Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP–dependent metabolic regulation of chromatin structure

Abstract

Temporal lobe epilepsy is a common form of drug-resistant epilepsy that sometimes responds to dietary manipulation such as the 'ketogenic diet'. Here we have investigated the effects of the glycolytic inhibitor 2-deoxy-D-glucose (2DG) in the rat kindling model of temporal lobe epilepsy. We show that 2DG potently reduces the progression of kindling and blocks seizure-induced increases in the expression of brain-derived neurotrophic factor and its receptor, TrkB. This reduced expression is mediated by the transcription factor NRSF, which recruits the NADH-binding co-repressor CtBP to generate a repressive chromatin environment around the BDNF promoter. Our results show that 2DG has anticonvulsant and antiepileptic properties, suggesting that anti-glycolytic compounds may represent a new class of drugs for treating epilepsy. The metabolic regulation of neuronal genes by CtBP will open avenues of therapy for neurological disorders and cancer.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Glycolytic inhibition abrogates epileptogenesis in vivo.
Figure 2: Glycolytic inhibition generates repressive chromatin over the NRSE in vivo.
Figure 3: NRSF repression is regulated by metabolism.
Figure 4: CtBP confers metabolic regulation on NRSF.
Figure 5: NRSF and CtBP interact in vivo.

Similar content being viewed by others

References

  1. Sinha, S.R. & Kossoff, E.H. The ketogenic diet. Neurologist 11, 161–170 (2005).

    Article  PubMed  Google Scholar 

  2. Gowers, W.R. Epilepsy and Other Chronic Convulsive Diseases (Churchill, London, 1881).

    Google Scholar 

  3. Sutula, T.P. Mechanisms of epilepsy progression: current theories and perspectives from neuroplasticity in adulthood and development. Epilepsy Res. 60, 161–171 (2004).

    Article  PubMed  Google Scholar 

  4. He, X.P. et al. Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model. Neuron 43, 31–42 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Maue, R.A., Kraner, S.D., Goodman, R.H. & Mandel, G. Neuron-specific expression of the rat brain type II sodium channel gene is directed by upstream regulatory elements. Neuron 4, 223–231 (1990).

    Article  CAS  PubMed  Google Scholar 

  6. Mori, N., Stein, R., Sigmund, O. & Anderson, D.J. A cell type-preferred silencer element that controls the neural-specific expression of the SCG10 gene. Neuron 4, 583–594 (1990).

    Article  CAS  PubMed  Google Scholar 

  7. Bruce, A.W. et al. Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes. Proc. Natl. Acad. Sci. USA 101, 10458–10463 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Roopra, A., Huang, Y. & Dingledine, R. Neurological disease: listening to gene silencers. Mol. Interv. 1, 219–228 (2001).

    CAS  PubMed  Google Scholar 

  9. Roopra, A. et al. Transcriptional repression by neuron-restrictive silencer factor is mediated via the Sin3-histone deacetylase complex. Mol. Cell. Biol. 20, 2147–2157 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Huang, Y., Myers, S.J. & Dingledine, R. Transcriptional repression by REST: recruitment of Sin3A and histone deacetylase to neuronal genes. Nat. Neurosci. 2, 867–872 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Grimes, J.A. et al. The co-repressor mSin3A is a functional component of the REST-CoREST repressor complex. J. Biol. Chem. 275, 9461–9467 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Andres, M.E. et al. CoREST: a functional corepressor required for regulation of neural-specific gene expression. Proc. Natl. Acad. Sci. USA 96, 9873–9878 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Battaglioli, E. et al. REST repression of neuronal genes requires components of the hSWI.SNF complex. J. Biol. Chem. 277, 41038–41045 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Roopra, A., Qazi, R., Schoenike, B., Daley, T.J. & Morrison, J.F. Localized domains of G9a-mediated histone methylation are required for silencing of neuronal genes. Mol. Cell 14, 727–738 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Luger, K., Mader, A.W., Richmond, R.K., Sargent, D.F. & Richmond, T.J. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389, 251–260 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Strahl, B.D. & Allis, C.D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Peterson, C.L. ATP-dependent chromatin remodeling: going mobile. FEBS Lett. 476, 68–72 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Guarente, L. & Picard, F. Calorie restriction—the SIR2 connection. Cell 120, 473–482 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Zhang, Q., Piston, D.W. & Goodman, R.H. Regulation of corepressor function by nuclear NADH. Science 295, 1895–1897 (2002).

