC TRANSMISSION; HUMAN; KETOGENIC DIET; NERVE CELL DIFFERENTIATION; NONHUMAN; PRIORITY JOURNAL; REVIEW; SEIZURE; SIGNAL TRANSDUCTION;

ANIMALS; ANTICONVULSANTS; CITRIC ACID CYCLE; ENERGY METABOLISM; EPILEPSY; HUMANS; KETOGENIC DIET; KETONE BODIES;

EID: 84858701982     PISSN: 00223042     EISSN: 14714159     Source Type: Journal    
DOI: 10.1111/j.1471-4159.2012.07670.x     Document Type: Review

References (71)

1. Al-Mudallal A. S., LaManna J. C., Lust W. D., and, Harik S. I., (1996) Diet-induced ketosis does not cause cerebral acidosis. Epilepsia 37, 258-261. (Pubitemid 26071827)
2. Appleton D. B., and, DeVivo D. C., (1974) An animal model for the ketogenic diet. Epilepsia 15, 211-227.
3. Aronica E., Iyer A., Zurolo E., and, Gorter J. A., (2011) Ontogenetic modifications of neuronal excitability during brain maturation: developmental changes of neurotransmitter receptors. Epilepsia 52 (Suppl. 8), 3-5.
4. Bilger A., and, Nehlig A., (1992) Quantitative histochemical changes in enzymes involved in energy metabolism in the rat brain during postnatal development. II. Glucose-6-phosphate dehydrogenase and beta-hydroxybutyrate dehydrogenase. Int. J. Dev. Neurosci. 10, 143-152.
5. Blazquez C., Woods A., de Ceballos M. L., Carling D., and, Guzman M., (1999) The AMP-activated protein kinase is involved in the regulation of ketone body production by astrocytes. J. Neurochem. 73, 1674-1682. (Pubitemid 29440171)
6. Bough K. J., and, Rho J. M., (2007) Anticonvulsant mechanisms of the ketogenic diet. Epilepsia 48, 43-58. (Pubitemid 46096022)
7. Bough K. J., Yao S. G., and, Eagles D. A., (2000) Higher ketogenic diet ratios confer protection from seizures without neurotoxicity. Epilepsy Res. 38, 15-25. (Pubitemid 30055312)
8. Bough K. J., Gudi K., Han F. T., Rathod A. H., and, Eagles D. A., (2002) An anticonvulsant profile of the ketogenic diet in the rat. Epilepsy Res. 50, 313-325. (Pubitemid 35015215)
9. Bough K. J., Wetherington J., Hassel B., et al. (2006) Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann. Neurol. 60, 223-235. (Pubitemid 44182397)
10. Bough K. J., Paquet M., Pare J. F., Hassel B., Smith Y., Hall R. A., and, Dingledine R., (2007) Evidence against enhanced glutamate transport in the anticonvulsant mechanism of the ketogenic diet. Epilepsy Res. 74, 232-236. (Pubitemid 46654743)
11. Dahlin M., Elfving A., Ungerstedt U., and, Amark P., (2005) The ketogenic diet influences the levels of excitatory and inhibitory amino acids in the CSF in children with refractory epilepsy. Epilepsy Res. 64, 115-125. (Pubitemid 40853924)
12. Deransart C., Hellwig B., Heupel-Reuter M., Leger J. F., Heck D., and, Lucking C. H., (2003) Single-unit analysis of substantia nigra pars reticulata neurons in freely behaving rats with genetic absence epilepsy. Epilepsia 44, 1513-1520. (Pubitemid 38020185)
13. DeVivo D. C., Leckie M. P., Ferrendelli J. S., and, McDougal D. B. Jr, (1978) Chronic ketosis and cerebral metabolism. Ann. Neurol. 3, 331-337.
