Control of seizures by ketogenic diet-induced modulation of metabolic pathways

Abstract

Epilepsy is too complex to be considered as a disease; it is more of a syndrome, characterized by seizures, which can be caused by a diverse array of afflictions. As such, drug interventions that target a single biological pathway will only help the specific individuals where that drug’s mechanism of action is relevant to their disorder. Most likely, this will not alleviate all forms of epilepsy nor the potential biological pathways causing the seizures, such as glucose/amino acid transport, mitochondrial dysfunction, or neuronal myelination. Considering our current inability to test every individual effectively for the true causes of their epilepsy and the alarming number of misdiagnoses observed, we propose the use of the ketogenic diet (KD) as an effective and efficient preliminary/long-term treatment. The KD mimics fasting by altering substrate metabolism from carbohydrates to fatty acids and ketone bodies (KBs). Here, we underscore the need to understand the underlying cellular mechanisms governing the KD’s modulation of various forms of epilepsy and how a diverse array of metabolites including soluble fibers, specific fatty acids, and functional amino acids (e.g., leucine, d-serine, glycine, arginine metabolites, and N-acetyl-cysteine) may potentially enhance the KD’s ability to treat and reverse, not mask, these neurological disorders that lead to epilepsy.

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References

  1. Ableitner A, Herz A (1987) Changes in local cerebral glucose utilization induced by the beta-carbolines FG 7142 and DMCM reveal brain structures involved in the control of anxiety and seizure activity. J Neurosci 7(4):1047–1055

    CAS  PubMed  Google Scholar 

  2. Ahmed SS, Gao G (2015) Making the white matter matters: progress in understanding Canavan’s disease and therapeutic interventions through eight decades. JIMD Rep 19:11–22. doi:10.1007/8904_2014_356

    PubMed  PubMed Central  Article  Google Scholar 

  3. Ahola-Erkkila S, Carroll CJ, Peltola-Mjosund K, Tulkki V, Mattila I, Seppanen-Laakso T, Oresic M, Tyynismaa H, Suomalainen A (2010) Ketogenic diet slows down mitochondrial myopathy progression in mice. Hum Mol Genet 19(10):1974–1984. doi:10.1093/hmg/ddq076

    CAS  PubMed  Article  Google Scholar 

  4. Arida RM, de Almeida A-CG, Cavalheiro EA, Scorza FA (2013) Experimental and clinical findings from physical exercise as complementary therapy for epilepsy. Epilepsy Behav 26(3):273–278. doi:10.1016/j.yebeh.2012.07.025

    PubMed  Article  Google Scholar 

  5. Auestad N, Korsak RA, Morrow JW, Edmond J (1991) Fatty acid oxidation and ketogenesis by astrocytes in primary culture. J Neurochem 56(4):1376–1386

    CAS  PubMed  Article  Google Scholar 

  6. Bailey EE, Pfeifer HH, Thiele EA (2005) The use of diet in the treatment of epilepsy. Epilepsy Behav 6(1):4–8. doi:10.1016/j.yebeh.2004.10.006

    PubMed  Article  Google Scholar 

  7. Ballard HJ (1991) The influence of lactic acid on adenosine release from skeletal muscle in anaesthetized dogs. J Physiol 433:95–108

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. BallarÍN M, Fredholm BB, Ambrosio S, Mahy N (1991) Extracellular levels of adenosine and its metabolites in the striatum of awake rats: inhibition of uptake and metabolism. Acta Physiol Scand 142(1):97–103. doi:10.1111/j.1748-1716.1991.tb09133.x

    PubMed  Article  Google Scholar 

  9. Barañano KW, Hartman AL (2008) The ketogenic diet: uses in epilepsy and other neurologic illnesses. Curr Treat Options Neurol 10(6):410–419

    PubMed  PubMed Central  Article  Google Scholar 

  10. Bélanger M, Allaman I, Magistretti Pierre J (2011) Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 14(6):724–738. doi:10.1016/j.cmet.2011.08.016

    PubMed  Article  CAS  Google Scholar 

  11. Bergersen LH, Magistretti PJ, Pellerin L (2005) Selective postsynaptic co-localization of MCT2 with AMPA receptor GluR2/3 subunits at excitatory synapses exhibiting AMPA receptor trafficking. Cereb Cortex 15(4):361–370. doi:10.1093/cercor/bhh138 (New York, NY: 1991)

    PubMed  Article  Google Scholar 

  12. Bilger A, 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(2):143–152

    CAS  PubMed  Article  Google Scholar 

  13. Bliss TM, Sapolsky RM (2001) Interactions among glucose, lactate and adenosine regulate energy substrate utilization in hippocampal cultures. Brain Res 899(1–2):134–141. doi:10.1016/S0006-8993(01)02218-1

    CAS  PubMed  Article  Google Scholar 

  14. Boison D (2008) The adenosine kinase hypothesis of epileptogenesis. Prog Neurobiol 84(3):249–262. doi:10.1016/j.pneurobio.2007.12.002

    CAS  PubMed  Article  Google Scholar 

  15. Boison D (2013) Adenosine and seizure termination: endogenous mechanisms. Epilepsy Curr 13(1):35–37. doi:10.5698/1535-7511-13.1.35

    PubMed  PubMed Central  Article  Google Scholar 

  16. Bough KJ, Wetherington J, Hassel B, Pare JF, Gawryluk JW, Greene JG, Shaw R, Smith Y, Geiger JD, Dingledine RJ (2006) Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol 60(2):223–235. doi:10.1002/ana.20899

    CAS  PubMed  Article  Google Scholar 

  17. Bough KJ, Paquet M, Paré J-F, Hassel B, Smith Y, Hall RA, Dingledine R (2007) Evidence against enhanced glutamate transport in the anticonvulsant mechanism of the ketogenic diet. Epilepsy Res 74(2–3):232–236. doi:10.1016/j.eplepsyres.2007.03.002

    CAS  PubMed  Article  Google Scholar 

  18. Brooks GA (1985) Lactate:Glycolytic end product and oxidative substrate during sustained exercise in mammals—the “Lactate Shuttle”. In: Gilles R (ed) Circulation, respiration, and metabolism: current comparative approaches. Springer, Berlin, pp 208–218. doi:10.1007/978-3-642-70610-3_15

    Google Scholar 

  19. Brooks GA (2009) Cell–cell and intracellular lactate shuttles. J Physiol 587(Pt 23):5591–5600. doi:10.1113/jphysiol.2009.178350