    CAS  PubMed  Google Scholar 

  20. Timmusk, T. & Metsis, M. Regulation of BDNF promoters in the rat hippocampus. Neurochem. Int. 25, 11–15 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Ballas, N., Grunseich, C., Lu, D.D., Speh, J.C. & Mandel, G. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121, 645–657 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Belyaev, N.D. et al. Distinct RE1 silencing transcription factor (REST)-containing complexes interact with different target genes. J. Biol. Chem. 279, 556–561 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Wood, I.C. et al. Interaction of the repressor element 1–silencing transcription factor (REST) with target genes. J. Mol. Biol. 334, 863–874 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Stryer, L. Biochemistry (W.H. Freeman and Co., New York, 2002).

    Google Scholar 

  25. Mirnezami, A.H. et al. Hdm2 recruits a hypoxia-sensitive corepressor to negatively regulate p53-dependent transcription. Curr. Biol. 13, 1234–1239 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Kim, J.H., Cho, E.J., Kim, S.T. & Youn, H.D. CtBP represses p300-mediated transcriptional activation by direct association with its bromodomain. Nat. Struct. Mol. Biol. 12, 423–428 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Wick, A.N., Drury, D.R. & Morita, T.N. 2-Deoxyglucose: a metabolic block for glucose. Proc. Soc. Exp. Biol. Med. 89, 579–582 (1955).

    Article  CAS  PubMed  Google Scholar 

  28. Chandramouli, V. & Carter, J.R., Jr. Metabolic effects of 2-deoxy-D-glucose in isolated fat cells. Biochim. Biophys. Acta 496, 278–291 (1977).

    Article  CAS  PubMed  Google Scholar 

  29. Kokaia, M. et al. Suppressed epileptogenesis in BDNF mutant mice. Exp. Neurol. 133, 215–224 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Golarai, G. & Sutula, T.P. Functional alterations in the dentate gyrus after induction of long-term potentiation, kindling, and mossy fiber sprouting. J. Neurophysiol. 75, 343–353 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Scharfman, H.E. Hyperexcitability in combined entorhinal/hippocampal slices of adult rat after exposure to brain-derived neurotrophic factor. J. Neurophysiol. 78, 1082–1095 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Conner, J.M., Lauterborn, J.C., Yan, Q., Gall, C.M. & Varon, S. Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J. Neurosci. 17, 2295–2313 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yan, Q. et al. Expression of brain-derived neurotrophic factor protein in the adult rat central nervous system. Neuroscience 78, 431–448 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Binder, D.K., Routbort, M.J. & McNamara, J.O. Immunohistochemical evidence of seizure-induced activation of trk receptors in the mossy fiber pathway of adult rat hippocampus. J. Neurosci. 19, 4616–4626 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Koyama, R. et al. Brain-derived neurotrophic factor induces hyperexcitable reentrant circuits in the dentate gyrus. J. Neurosci. 24, 7215–7224 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Scharfman, H.E., Goodman, J.H. & Sollas, A.L. Actions of brain-derived neurotrophic factor in slices from rats with spontaneous seizures and mossy fiber sprouting in the dentate gyrus. J. Neurosci. 19, 5619–5631 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Binder, D.K., Croll, S.D., Gall, C.M. & Scharfman, H.E. BDNF and epilepsy: too much of a good thing? Trends Neurosci 24, 47–53 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Lahteinen, S. et al. Decreased BDNF signalling in transgenic mice reduces epileptogenesis. Eur. J. Neurosci. 15, 721–734 (2002).