14. Erecinska M., Nelson D., Daikhin Y., and, Yudkoff M., (1996) 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. 67, 2325-2334. (Pubitemid 26392502)
15. Fraser D. D., Whiting S., Andrew R. D., Macdonald E. A., Musa-Veloso K., and, Cunnane S. C., (2003) Elevated polyunsaturated fatty acids in blood serum obtained from children on the ketogenic diet. Neurology 60, 1026-1029. (Pubitemid 36348942)
16. Gasior M., French A., Joy M. T., Tang R. S., Hartman A. L., and, Rogawski M. A., (2007) The anticonvulsant activity of acetone, the major ketone body in the ketogenic diet, is not dependent on its metabolites acetol, 1,2-propanediol, methylglyoxal, or pyruvic acid. Epilepsia 48, 793-800. (Pubitemid 46587607)
17. Gilbert D. L., Pyzik P. L., and, Freeman J. M., (2000) The ketogenic diet: seizure control correlates better with serum beta-hydroxybutyrate than with urine ketones. J. Child Neurol. 15, 787-790. (Pubitemid 32151052)
18. Hartman A. L., and, Vining E. P., (2007) Clinical aspects of the ketogenic diet. Epilepsia 48, 31-42. (Pubitemid 46096021)
19. Hauser W. A., and, Kurland L. T., (1975) The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia 16, 1-66.
20. Henderson S. T., Vogel J. L., Barr L. J., Garvin F., Jones J. J., and, Costantini L. C., (2009) Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr. Metab. (Lond) 6, 31.
21. Hirtz D., Thurman D. J., Gwinn-Hardy K., Mohamed M., Chaudhuri A. R., and, Zalutsky R., (2007) How common are the "common" neurologic disorders? Neurology 68, 326-337. (Pubitemid 46188246)
22. Holmgren C. D., Mukhtarov M., Malkov A. E., Popova I. Y., Bregestovski P., and, Zilberter Y., (2010) Energy substrate availability as a determinant of neuronal resting potential, GABA signaling and spontaneous network activity in the neonatal cortex in vitro. J. Neurochem. 112, 900-912.
23. Imamura K., Takeshima T., Kashiwaya Y., Nakaso K., and, Nakashima K., (2006) D-beta-hydroxybutyrate protects dopaminergic SH-SY5Y cells in a rotenone model of Parkinson's disease. J. Neurosci. Res. 84, 1376-1384. (Pubitemid 44654461)
24. Juge N., Gray J. A., Omote H., et al. (2010) Metabolic control of vesicular glutamate transport and release. Neuron 68, 99-112.
25. Kawamura M. Jr, Ruskin D. N., and, Masino S. A., (2010) Metabolic autocrine regulation of neurons involves cooperation among pannexin hemichannels, adenosine receptors, and KATP channels. J. Neurosci. 30, 3886-3895.
26. Keith H., (1935) Experimental convulsions induced by administration of thujone. Arch. Neurol. Psychiatry 34, 1022-1040.
27. Kim do Y., Davis L. M., Sullivan P. G., Maalouf M., Simeone T. A., van Brederode J., and, Rho J. M., (2007) Ketone bodies are protective against oxidative stress in neocortical neurons. J. Neurochem. 101, 1316-1326. (Pubitemid 46718821)
28. Kim do Y., Vallejo J., and, Rho J. M., (2010) Ketones prevent synaptic dysfunction induced by mitochondrial respiratory complex inhibitors. J. Neurochem. 114, 130-141.
29. Kirmse K., Witte O. W., and, Holthoff K., (2010) GABA depolarizes immature neocortical neurons in the presence of the ketone body ss-hydroxybutyrate. J. Neurosci. 30, 16002-16007.
30. Kobau R., Zahran H., Thurman D. J., Zack M. M., Henry T. R., Schachter S. C., and, Price P. H., (2008) Epilepsy surveillance among adults - 19 states, behavioral risk factor surveillance system, 2005. MMWR Surveill. Summ. 57, 1-20.
31. Koranda J. L., Ruskin D. N., Masino S. A., and, Blaise J. H., (2011) A ketogenic diet reduces long-term potentiation in the dentate gyrus of freely behaving rats. J. Neurophysiol. 106, 662-666.
32. Kwan P., and, Brodie M. J., (2000) Epilepsy after the first drug fails: substitution or add-on? Seizure 9, 464-468.
33. Likhodii S. S., Musa K., Mendonca A., Dell C., Burnham W. M., and, Cunnane S. C., (2000) Dietary fat, ketosis, and seizure resistance in rats on the ketogenic diet. Epilepsia 41, 1400-1410.