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Caraballo RH, Flesler S, Armeno M, Fortini S, Agustinho A, Mestre G, Cresta A, Buompadre MC, Escobal N (2014) Ketogenic diet in pediatric patients with refractory focal status epilepticus. Epilepsy Res 108(10):1912–1916. doi:10.1016/j.eplepsyres.2014.09.033

    PubMed  Article  Google Scholar 

  21. Chan O, Paranjape SA, Horblitt A, Zhu W, Sherwin RS (2013) Lactate-induced release of GABA in the ventromedial hypothalamus contributes to counter regulatory failure in recurrent hypoglycemia and diabetes. Diabetes 62(12):4239–4246. doi:10.2337/db13-0770

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Cheng CM, Kelley B, Wang J, Strauss D, Eagles DA, Bondy CA (2003) A ketogenic diet increases brain insulin-like growth factor receptor and glucose transporter gene expression. Endocrinology 144(6):2676–2682. doi:10.1210/en.2002-0057

    CAS  PubMed  Article  Google Scholar 

  23. Chu AC-Y, Ho PW-L, Kwok KH-H, Ho JW-M, Chan K-H, Liu H-F, Kung MH-W, Ramsden DB, Ho S-L (2009) Mitochondrial UCP4 attenuates MPP+- and dopamine-induced oxidative stress, mitochondrial depolarization, and ATP deficiency in neurons and is interlinked with UCP2 expression. Free Radic Biol Med 46(6):810–820. doi:10.1016/j.freeradbiomed.2008.12.015

    CAS  PubMed  Article  Google Scholar 

  24. Chuang Y-C, Lin T-K, Huang H-Y, Chang W-N, Liou C-W, Chen S-D, Chang AY, Chan SH (2012) Peroxisome proliferator-activated receptors γ/mitochondrial uncoupling protein 2 signaling protects against seizure-induced neuronal cell death in the hippocampus following experimental status epilepticus. J Neuroinflammation 9(1):1–18. doi:10.1186/1742-2094-9-184

    Article  CAS  Google Scholar 

  25. Cowansage KK, LeDoux JE, Monfils MH (2010) Brain-derived neurotrophic factor: a dynamic gatekeeper of neural plasticity. Curr Mol Pharmacol 3(1):12–29

    CAS  PubMed  Article  Google Scholar 

  26. Cullingford TE, Eagles DA, Sato H (2002) The ketogenic diet upregulates expression of the gene encoding the key ketogenic enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in rat brain. Epilepsy Res 49(2):99–107

    CAS  PubMed  Article  Google Scholar 

  27. Dahlin M, Elfving Å, Ungerstedt U, Åmark 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(3):115–125. doi:10.1016/j.eplepsyres.2005.03.008

    CAS  PubMed  Article  Google Scholar 

  28. Dahlin M, Martin DA, Hedlund Z, Jonsson M, von Dobeln U, Wedell A (2015) The ketogenic diet compensates for AGC1 deficiency and improves myelination. Epilepsia 56(11):e176–e181. doi:10.1111/epi.13193

    CAS  PubMed  Article  Google Scholar 

  29. Daikhin Y, Yudkoff M (1998) Ketone bodies and brain glutamate and GABA metabolism. Dev Neurosci 20(4–5):358–364

    CAS  PubMed  Article  Google Scholar 

  30. Deng-Bryant Y, Prins ML, Hovda DA, Harris NG (2011) Ketogenic diet prevents alterations in brain metabolism in young but not adult rats after traumatic brain injury. J Neurotrauma 28(9):1813–1825. doi:10.1089/neu.2011.1822

    PubMed  PubMed Central  Article  Google Scholar 

  31. Diano S, Matthews RT, Patrylo P, Yang L, Beal MF, Barnstable CJ, Horvath TL (2003) Uncoupling protein 2 prevents neuronal death including that occurring during seizures: a mechanism for preconditioning. Endocrinology 144(11):5014–5021. doi:10.1210/en.2003-0667

    CAS  PubMed  Article  Google Scholar 

  32. Eftekhari S, Mehrabi S, Soleimani M, Hassanzadeh G, Shahrokhi A, Mostafavi H, Hayat P, Barati M, Mehdizadeh H, Rahmanzadeh R, Hadjighassem MR, Joghataei MT (2014) BDNF modifies hippocampal KCC2 and NKCC1 expression in a temporal lobe epilepsy model. Acta Neurobiol Exp 74(3):276–287

    Google Scholar 

  33. Eintrei C, Sokoloff L, Smith CB (1999) Effects of diazepam and ketamine administered individually or in combination on regional rates of glucose utilization in rat brain. Br J Anaesth 82(4):596–602

    CAS  PubMed  Article  Google Scholar 

  34. Falk MJ, Li D, Gai X, McCormick E, Place E, Lasorsa FM, Otieno FG, Hou C, Kim CE, Abdel-Magid N, Vazquez L, Mentch FD, Chiavacci R, Liang J, Liu X, Jiang H, Giannuzzi G, Marsh ED, Yiran G, Tian L, Palmieri F, Hakonarson H (2014) AGC1 deficiency causes infantile epilepsy, abnormal myelination, and reduced N-acetylaspartate. JIMD Rep 14:77–85. doi:10.1007/8904_2013_287

    PubMed  PubMed Central  Article  Google Scholar 

  35. Fontanesi F, Jin C, Tzagoloff A, Barrientos A (2008) Transcriptional activators HAP/NF-Y rescue a cytochrome c oxidase defect in yeast and human cells. Hum Mol Genet 17(6):775–788. doi:10.1093/hmg/ddm349

    CAS  PubMed  Article  Google Scholar 

  36. Fornai F, Dybdal DJ, Proctor MR, Gale K (1994) Focal intracerebral elevation of l-lactate is anticonvulsant. Eur J Pharmacol 254(3):R1–R2

    CAS  PubMed  Article  Google Scholar 

  37. Ganzella M, Faraco RB, Almeida RF, Fernandes VF, Souza DO (2011) Intracerebroventricular administration of inosine is anticonvulsant against quinolinic acid-induced seizures in mice: an effect independent of benzodiazepine and adenosine receptors. Pharmacol Biochem Behav 100(2):271–274. doi:10.1016/j.pbb.2011.09.001

    CAS  PubMed  Article  Google Scholar 

  38. Garriga-Canut M, Schoenike B, Qazi R, Bergendahl K, Daley TJ, Pfender RM, Morrison JF, Ockuly J, Stafstrom C, Sutula T, Roopra A (2006) 2-Deoxy-d-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure. Nat Neurosci 9(11):1382–1387. doi:10.1038/nn1791