    Article  PubMed  Google Scholar 

  39. Stafstrom, C.E. Dietary approaches to epilepsy treatment: old and new options on the menu. Epilepsy Curr. 4, 215–222 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Murray, K.D. et al. Altered mRNA expression for brain-derived neurotrophic factor and type II calcium/calmodulin-dependent protein kinase in the hippocampus of patients with intractable temporal lobe epilepsy. J. Comp. Neurol. 418, 411–422 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Mohanti, B.K. et al. Improving cancer radiotherapy with 2-deoxy-D-glucose: phase I/II clinical trials on human cerebral gliomas. Int. J. Radiat. Oncol. Biol. Phys. 35, 103–111 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Imai, S., Armstrong, C.M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011–2015 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Douma, S. et al. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 430, 1034–1039 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Pearse, R.N., Swendeman, S.L., Li, Y., Rafii, D. & Hempstead, B.L. A neurotrophin axis in myeloma: TrkB and BDNF promote tumor-cell survival. Blood 105, 4429–4436 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Warburg, O. The Metabolism of Tumors (Arnold Constable, London, 1930).

    Google Scholar 

  47. Mazumdar, A. et al. Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nat. Cell Biol. 3, 30–37 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Westbrook, T.F. et al. A genetic screen for candidate tumor suppressors identifies REST. Cell 121, 837–848 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Sutula, T. & Steward, O. Quantitative analysis of synaptic potentiation during kindling of the perforant path. J. Neurophysiol. 56, 732–746 (1986).

    Article  CAS  PubMed  Google Scholar 

  50. Sayin, U., Osting, S., Hagen, J., Rutecki, P. & Sutula, T. Spontaneous seizures and loss of axo-axonic and axo-somatic inhibition induced by repeated brief seizures in kindled rats. J. Neurosci. 23, 2759–2768 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank J. Hildebrand for the KT3-CtBP2 expression plasmid and CtBP mutant MEFs; J. Blaydes for the CtBP(G189) mutant construct; and C. Alexander for discussion and critically reading the manuscript. This work was supported by grants from the Epilepsy Foundation (to A.R.) and the National Institutes of Health (RO1 25020 to T.S.), and by the Department of Neurology.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Avtar Roopra.

Ethics declarations

Competing interests

A.R., T.S., C.S. and B.S. are inventors in applications submitted by the Wisconsin Alumni Research Foundation (WARF) for therapeutic use of 2-deoxy-D-glucose.

T.S. has an equity interest in Neurogenomex, Inc., which has a license from WARF for therapeutic development of 2-deoxy- D-glucose.

Supplementary information

Supplementary Fig. 1

Prior to assessing the effects of 2DG on kindling, we sought to determine whether administration of 2DG resulted in gene expression changes indicative of reduced glycolysis in the hippocampus. (PDF 46 kb)

Supplementary Fig. 2

Hippocampii from rats treated with saline or 250mg/kg 2DG for 2 weeks were harvested and protein extracted using IP buffer. (PDF 54 kb)

Supplementary Fig. 3

The TrkB possesses a functional NRSE. The TrkB NRSE functions in reporter assays. The chromosomal TrkB gene is repressed by NRSF. (PDF 56 kb)

Supplementary Fig. 4

Repression of chromosomal NRSF target genes JTC-19 cells is augmented by 2DG. (PDF 62 kb)

Supplementary Fig. 5

Wild type MEFs or MEFs heterozygous for both CtBP1 and CtBP2 (CtBP1−/+2−/+) or homozygous for both CtBP1 and CtBP2 (CtBP1−/−2−/−) grown in the absence or presence of 1mM 2DG were analysed for CHRM4 and HPRT expression by QRT-PCR. (PDF 32 kb)

Supplementary Fig. 6

Animal handling and kindling. (PDF 27 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Garriga-Canut, M., Schoenike, B., Qazi, R. et al. 2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP–dependent metabolic regulation of chromatin structure. Nat Neurosci 9, 1382–1387 (2006). https://doi.org/10.1038/nn1791

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1791

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing