Skip to main content

Advertisement

SpringerLink
Log in

The Emerging Role of Epigenetics on Dietary Treatment for Epilepsy

  • Genetics (GVZ Dedoussis, Section Editor)
  • Published:
Current Nutrition Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Seizures are able to induce a wide range of complex alterations that may be due to abnormalities in gene expression patterns. In recent years, there has been resurgence regarding the use of dietary therapies for seizure treatment. Unfortunately, the precise mechanisms by which these therapies exert its effects remain unknown.

Recent Findings

Recent evidence suggest that dietary treatment, throughout a metabolic shift, could impact the concentration of some metabolites, such as beta-hydroxybutyrate (B-HB) or S-adenosyl methionine (SAM), which are able to modulate the activity of enzymes involved in regulatory processes that control gene expression. Despite of this evidence, only a few studies have fully explored this emerging field.

Summary

The purpose of this article is to discuss how dietary treatment, throughout these molecules, could influence epigenetic modifications that may be able to restore aberrant patterns of gene expression produced by seizures, having an impact on this complex disease, such as seizures or even in epileptogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Loscher W, Klitgaard H, Twyman RE, Schmidt D. New avenues for anti-epileptic drug discovery and development. Nat Rev Drug Discov. 2013;12(10):757–76.

    Article  PubMed  Google Scholar 

  2. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475–82.

    Article  PubMed  Google Scholar 

  3. Huberfeld G, Vecht CJ. Seizures and gliomas towards a single therapeutic approach. Nat Rev Neurol. 2016;12(4):204–16.

    Article  PubMed  Google Scholar 

  4. Kossoff EH, Nabbout R. Use of dietary therapy for status epilepticus. J Child Neurol. 2013;28(8):1049–51.

    Article  PubMed  Google Scholar 

  5. Hartman AL, Rubenstein JE, Kossoff EH. Intermittent fasting: a “new” historical strategy for controlling seizures? Epilepsy Res. 2013;104(3):275–9.

    Article  PubMed  Google Scholar 

  6. Bough KJ, Rho JM. Anticonvulsant mechanisms of the ketogenic diet. Epilepsia. 2007;48(1):43–58.

    Article  CAS  PubMed  Google Scholar 

  7. Sassone-Corsi P. When metabolism and epigenetics converge. Science. 2013;339(6116):148–50.

    Article  CAS  PubMed  Google Scholar 

  8. Landgrave-Gómez J, Mercado-Gómez OF, Guevara-Guzman R. Epigenetic mechanisms in neurological and neurodegenerative diseases. Front Cell Neurosci. 2015;9:58.

    PubMed  PubMed Central  Google Scholar 

  9. Roopra A, Dingledine R, Hsieh J. Epigenetics and epilepsy. Epilepsia. 2012;53:2–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lubin FD. Epileptogenesis: can the science of epigenetics give us answers? Epilepsy Currents. 2012;12(3):105–10.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bough KJ, Schwartzkroin PA, Rho JM. Calorie restriction and ketogenic diet diminish neuronal excitability in rat dentate gyrus in vivo. Epilepsia. 2003;44(6):752–60.

    Article  PubMed  Google Scholar 

  12. Gano LB, Patel M, Rho JM. Ketogenic diets, mitochondria, and neurological diseases. J Lipid Res. 2014;55(11):2211–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lutas A, Yellen G. The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci. 2013;36(1):32–40.

    Article  CAS  PubMed  Google Scholar 

  14. Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab. 2014;25(1):42–52.

    Article  CAS  PubMed  Google Scholar 

  15. Yuen AWC, Sander JW. Rationale for using intermittent calorie restriction as a dietary treatment for drug resistant epilepsy. Epilepsy Behav. 2014;33:110–4.

    Article  PubMed  Google Scholar 

  16. Longo Valter D, Mattson Mark P. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014;19(2):181–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wheless JW. History of the ketogenic diet. Epilepsia. 2008;49:3–5.

    Article  PubMed  Google Scholar 

  18. Chaix A, Zarrinpar A, Miu P, Panda S. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab. 2014;20(6):991–1005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. • Landgrave-Gómez J, Mercado-Gómez OF, Vázquez-García M, Rodríguez-Molina V, Córdova-Dávalos L, Arriaga-Ávila V, et al. Anticonvulsant effect of time-restricted feeding in a pilocarpine-induced seizure model: Metabolic and epigenetic implications. Front Cell Neurosci. 2016;10. This work shows a correlation between the concentration of B-HB and seizure amelioration in a murine model of acute seizures; moreover, they suggest that the beneficial effect of this diet is mediated via inhibition of HDACs.