    CAS  PubMed  Article  Google Scholar 

  39. Genc S, Kurnaz IA, Ozilgen M (2011) Astrocyte–neuron lactate shuttle may boost more ATP supply to the neuron under hypoxic conditions—in silico study supported by in vitro expression data. BMC Syst Biol 5(1):1–13. doi:10.1186/1752-0509-5-162

    Article  CAS  Google Scholar 

  40. Gomez-Lira G, Mendoza-Torreblanca JG, Granados-Rojas L (2011) Ketogenic diet does not change NKCC1 and KCC2 expression in rat hippocampus. Epilepsy Res 96(1–2):166–171. doi:10.1016/j.eplepsyres.2011.05.017

    CAS  PubMed  Article  Google Scholar 

  41. Haces ML, Hernandez-Fonseca K, Medina-Campos ON, Montiel T, Pedraza-Chaverri J, Massieu L (2008) Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions. Exp Neurol 211(1):85–96. doi:10.1016/j.expneurol.2007.12.029

    CAS  PubMed  Article  Google Scholar 

  42. Hagberg H, Andersson P, Lacarewicz J, Jacobson I, Butcher S, Sandberg M (1987) Extracellular adenosine, inosine, hypoxanthine, and xanthine in relation to tissue nucleotides and purines in rat striatum during transient ischemia. J Neurochem 49(1):227–231. doi:10.1111/j.1471-4159.1987.tb03419.x

    CAS  PubMed  Article  Google Scholar 

  43. Hagenfeldt L, Bollgren I, Venizelos N (1987) N-acetylaspartic aciduria due to aspartoacylase deficiency—a new aetiology of childhood leukodystrophy. J Inherit Metab Dis 10(2):135–141. doi:10.1007/bf01800038

    CAS  PubMed  Article  Google Scholar 

  44. Han Y, Lin Y, Xie N, Xue Y, Tao H, Rui C, Xu J, Cao L, Liu X, Jiang H, Chi Z (2011) Impaired mitochondrial biogenesis in hippocampi of rats with chronic seizures. Neuroscience 194:234–240. doi:10.1016/j.neuroscience.2011.07.068

    CAS  PubMed  Article  Google Scholar 

  45. Hartman AL, Gasior M, Vining EPG, Rogawski MA (2007) The neuropharmacology of the ketogenic diet. Pediatr Neurol 36(5):281–292. doi:10.1016/j.pediatrneurol.2007.02.008

    PubMed  PubMed Central  Article  Google Scholar 

  46. Hartman AL, Zheng X, Bergbower E, Kennedy M, Hardwick JM (2010) Seizure tests distinguish intermittent fasting from the ketogenic diet. Epilepsia 51(8):1395–1402. doi:10.1111/j.1528-1167.2010.02577.x

    PubMed  PubMed Central  Article  Google Scholar 

  47. Hartman AL, Rubenstein JE, Kossoff EH (2013) Intermittent fasting: a “new” historical strategy for controlling seizures? Epilepsy Res 104(3):275–279. doi:10.1016/j.eplepsyres.2012.10.011

    PubMed  Article  Google Scholar 

  48. Hartman AL, Santos P, O’Riordan KJ, Stafstrom CE, Hardwick JM (2015) Potent anti-seizure effects of d-leucine. Neurobiol Dis 82:46–53. doi:10.1016/j.nbd.2015.05.013

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Hashimoto T, Hussien R, Cho H-S, Kaufer D, Brooks GA (2008) Evidence for the mitochondrial lactate oxidation complex in rat neurons: demonstration of an essential component of brain lactate shuttles. PLoS One 3(8):e2915. doi:10.1371/journal.pone.0002915

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. Hentschke M, Wiemann M, Hentschke S, Kurth I, Hermans-Borgmeyer I, Seidenbecher T, Jentsch TJ, Gal A, Hübner CA (2006) Mice with a targeted disruption of the Cl/HCO3 exchanger AE3 display a reduced seizure threshold. Mol Cell Biol 26(1):182–191. doi:10.1128/mcb.26.1.182-191.2006

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Ho PW, Ho JW, Liu H-F, So DH, Tse ZH, Chan K-H, Ramsden DB, Ho S-L (2012a) Mitochondrial neuronal uncoupling proteins: a target for potential disease-modification in Parkinson’s disease. Transl Neurodegener 1(1):1–9. doi:10.1186/2047-9158-1-3

    Article  CAS  Google Scholar 

  52. Ho PW-L, Ho JW-M, Tse H-M, So DH-F, Yiu DC-W, Liu H-F, Chan K-H, Kung MH-W, Ramsden DB, Ho S-L (2012b) Uncoupling protein-4 (UCP4) increases ATP supply by interacting with mitochondrial complex II in neuroblastoma cells. PLoS One 7(2):e32810. doi:10.1371/journal.pone.0032810

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Hogg DW, Pamenter ME, Dukoff DJ, Buck LT (2015) Decreases in mitochondrial reactive oxygen species initiate GABA(A) receptor-mediated electrical suppression in anoxia-tolerant turtle neurons. J Physiol 593(10):2311–2326. doi:10.1113/jp270474

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Horvath TL, Warden CH, Hajos M, Lombardi A, Goglia F, Diano S (1999) Brain uncoupling protein 2: uncoupled neuronal mitochondria predict thermal synapses in homeostatic centers. J Neurosci 19(23):10417–10427

    CAS  PubMed  Google Scholar 

  55. Hou YQ, Yao K, Yin YL, Wu G (2016) Endogenous synthesis of amino acids limits growth, lactation and reproduction of animals. Adv Nutr 7:331–342

  56. Hu ZG, Wang HD, Jin W, Yin HX (2009) Ketogenic diet reduces cytochrome c release and cellular apoptosis following traumatic brain injury in juvenile rats. Ann Clin Lab Sci 39(1):76–83

    CAS  PubMed  Google Scholar 

  57. Huang H-S, Chen C-J, Chang W-C (1999) The CCAAT-box binding factor NF-Y is required for the expression of phospholipid hydroperoxide glutathione peroxidase in human epidermoid carcinoma A431 cells. FEBS Lett 455(1–2):111–116. doi:10.1016/S0014-5793(99)00866-2