34. Likhodii S. S., Serbanescu I., Cortez M. A., Murphy P., Snead O. C. 3rd, and, Burnham W. M., (2003) Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet. Ann. Neurol. 54, 219-226. (Pubitemid 36909620)
35. Ma W., Berg J., and, Yellen G., (2007) Ketogenic diet metabolites reduce firing in central neurons by opening K(ATP) channels. J. Neurosci. 27, 3618-3625. (Pubitemid 46557685)
36. Maalouf M., and, Rho J. M., (2008) Oxidative impairment of hippocampal long-term potentiation involves activation of protein phosphatase 2A and is prevented by ketone bodies. J. Neurosci. Res. 86, 3322-3330.
37. Maalouf M., Sullivan P. G., Davis L., Kim D. Y., and, Rho J. M., (2007) Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience 145, 256-264. (Pubitemid 46227735)
38. Masino S. A., Li T., Theofilas P., Sandau U. S., Ruskin D. N., Fredholm B. B., Geiger J. D., Aronica E., and, Boison D., (2011) A ketogenic diet suppresses seizures in mice through adenosine A receptors. J. Clin. Invest. 121, 2679-2683.
39. Melo T. M., Nehlig A., and, Sonnewald U., (2006) Neuronal-glial interactions in rats fed a ketogenic diet. Neurochem. Int. 48, 498-507.
40. Milder J. B., Liang L. P., and, Patel M., (2010) Acute oxidative stress and systemic Nrf2 activation by the ketogenic diet. Neurobiol. Dis. 40, 238-244.
41. Minlebaev M., and, Khazipov R., (2011) Antiepileptic effects of endogenous beta-hydroxybutyrate in suckling infant rats. Epilepsy Res. 95, 100-109.
42. Musa-Veloso K., Likhodii S. S., Rarama E., et al. (2006) Breath acetone predicts plasma ketone bodies in children with epilepsy on a ketogenic diet. Nutrition 22, 1-8. (Pubitemid 43175778)
43. Neal E. G., Chaffe H., Schwartz R. H., Lawson M. S., Edwards N., Fitzsimmons G., Whitney A., and, Cross J. H., (2008) The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 7, 500-506.
44. Nehlig A., (1999) Age-dependent pathways of brain energy metabolism: the suckling rat, a natural model of the ketogenic diet. Epilepsy Res. 37, 211-221. (Pubitemid 29476519)
45. Nehlig A., and, Pereira de Vasconcelos A., (1993) Glucose and ketone body utilization by the brain of neonatal rats. Prog. Neurobiol. 40, 163-221.
46. Nordli D. R. Jr, and, de Vivo D. C., (1997) The ketogenic diet revisited: back to the future. Epilepsia 38, 743-749. (Pubitemid 27299015)
47. Nylen K., Likhodii S. S., Hum K. M., and, Burnham W. M., (2006) A ketogenic diet and diallyl sulfide do not elevate afterdischarge thresholds in adult kindled rats. Epilepsy Res. 71, 23-31. (Pubitemid 44233195)
48. Nylen K., Velazquez J. L., Sayed V., Gibson K. M., Burnham W. M., and, Snead O. C. 3rd, (2009) The effects of a ketogenic diet on ATP concentrations and the number of hippocampal mitochondria in Aldh5a1(-/-) mice. Biochim. Biophys. Acta 1790, 208-212.
49. Owen O. E., Morgan A. P., Kemp H. G., Sullivan J. M., Herrera M. G., and, Cahill G. F. Jr, (1967) Brain metabolism during fasting. J. Clin. Invest. 46, 1589-1595.
50. Prins M. L., (2008) Cerebral metabolic adaptation and ketone metabolism after brain injury. J. Cereb. Blood Flow Metab. 28, 1-16.
51. Rheims S., Holmgren C. D., Chazal G., Mulder J., Harkany T., Zilberter T., and, Zilberter Y., (2009) GABA action in immature neocortical neurons directly depends on the availability of ketone bodies. J. Neurochem. 110, 1330-1338.