  20. Mattson MP, Allison DB, Fontana L, Harvie M, Longo VD, Malaisse WJ, et al. Meal frequency and timing in health and disease. Proc Natl Acad Sci. 2014;111(47):16647–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, et al. Time restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high fat diet. Cell Metab. 2012;15(6):848–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  23. Mattson MP. Challenging oneself intermittently to improve health. Dose-Response. 2014;12(4):600–18.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Juge N, Gray JA, Omote H, Miyaji T, Inoue T, Hara C, et al. Metabolic control of vesicular glutamate transport and release. Neuron. 2010;68(1):99–112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yudkoff M, Daikhin Y, Horyn O, Nissim I, Nissim I. Ketosis and brain handling of glutamate, glutamine and GABA. Epilepsia. 2008;49 Suppl 8:73–5.

    Article  PubMed  PubMed Central  Google Scholar 

  26. • Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science (New York, NY). 2013;339(6116):211–4. This article describes B-HB as the first endogenous inhibitor of HDACs.

    Article  CAS  Google Scholar 

  27. Mercado-Gómez O, Landgrave-Gómez J, Arriaga-Avila V, Nebreda-Corona A, Guevara-Guzmán R. Role of TGF-β signaling pathway on Tenascin C protein upregulation in a pilocarpine seizure model. Epilepsy Res. 2014;108(10):1694–704.

    Article  PubMed  Google Scholar 

  28. Heck N, Garwood J, Loeffler JP, Larmet Y, Faissner A. Differential upregulation of extracellular matrix molecules associated with the appearance of granule cell dispersion and mossy fiber sprouting during epileptogenesis in a murine model of temporal lobe epilepsy. Neuroscience. 2004;129(2):309–24.

    Article  CAS  PubMed  Google Scholar 

  29. Huttenlocher PR. Ketonemia and seizures: metabolic and anticonvulsant effects of two ketogenic diets in childhood epilepsy. Pediatr Res. 1976;10(5):536–40.

    Article  CAS  PubMed  Google Scholar 

  30. Waldbaum S, Patel M. Mitochondrial dysfunction and oxidative stress: a contributing link to acquired epilepsy? J Bioenerg Biomembr. 2010;42(6):449–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nei M, Ngo L, Sirven JI, Sperling MR. Ketogenic diet in adolescents and adults with epilepsy. Seizure. 2014;23(6):439–42.

    Article  PubMed  Google Scholar 

  32. Rho J, Stafstrom C. The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol. 2012;3(59).

  33. Kobow K, El-Osta A, Blümcke I. The methylation hypothesis of pharmacoresistance in epilepsy. Epilepsia. 2013;54:41–7.

    Article  CAS  PubMed  Google Scholar 

  34. Schoeler NE, Cross JH, Sander JW, Sisodiya SM. Can we predict a favourable response to ketogenic diet therapies for drug-resistant epilepsy? Epilepsy Res. 2013;106(1–2):1–16.

    Article  PubMed  Google Scholar 

  35. Kobow K, Jeske I, Hildebrandt M, Hauke J, Hahnen E, Buslei R, et al. Increased reelin promoter methylation is associated with granule cell dispersion in human temporal lobe epilepsy. J Neuropathol Exp Neurol. 2009;68(4):356–64.

    Article  CAS  PubMed  Google Scholar 

  36. • Kobow K, Kaspi A, Harikrishnan KN, Kiese K, Ziemann M, Khurana I, et al. Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. Acta Neuropathol. 2013;126(5):741–56. This work shows an aberrant increase in genome-wide DNA methylation patterns in a chronic model of epilepsy in rats suggesting strongly that DNA hypermethylation is a molecular pathological mechanism event in chronic epilepsy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mentch SJ, Locasale JW. One-carbon metabolism and epigenetics: understanding the specificity. Ann N Y Acad Sci. 2016;1363(1):91–8.

    Article  CAS  PubMed  Google Scholar 

  38. Cantoni GL. S-adenosylmethionine; a new intermediate formed enzymatically from L-methionine and adenosinetriphosphate. J Biol Chem. 1953;204(1):403–16.

    CAS  Google Scholar 

  39. Zhu Q, Wang L, Zhang Y, Zhao F-h, Luo J, Xiao Z, et al. Increased expression of DNA methyltransferase 1 and 3a in human temporal lobe epilepsy. J Mol Neurosci. 2012;46(2):420–6.

    Article  CAS  PubMed  Google Scholar 

  40. Phillips-Farfan BV, Rubio Osornio MC, Custodio Ramírez V, Paz Tres C, Carvajal KG. Caloric restriction protects against electrical kindling of the amygdala by inhibiting the mTOR signaling pathway. Front Cell Neurosci. 2015;9:90.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Hallböök T, Köhler S, Rosén I, Lundgren J. Effects of ketogenic diet on epileptiform activity in children with therapy resistant epilepsy. Epilepsy Res. 2007;77(2–3):134–40.

    Article  PubMed  Google Scholar 

  42. Julio-Amilpas A, Montiel T, Soto-Tinoco E, Gerónimo-Olvera C, Massieu L. Protection of hypoglycemia-induced neuronal death by β-hydroxybutyrate involves the preservation of energy levels and decreased production of reactive oxygen species. J Cereb Blood Flow Metab. 2015;35(5):851–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Netzahualcoyotzi C, Tapia R. Energy substrates protect hippocampus against endogenous glutamate-mediated neurodegeneration in awake rats. Neurochem Res. 2014;39(7):1346–54.

    Article  CAS  PubMed  Google Scholar 

  44. Camberos-Luna L, Gerónimo-Olvera C, Montiel T, Rincon-Heredia R, Massieu L. The ketone body, β-hydroxybutyrate stimulates the autophagic flux and prevents neuronal death induced by glucose deprivation in cortical cultured neurons. Neurochem Res. 2015;41(3):600–9.

    Article  PubMed  Google Scholar 

  45. Youm Y-H, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite [beta]-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21(3):263–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. • Xie Z, Zhang D, Chung D, Tang Z, Huang H, Dai L, et al. Metabolic Regulation of Gene Expression by Histone Lysine Beta-Hydroxybutyrylation. Mol Cell. 62(2):194–206. This work shows beta-hydroxybutyrylation as new posttranslational modification of histones.

  47. de la Haba G, Cantoni GL. The enzymatic synthesis of S-adenosyl-l-homocysteine from adenosine and homocysteine. J Biol Chem. 1959;234(3):603–8.

    Google Scholar 

  48. Miller-Delaney SFC, Das S, Sano T, Jimenez-Mateos EM, Bryan K, Buckley PG, et al. Differential DNA methylation patterns define status epilepticus and epileptic tolerance. J Neurosci. 2012;32(5):1577–88.

    Article  CAS  PubMed  Google Scholar 

  49. • Wang L, Fu X, Peng X, Xiao Z, Li Z, Chen G, et al. DNA methylation profiling reveals correlation of differential methylation patterns with gene expression in human epilepsy. J Mol Neurosci. 2016;59(1):68–77. This works shows for the first time that global aberrant methylation present in epilepsy correlates with gene expression in human epilepsy.

    Article  CAS  PubMed  Google Scholar 

  50. Li T, Ren G, Lusardi T, Wilz A, Lan JQ, Iwasato T, et al. Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice. J Clin Invest. 2008;118(2):571–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Boison D. The biochemistry and epigenetics of epilepsy: focus on adenosine and glycine. Front Mol Neurosci. 2016;9:26.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Shen H-Y, van Vliet Erwin A, Bright K-A, Hanthorn M, Lytle NK, Gorter J, et al. Glycine transporter 1 is a target for the treatment of epilepsy. Neuropharmacology. 2015;99:554–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Williams-Karnesky RL, Sandau US, Lusardi TA, Lytle NK, Farrell JM, Pritchard EM, et al. Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J Clin Invest.123(8):3552–63.

  54. van Praag H, Fleshner M, Schwartz MW, Mattson MP. Exercise, energy intake, glucose homeostasis, and the brain. J Neurosci. 2014;34(46):15139–49.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Shyh-Chang N, Locasale JW, Lyssiotis CA, Zheng Y, Teo RY, Ratanasirintrawoot S, et al. Influence of threonine metabolism on S-adenosyl-methionine and histone methylation. Science (New York, NY). 2013;339(6116):222–6.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, 70250, 04510, Mexico, DF, Mexico

    Jorge Landgrave-Gómez, Octavio Fabian Mercado-Gómez & Rosalinda Guevara-Guzmán

  2. Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia

    Jorge Landgrave-Gómez & Fernanda Vargas-Romero

  3. Instituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México, 04510, Mexico, DF, Mexico

    Fernanda Vargas-Romero

Authors
  1. Jorge Landgrave-Gómez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fernanda Vargas-Romero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Octavio Fabian Mercado-Gómez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rosalinda Guevara-Guzmán
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rosalinda Guevara-Guzmán.

Ethics declarations

Conflict of Interest

Jorge Landgrave-Gómez Jorge, Fernanda Vargas-Romero, Octavio Fabian Mercado-Gómez, and Rosalinda Guevara-Guzmán declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Genetics

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Landgrave-Gómez, J., Vargas-Romero, F., Mercado-Gómez, O.F. et al. The Emerging Role of Epigenetics on Dietary Treatment for Epilepsy. Curr Nutr Rep 6, 9–15 (2017). https://doi.org/10.1007/s13668-017-0189-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13668-017-0189-7

Keywords

Search

Navigation