    CAS  PubMed  Article  Google Scholar 

  58. Hughes SD, Kanabus M, Anderson G, Hargreaves IP, Rutherford T, O’Donnell M, Cross JH, Rahman S, Eaton S, Heales SJ (2014) The ketogenic diet component decanoic acid increases mitochondrial citrate synthase and complex I activity in neuronal cells. J Neurochem 129(3):426–433. doi:10.1111/jnc.12646

    CAS  PubMed  Article  Google Scholar 

  59. Hussien R, Brooks GA (2011) Mitochondrial and plasma membrane lactate transporter and lactate dehydrogenase isoform expression in breast cancer cell lines. Physiol Genomics 43(5):255–264. doi:10.1152/physiolgenomics.00177.2010

    CAS  PubMed  Article  Google Scholar 

  60. Ilie A, Raimondo JV, Akerman CJ (2012) Adenosine release during seizures attenuates GABAA receptor-mediated depolarization. J Neurosci 32(15):5321–5332. doi:10.1523/jneurosci.5412-11.2012

    CAS  PubMed  Article  Google Scholar 

  61. Jarrett SG, Milder JB, Liang LP, Patel M (2008) The ketogenic diet increases mitochondrial glutathione levels. J Neurochem 106(3):1044–1051. doi:10.1111/j.1471-4159.2008.05460.x

    CAS  PubMed  Article  Google Scholar 

  62. Jeong HJ, Kim H, Kim YK, Park SK, Kang DW, Yoon D (2010) The ketogenic diet suppresses the cathepsin E expression induced by kainic acid in the rat brain. Yonsei Med J 51(5):653–660. doi:10.3349/ymj.2010.51.5.653

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Jobgen WS, Fried SK, Fu WJ et al (2006) Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. J Nutr Biochem 17:571–588

  64. Jourdain P, Allaman I, Rothenfusser K, Fiumelli H, Marquet P, Magistretti PJ (2016) l-Lactate protects neurons against excitotoxicity: implication of an ATP-mediated signaling cascade. Sci Rep 6. doi:10.1038/srep21250

  65. Juge N, Gray JA, Omote H, Miyaji T, Inoue T, Hara C, Uneyama H, Edwards RH, Nicoll RA, Moriyama Y (2010) Metabolic control of vesicular glutamate transport and release. Neuron 68(1):99–112. doi:10.1016/j.neuron.2010.09.002

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Kang HC, Lee YM, Kim HD, Lee JS, Slama A (2007) Safe and effective use of the ketogenic diet in children with epilepsy and mitochondrial respiratory chain complex defects. Epilepsia 48(1):82–88. doi:10.1111/j.1528-1167.2006.00906.x

    CAS  PubMed  Google Scholar 

  67. Kim DY, Davis LM, Sullivan PG, Maalouf M, Simeone TA, van Brederode J, Rho JM (2007) Ketone bodies are protective against oxidative stress in neocortical neurons. J Neurochem 101(5):1316–1326. doi:10.1111/j.1471-4159.2007.04483.x

    CAS  PubMed  Article  Google Scholar 

  68. Kim-Han JS, Reichert SA, Quick KL, Dugan LL (2001) BMCP1: a mitochondrial uncoupling protein in neurons which regulates mitochondrial function and oxidant production. J Neurochem 79(3):658–668. doi:10.1046/j.1471-4159.2001.00604.x

    CAS  PubMed  Article  Google Scholar 

  69. Kinsella JE (1990) Lipids, membrane receptors, and enzymes: effects of dietary fatty acids. J Parenter Enteral Nutr 14(5 suppl):200S–217S. doi:10.1177/014860719001400511

    CAS  Article  Google Scholar 

  70. Kleene R, Loers G, Langer J, Frobert Y, Buck F, Schachner M (2007) Prion protein regulates glutamate-dependent lactate transport of astrocytes. J Neurosci 27(45):12331–12340. doi:10.1523/jneurosci.1358-07.2007

    CAS  PubMed  Article  Google Scholar 

  71. Klepper J, Diefenbach S, Kohlschütter A, Voit T (2004) Effects of the ketogenic diet in the glucose transporter 1 deficiency syndrome. Prostaglandins Leukot Essent Fatty Acids 70(3):321–327. doi:10.1016/j.plefa.2003.07.004

    CAS  PubMed  Article  Google Scholar 

  72. Klepper J, Engelbrecht V, Scheffer H, van der Knaap MS, Fiedler A (2007) GLUT1 deficiency with delayed myelination responding to ketogenic diet. Pediatr Neurol 37(2):130–133. doi:10.1016/j.pediatrneurol.2007.03.009

    PubMed  Article  Google Scholar 

  73. Kobow K, Kaspi A, Harikrishnan KN, Kiese K, Ziemann M, Khurana I, Fritzsche I, Hauke J, Hahnen E, Coras R, Muhlebner A, El-Osta A, Blumcke I (2013) Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. Acta Neuropathol 126(5):741–756. doi:10.1007/s00401-013-1168-8

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Kuhr WG, Korf J (1988) Extracellular lactic acid as an indicator of brain metabolism: continuous on-line measurement in conscious, freely moving rats with intrastriatal dialysis. J Cereb Blood Flow Metab 8(1):130–137. doi:10.1038/jcbfm.1988.17

    CAS  PubMed  Article  Google Scholar 

  75. Lapin IP (1981) Nicotinamide, inosine and hypoxanthine, putative endogenous ligands of the benzodiazepine receptor, opposite to diazepam are much more effective against kynurenine-induced seizures than against pentylenetetrazol-induced seizures. Pharmacol Biochem Behav 14(5):589–593. doi:10.1016/0091-3057(81)90117-9

    CAS  PubMed  Article  Google Scholar 

  76. Larmet Y, Reibel S, Carnahan J, Nawa H, Marescaux C, Depaulis A (1995) Protective effects of brain-derived neurotrophic factor on the development of hippocampal kindling in the rat. Neuroreport 6(14):1937–1941

    CAS  PubMed  Article  Google Scholar 

  77. Lauritzen F, Perez EL, Melillo ER, Roh J-M, Zaveri HP, Lee T-SW, Wang Y, Bergersen LH, Eid T (2012) Altered expression of brain monocarboxylate transporter 1 in models of temporal lobe epilepsy. Neurobiol Dis 45(1):165–176. doi:10.1016/j.nbd.2011.08.001

    CAS  PubMed  Article  Google Scholar 

  78. Lee HHC, Deeb TZ, Walker JA, Davies PA, Moss SJ (2011) NMDA receptor activity downregulates KCC2 resulting in depolarizing GABA(A) receptor mediated currents. Nat Neurosci 14(6):736–743. doi:10.1038/nn.2806