52. Rho J. M., Anderson G. D., Donevan S. D., and, White H. S., (2002) Acetoacetate, acetone, and dibenzylamine (a contaminant in l-(+)-beta- hydroxybutyrate) exhibit direct anticonvulsant actions in vivo. Epilepsia 43, 358-361. (Pubitemid 34297173)
53. Ross D. L., Swaiman K. F., Torres F., and, Hansen J., (1985) Early biochemical and EEG correlates of the ketogenic diet in children with atypical absence epilepsy. Pediatr. Neurol. 1, 104-108. (Pubitemid 17029876)
54. Samala R., Willis S., and, Borges K., (2008) Anticonvulsant profile of a balanced ketogenic diet in acute mouse seizure models. Epilepsy Res. 81, 119-127.
55. Samala R., Klein J., and, Borges K., (2011) The ketogenic diet changes metabolite levels in hippocampal extracellular fluid. Neurochem. Int. 58, 5-8.
56. Seymour K. J., Bluml S., Sutherling J., Sutherling W., and, Ross B. D., (1999) Identification of cerebral acetone by 1H-MRS in patients with epilepsy controlled by ketogenic diet. MAGMA 8, 33-42. (Pubitemid 29238710)
57. Sokoloff L., (1973) Metabolism of ketone bodies by the brain. Annu. Rev. Med. 24, 271-280.
58. Szot P., Weinshenker D., Rho J. M., Storey T. W., and, Schwartzkroin P. A., (2001) Norepinephrine is required for the anticonvulsant effect of the ketogenic diet. Brain Res. Dev. Brain Res. 129, 211-214. (Pubitemid 32744784)
59. Tanner G. R., Lutas A., Martinez-Francois J. R., and, Yellen G., (2011) Single K ATP channel opening in response to action potential firing in mouse dentate granule neurons. J. Neurosci. 31, 8689-8696.
60. Thio L. L., Wong M., and, Yamada K. A., (2000) Ketone bodies do not directly alter excitatory or inhibitory hippocampal synaptic transmission. Neurology 54, 325-331. (Pubitemid 30078061)
61. Tieu K., Perier C., Caspersen C., et al. (2003) D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J. Clin. Invest. 112, 892-901. (Pubitemid 38063747)
62. Tyzio R., Allene C., Nardou R., et al. (2011) Depolarizing actions of GABA in immature neurons depend neither on ketone bodies nor on pyruvate. J. Neurosci. 31, 34-45.
63. Uhlemann E. R., and, Neims A. H., (1972) Anticonvulsant properties of the ketogenic diet in mice. JPET 180, 231-238.
64. Wang Z. J., Bergqvist C., Hunter J. V., Jin D., Wang D. J., Wehrli S., and, Zimmerman R. A., (2003) In vivo measurement of brain metabolites using two-dimensional double-quantum MR spectroscopy - exploration of GABA levels in a ketogenic diet. Magn. Reson. Med. 49, 615-619. (Pubitemid 36389969)
65. Yang L., Zhao J., Milutinovic P. S., Brosnan R. J., Eger E. I. 2nd, and, Sonner J. M., (2007) Anesthetic properties of the ketone bodies beta-hydroxybutyric acid and acetone. Anesth. Analg. 105, 673-679. (Pubitemid 47300842)
66. Yellen G., (2008) Ketone bodies, glycolysis, and KATP channels in the mechanism of the ketogenic diet. Epilepsia 49 (Suppl. 8), 80-82.
67. Yudkoff M., Daikhin Y., Nissim I., and, Grunstein R., (1997) Effects of ketone bodies on astrocyte amino acid metabolism. J. Neurochem. 69, 682-692. (Pubitemid 27327971)
68. Yudkoff M., Daikhin Y., Nissim I., and, Lazarow A., (2001) Brain amino acid metabolism and ketosis. J. Neurosci. Res. 66, 272-281. (Pubitemid 32912296)
69. Yudkoff M., Daikhin Y., Nissim I., Horyn O., Lazarow A., Luhovyy B., and, Wehrli S., (2005) Response of brain amino acid metabolism to ketosis. Neurochem. Int. 47, 119-128. (Pubitemid 40848700)
70. Yudkoff M., Daikhin Y., Horyn O., and, Nissim I., (2008) Ketosis and brain handling of glutamate, glutamine, and GABA. Epilepsia 49 (Suppl. 8), 73-75.
71. Zhao Z., Lange D. J., Voustianiouk A., et al. (2006) A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. BMC Neurosci. 7, 29.