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. Leino RL, Gerhart DZ, Duelli R, Enerson BE, Drewes LR (2001) Diet-induced ketosis increases monocarboxylate transporter (MCT1) levels in rat brain. Neurochem Int 38(6):519–527

    CAS  PubMed  Article  Google Scholar 

  80. Liu Y-mC (2008) Medium-chain triglyceride (MCT) ketogenic therapy. Epilepsia 49:33–36. doi:10.1111/j.1528-1167.2008.01830.x

    PubMed  Article  Google Scholar 

  81. Liu YM, Wang HS (2013) Medium-chain triglyceride ketogenic diet, an effective treatment for drug-resistant epilepsy and a comparison with other ketogenic diets. Biomed J 36(1):9–15. doi:10.4103/2319-4170.107154

    PubMed  Article  Google Scholar 

  82. Lloyd HG, Fredholm BB (1995) Involvement of adenosine deaminase and adenosine kinase in regulating extracellular adenosine concentration in rat hippocampal slices. Neurochem Int 26(4):387–395

    CAS  PubMed  Article  Google Scholar 

  83. Loaiza A, Porras OH, Barros LF (2003) Glutamate triggers rapid glucose transport stimulation in astrocytes as evidenced by real-time confocal microscopy. J Neurosci 23(19):7337–7342

    CAS  PubMed  Google Scholar 

  84. Maalouf M, Sullivan PG, Davis L, Kim DY, Rho JM (2007) Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience 145(1):256–264. doi:10.1016/j.neuroscience.2006.11.065

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. Maalouf M, Rho JM, Mattson MP (2009) The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev 59(2):293–315

    CAS  PubMed  Article  Google Scholar 

  86. MacMillan V, Leake J, Chung T, Bovell M (1987) The effect of valproic acid on the 5-hydroxyindoleacetic, homovanillic and lactic acid levels of cerebrospinal fluid. Brain Res 420(2):268–276

    CAS  PubMed  Article  Google Scholar 

  87. Mangia S, Simpson IA, Vannucci SJ, Carruthers A (2009) The in vivo neuron-to-astrocyte lactate shuttle in human brain: evidence from modeling of measured lactate levels during visual stimulation. J Neurochem 109(Suppl 1):55–62. doi:10.1111/j.1471-4159.2009.06003.x

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Marangos PJ, Martino AM, Paul SM, Skolnick P (1981) The benzodiazepines and inosine antagonize caffeine-induced seizures. Psychopharmacology 72(3):269–273. doi:10.1007/bf00431829

    CAS  PubMed  Article  Google Scholar 

  89. Marosi K, Mattson MP (2014) BDNF mediates adaptive brain and body responses to energetic challenges. Trends Endocrinol Metab 25(2):89–98

    CAS  PubMed  Article  Google Scholar 

  90. Masino SA, Dunwiddie TV (1999) Temperature-dependent modulation of excitatory transmission in hippocampal slices is mediated by extracellular adenosine. J Neurosci 19(6):1932–1939

    CAS  PubMed  Google Scholar 

  91. Masino SA, Rho JM (2012) Mechanisms of ketogenic diet action. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds) Jasper’s basic mechanisms of the epilepsies. National Center for Biotechnology Information (US), Bathesda

    Google Scholar 

  92. Masino SA, Kawamura M, Wasser CD, Pomeroy LT, Ruskin DN (2009) Adenosine, ketogenic diet and epilepsy: the emerging therapeutic relationship between metabolism and brain activity. Curr Neuropharmacol 7(3):257–268. doi:10.2174/157015909789152164

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Masino SA, Li T, Theofilas P, Sandau US, Ruskin DN, Fredholm BB, Geiger JD, Aronica E, Boison D (2011) A ketogenic diet suppresses seizures in mice through adenosine A(1) receptors. J Clin Invest 121(7):2679–2683. doi:10.1172/JCI57813

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Masino SA, Kawamura M Jr, Ruskin DN (2014) Chapter eleven—adenosine receptors and epilepsy: current evidence and future potential. In: Akihisa M (ed) International review of neurobiology, 119th edn. Academic Press, New York, pp 233–255. doi:10.1016/B978-0-12-801022-8.00011-8

    Google Scholar 

  95. Mathews GC (2007) The dual roles of GABA in seizures and epilepsy generate more excitement. Epilepsy Curr 7(1):28–30. doi:10.1111/j.1535-7511.2007.00159.x

    PubMed  PubMed Central  Article  Google Scholar 

  96. Matsumoto T, Numakawa T, Adachi N, Yokomaku D, Yamagishi S, Takei N, Hatanaka H (2001) Brain-derived neurotrophic factor enhances depolarization-evoked glutamate release in cultured cortical neurons. J Neurochem 79(3):522–530

    CAS  PubMed  Article  Google Scholar 

  97. Matsuzawa T, Sakazume M (1994) Effects of fasting on haematology and clinical chemistry values in the rat and dog. Comp Haematol Int 4(3):152–156. doi:10.1007/bf00798356

    Article  Google Scholar 

  98. Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV, Browne TR, Williamson PD, Treiman DM, McNamara JO, McCutchen CB et al (1985) Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 313(3):145–151. doi:10.1056/nejm198507183130303

    CAS  PubMed  Article  Google Scholar 

  99. McGowan PO, Meaney MJ, Szyf M (2008) Diet and the epigenetic (re)programming of phenotypic differences in behavior. Brain Res 1237:12–24. doi:10.1016/j.brainres.2008.07.074

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. McNally MA, Hartman AL (2012) Ketone bodies in epilepsy. J Neurochem 121(1):28–35. doi:10.1111/j.1471-4159.2012.07670.x

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. McNamara JO, Scharfman HE (2012) Temporal lobe epilepsy and the BDNF receptor, TrkB. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds) Jasper’s basic mechanisms of the epilepsies. National Center for Biotechnology Information (US), Bethesda

    Google Scholar 

  102. Millichap J, Jones JD, Rudis BP (1964) Mechanism of anticonvulsant action of ketogenic diet: studies in animals with experimental seizures and in children with petit mal epilepsy. Am J Dis Child 107(6):593–604. doi:10.1001/archpedi.1964.02080060595008

    CAS  PubMed  Article  Google Scholar 

  103. Misiewicz Runyon A, So T-Y (2012) The use of ketogenic diet in pediatric patients with epilepsy. ISRN Pediatrics 2012:10. doi:10.5402/2012/263139

    Article  Google Scholar 

  104. Mitch WE, Medina R, Grieber S, May RC, England BK, Price SR, Bailey JL, Goldberg AL (1994) Metabolic acidosis stimulates muscle protein degradation by activating the adenosine triphosphate-dependent pathway involving ubiquitin and proteasomes. J Clin Invest 93(5):2127–2133

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Mo FM, Ballard HJ (2000) The effect of lactic acid on intracellular pH and adenosine output from superfused rat soleus muscle fibres. Life Sci 67(3):227–234. doi:10.1016/S0024-3205(00)00624-X

    CAS  PubMed  Article  Google Scholar 

  106. Moffett JR, Arun P, Ariyannur PS, Namboodiri AMA (2013) N-Acetylaspartate reductions in brain injury: impact on post-injury neuroenergetics, lipid synthesis, and protein acetylation. Front Neuroenergetics 5:11. doi:10.3389/fnene.2013.00011

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. Mueller SG, Trabesinger AH, Boesiger P, Wieser HG (2001) Brain glutathione levels in patients with epilepsy measured by in vivo (1)H-MRS. Neurology 57(8):1422–1427

    CAS  PubMed  Article  Google Scholar 

  108. Nakagawa Y (2004) Role of mitochondrial phospholipid hydroperoxide glutathione peroxidase (PHGPx) as an antiapoptotic factor. Biol Pharm Bull 27(7):956–960

    CAS  PubMed  Article  Google Scholar 

  109. Nyberg J, Åberg MAI, Torén K, Nilsson M, Ben-Menachem E, Kuhn HG (2013) Cardiovascular fitness and later risk of epilepsy: a Swedish population-based cohort study. Neurology 81(12):1051–1057. doi:10.1212/WNL.0b013e3182a4a4c0

    PubMed  Article  Google Scholar 

  110. Owen OE (2005) Ketone bodies as a fuel for the brain during starvation. Biochem Mol Biol Educ 33(4):246–251. doi:10.1002/bmb.2005.49403304246

    CAS  Article  Google Scholar 

  111. Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GF (1967) Brain metabolism during fasting. J Clin Invest 46(10):1589–1595

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. Pan JW, de Graaf RA, Petersen KF, Shulman GI, Hetherington HP, Rothman DL (2002) [2,4-13 C2]-beta-Hydroxybutyrate metabolism in human brain. J Cereb Blood Flow Metab 22(7):890–898

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Pellerin L, Magistretti PJ (1994) Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. P Natl Acad Sci USA 91(22):10625–10629. doi:10.1073/pnas.91.22.10625

    CAS  Article  Google Scholar 

  114. Pellerin L, Halestrap AP, Pierre K (2005) Cellular and subcellular distribution of monocarboxylate transporters in cultured brain cells and in the adult brain. J Neurosci Res 79(1–2):55–64. doi:10.1002/jnr.20307

    CAS  PubMed  Article  Google Scholar 

  115. Pellerin L, Bouzier-Sore A-K, Aubert A, Serres S, Merle M, Costalat R, Magistretti PJ (2007) Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia 55(12):1251–1262. doi:10.1002/glia.20528

    PubMed  Article  Google Scholar 

  116. Perlman BJ, Goldstein DB (1984) Membrane-disordering potency and anticonvulsant action of valproic acid and other short-chain fatty acids. Mol Pharmacol 26(1):83–89

    CAS  PubMed  Google Scholar 

  117. Pierce JMS (2002) A disease once sacred. A history of the medical understanding of epilepsy. Brain 125(2):441–442. doi:10.1093/brain/125.2.441

    Article  Google Scholar 

  118. Pierre K, Magistretti PJ, Pellerin L (2002) MCT2 is a major neuronal monocarboxylate transporter in the adult mouse brain. J Cereb Blood Flow Metab 22(5):586–595. doi:10.1097/00004647-200205000-00010

    CAS  PubMed  Article  Google Scholar 

  119. Pooya S, Liu X, Kumar VBS, Anderson J, Imai F, Zhang W, Ciraolo G, Ratner N, Setchell KDR, Yoshida Y, Jankowski MP, Dasgupta B (2014) The tumour suppressor LKB1 regulates myelination through mitochondrial metabolism. Nat Commun. doi:10.1038/ncomms5993

    PubMed  PubMed Central  Google Scholar 

  120. Prasad C, Rupar T, Prasad AN (2011) Pyruvate dehydrogenase deficiency and epilepsy. Brain Dev 33(10):856–865. doi:10.1016/j.braindev.2011.08.003

    PubMed  Article  Google Scholar 

  121. Puckett SW, Reddy WJ (1979) A decrease in the malate-aspartate shuttle and glutamate translocase activity in heart mitochondria from alloxan-diabetic rats. J Mol Cell Cardiol 11(2):173–187. doi:10.1016/0022-2828(79)90462-0

    CAS  PubMed  Article  Google Scholar 

  122. Rahman S (2012) Mitochondrial disease and epilepsy. Dev Med Child Neurol 54(5):397–406. doi:10.1111/j.1469-8749.2011.04214.x

    PubMed  Article  Google Scholar 

  123. Randle P, Garland P, Hales C, Newsholme E (1963) The glucose fatty-acid cycle its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 281(7285):785–789

    Article  Google Scholar 

  124. Rheims S, Holmgren CD, Chazal G, Mulder J, Harkany T, Zilberter T, Zilberter Y (2009) GABA action in immature neocortical neurons directly depends on the availability of ketone bodies. J Neurochem 110(4):1330–1338. doi:10.1111/j.1471-4159.2009.06230.x

    CAS  PubMed  Article  Google Scholar 

  125. Rho JM (2010) Another look at early GABAergic neurotransmission: maybe it’s not so exciting after all! Epilepsy Curr 10(5):128–130. doi:10.1111/j.1535-7511.2010.01378.x

    PubMed  PubMed Central  Article  Google Scholar 

  126. Ringholm S, Grunnet Knudsen J, Leick L, Lundgaard A, Munk Nielsen M, Pilegaard H (2013) PGC-1α is required for exercise- and exercise training-induced UCP1 up-regulation in mouse white adipose tissue. PLoS One 8(5):e64123. doi:10.1371/journal.pone.0064123

    PubMed  PubMed Central  Article  Google Scholar 

  127. Riss J, Cloyd J, Gates J, Collins S (2008) Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand 118(2):69–86. doi:10.1111/j.1600-0404.2008.01004.x

    CAS  PubMed  Article  Google Scholar 

  128. Rivera C, Li H, Thomas-Crusells J, Lahtinen H, Viitanen T, Nanobashvili A, Kokaia Z, Airaksinen MS, Voipio J, Kaila K, Saarma M (2002) BDNF-induced TrkB activation down-regulates the K(+)–Cl(−) cotransporter KCC2 and impairs neuronal Cl(−) extrusion. J Cell Biol 159(5):747–752. doi:10.1083/jcb.200209011

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Robinet C, Pellerin L (2010) Brain-derived neurotrophic factor enhances the expression of the monocarboxylate transporter 2 through translational activation in mouse cultured cortical neurons. J Cereb Blood Flow Metab 30(2):286–298. doi:10.1038/jcbfm.2009.208

    CAS  PubMed  Article  Google Scholar 

  130. Robinson AM, Williamson DH (1980) Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev 60(1):143–187

    CAS  PubMed  Google Scholar 

  131. Rolleston FS, Newsholme EA (1967) Effects of fatty acids, ketone bodies, lactate and pyruvate on glucose utilization by guinea-pig cerebral cortex slices. Biochem J 104(2):519–523

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. Rosen AS, David Andrew R (1991) Glucose concentration inversely alters neocortical slice excitability through an osmotic effect. Brain Res 555(1):58–64. doi:10.1016/0006-8993(91)90859-T

    CAS  PubMed  Article  Google Scholar 

  133. Sabatini S, Kurtzman NA (2009) Bicarbonate therapy in severe metabolic acidosis. J Am Soc Nephrol 20(4):692–695. doi:10.1681/asn.2007121329

    CAS  PubMed  Article  Google Scholar 

  134. Sakurai T, Ramoz N, Barreto M, Gazdoiu M, Takahashi N, Gertner M, Dorr N, Gama Sosa MA, De Gasperi R, Perez G, Schmeidler J, Mitropoulou V, Le HC, Lupu M, Hof PR, Elder GA, Buxbaum JD (2010) Slc25a12 disruption alters myelination and neurofilaments: a model for a hypomyelination syndrome and childhood neurodevelopmental disorders. Biol Psychiatry 67(9):887–894. doi:10.1016/j.biopsych.2009.08.042

    CAS  PubMed  Article  Google Scholar 

  135. Scharfman HE (2005) Brain-derived neurotrophic factor and epilepsy—a missing link? Epilepsy Curr 5(3):83–88. doi:10.1111/j.1535-7511.2005.05312.x

    PubMed  PubMed Central  Article  Google Scholar 

  136. Scharfman HE, Goodman JH, Sollas AL, Croll SD (2002) Spontaneous limbic seizures after intrahippocampal infusion of brain-derived neurotrophic factor. Exp Neurol 174(2):201–214. doi:10.1006/exnr.2002.7869

    CAS  PubMed  Article  Google Scholar 

  137. Schousboe A, Waagepetersen HS (2005) Role of astrocytes in glutamate homeostasis: implications for excitotoxicity. Neurotox Res 8(3):221–225. doi:10.1007/bf03033975

    CAS  PubMed  Article  Google Scholar 

  138. Schutkowski A, Wege N, Stangl GI, König B B (2014) Tissue-specific expression of monocarboxylate transporters during fasting in mice. PLoS One 9(11):e112118. doi:10.1371/journal.pone.0112118

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  139. Schwartzkroin PA (1999) Mechanisms underlying the anti-epileptic efficacy of the ketogenic diet. Epilepsy Res 37(3):171–180. doi:10.1016/S0920-1211(99)00069-8

    CAS  PubMed  Article  Google Scholar 

  140. Shimizu-Okabe C, Tanaka M, Matsuda K, Mihara T, Okabe A, Sato K, Inoue Y, Fujiwara T, Yagi K, Fukuda A (2011) KCC2 was downregulated in small neurons localized in epileptogenic human focal cortical dysplasia. Epilepsy Res 93(2–3):177–184. doi:10.1016/j.eplepsyres.2010.12.008

    CAS  PubMed  Article  Google Scholar 

  141. Siebel AM, Piato AL, Capiotti KM, Seibt KJ, Bogo MR, Bonan CD (2011) PTZ-induced seizures inhibit adenosine deamination in adult zebrafish brain membranes. Brain Res Bull 86(5–6):385–389. doi:10.1016/j.brainresbull.2011.08.017

    CAS  PubMed  Article  Google Scholar 

  142. Siebel AM, Piato AL, Schaefer IC, Nery LR, Bogo MR, Bonan CD (2013) Antiepileptic drugs prevent changes in adenosine deamination during acute seizure episodes in adult zebrafish. Pharmacol Biochem Behav 104:20–26. doi:10.1016/j.pbb.2012.12.021

    CAS  PubMed  Article  Google Scholar 

  143. Simard-Tremblay E, Berry P, Owens A, Cook WB, Sittner HR, Mazzanti M, Huber J, Warner M, Shurtleff H, Saneto RP (2015) High-fat diets and seizure control in myoclonic-astatic epilepsy: a single center’s experience. Seizure 25:184–186. doi:10.1016/j.seizure.2014.10.009

    PubMed  Article  Google Scholar 

  144. Simpson IA, Dwyer D, Malide D, Moley KH, Travis A, Vannucci SJ (2008) The facilitative glucose transporter GLUT3: 20 years of distinction. Am J Physiol Endocrinol Metab 295(2):E242–E253. doi:10.1152/ajpendo.90388.2008

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. Skolnick P, Syapin PJ, Paugh BA, Moncada V, Marangos PJ, Paul SM (1979) Inosine, an endogenous ligand of the brain benzodiazepine receptor, antagonizes pentylenetetrazole-evoked seizures. Proc Natl Acad Sci U S A 76(3):1515–1518

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. Sokoloff L (1973) Metabolism of ketone bodies by the brain. Annu Rev Med 24:271–280. doi:10.1146/annurev.me.24.020173.001415

    CAS  PubMed  Article  Google Scholar 

  147. Stafford P, Abdelwahab MG, Kim DY, Preul MC, Rho JM, Scheck AC (2010) The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutr Metab 7(1):1–11. doi:10.1186/1743-7075-7-74

    Article  CAS  Google Scholar 

  148. Stafstrom CE, Rho JM (2004) Epilepsy and the ketogenic diet., Nutrition and healthHumana Press, Totowa

    Google Scholar 

  149. Sullivan PG, Rippy NA, Dorenbos K, Concepcion RC, Agarwal AK, Rho JM (2004) The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann Neurol 55(4):576–580. doi:10.1002/ana.20062

    CAS  PubMed  Article  Google Scholar 

  150. Thiry A, Dogne JM, Supuran CT, Masereel B (2007) Carbonic anhydrase inhibitors as anticonvulsant agents. Curr Top Med Chem 7(9):855–864

    CAS  PubMed  Article  Google Scholar 

  151. Tieu K, Perier C, Caspersen C, Teismann P, Wu DC, Yan SD, Naini A, Vila M, Jackson-Lewis V, Ramasamy R, Przedborski S (2003) d-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J Clin Invest 112(6):892–901. doi:10.1172/jci18797

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. Uehara T, Sumiyoshi T, Matsuoka T, Tanaka K, Tsunoda M, Itoh H, Kurachi M (2005) Enhancement of lactate metabolism in the basolateral amygdala by physical and psychological stress: role of benzodiazepine receptors. Brain Res 1065(1–2):86–91. doi:10.1016/j.brainres.2005.10.035

    CAS  PubMed  Article  Google Scholar 

  153. Valle I, Álvarez-Barrientos A, Arza E, Lamas S, Monsalve M (2005) PGC-1α regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovasc Res 66(3):562–573

    CAS  PubMed  Article  Google Scholar 

  154. Vanderperre B, Herzig S, Krznar P, Hörl M, Ammar Z, Montessuit S, Pierredon S, Zamboni N, Martinou J-C (2016) Embryonic lethality of mitochondrial pyruvate carrier 1 deficient mouse can be rescued by a ketogenic diet. PLoS Genet 12(5):e1006056. doi:10.1371/journal.pgen.1006056

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  155. Vijay N, Morris ME (2014) Role of monocarboxylate transporters in drug delivery to the brain. Curr Pharm Des 20(10):1487–1498

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. Vilas GL, Johnson DE, Freund P, Casey JR (2009) Characterization of an epilepsy-associated variant of the human Cl/HCO3(−) exchanger AE3. Am J Physiol Cell Physiol 297(3):C526–C536. doi:10.1152/ajpcell.00572.2008

    CAS  PubMed  Article  Google Scholar 

  157. Vozza A, Parisi G, De Leonardis F, Lasorsa FM, Castegna A, Amorese D, Marmo R, Calcagnile VM, Palmieri L, Ricquier D, Paradies E, Scarcia P, Palmieri F, Bouillaud F, Fiermonte G (2014) UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation. Proc Natl Acad Sci U S A 111(3):960–965. doi:10.1073/pnas.1317400111

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. Waagepetersen HS, Bakken IJ, Larsson OM, Sonnewald U, Schousboe A (1998) Metabolism of lactate in cultured GABAergic neurons studied by 13C nuclear magnetic resonance spectroscopy. J Cereb Blood Flow Metab 18(1):109–117. doi:10.1097/00004647-199801000-00011

    CAS  PubMed  Article  Google Scholar 

  159. Wilson L, Yang Q, Szustakowski JD, Gullicksen PS, Halse R (2007) Pyruvate induces mitochondrial biogenesis by a PGC-1 α-independent mechanism. Am J Physiol Cell Physiol 292(5):C1599–C1605

    CAS  PubMed  Article  Google Scholar 

  160. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98(1):115–124. doi:10.1016/S0092-8674(00)80611-X

    CAS  PubMed  Article  Google Scholar 

  161. Wu GY, Fang YZ, Yang S, Lupton JR, Turner ND (2004) Glutathione metabolism and its implications for health. J Nutr 134(3):489–492

    CAS  PubMed  Google Scholar 

  162. Wu G (2013) Amino acids: biochemistry and nutrition. Taylor & Francis, Boca Raton

    Google Scholar 

  163. Wu GY (2016) Dietary protein intake and human health. Food Funct 7(3):1251–1265. doi:10.1039/c5fo01530h

    CAS  PubMed  Article  Google Scholar 

  164. Wu GY, Wu ZL, Dai ZL, Yang Y, Wang WW, Liu C, Wang B, Wang JJ, Yin YL (2013) Dietary requirements of “nutritionally non-essential amino acids” by animals and humans. Amino Acids 44(4):1107–1113. doi:10.1007/s00726-012-1444-2

    CAS  PubMed  Article  Google Scholar 

  165. Xu B, Michalski B, Racine RJ, Fahnestock M (2004) The effects of brain-derived neurotrophic factor (BDNF) administration on kindling induction, Trk expression and seizure-related morphological changes. Neuroscience 126(3):521–531. doi:10.1016/j.neuroscience.2004.03.044

    CAS  PubMed  Article  Google Scholar 

  166. Yoboue ED, Augier E, Galinier A, Blancard C, Pinson B, Casteilla L, Rigoulet M, Devin A (2012) cAMP-induced mitochondrial compartment biogenesis: role of glutathione redox state. J Biol Chem 287(18):14569–14578. doi:10.1074/jbc.M111.302786

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. Yoboue ED, Mougeolle A, Kaiser L, Averet N, Rigoulet M, Devin A (2014) The role of mitochondrial biogenesis and ROS in the control of energy supply in proliferating cells. Bba-Bioenergetics 1837(7):1093–1098. doi:10.1016/j.bbabio.2014.02.023

    CAS  PubMed  Article  Google Scholar 

  168. Yudkoff M, Daikhin Y, Nissim I, Lazarow A, Nissim I (2001) Brain amino acid metabolism and ketosis. J Neurosci Res 66(2):272–281

    CAS  PubMed  Article  Google Scholar 

  169. Yudkoff M, Daikhin Y, Horyn O, Nissim I, Nissim I (2008) Ketosis and brain handling of glutamate, glutamine and GABA. Epilepsia 49(Suppl 8):73–75. doi:10.1111/j.1528-1167.2008.01841.x

    PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgments

Ryan Clanton was supported by the National Space Biomedical Research Institute funded Mentored Research Fellowship in Space Life Sciences (NASA NCC 9-58). This work was supported by U. S. Public Health Service Grant GM58770 to R.A.

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Clanton, R.M., Wu, G., Akabani, G. et al. Control of seizures by ketogenic diet-induced modulation of metabolic pathways. Amino Acids 49, 1–20 (2017). https://doi.org/10.1007/s00726-016-2336-7

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Keywords

  • Epilepsy
  • Ketogenic diet
  • Hypomyelination
  • Malate-aspartate shuttle
  • Ketone bodies
  • Mitochondrial disorders
  • Short chain fatty acids
  • Medium chain fatty acids
  • Monocarboxylic acid transporters