2-Deoxy-D-glucose Reduces Epilepsy Progression by NRSF-CtBP-dependent Metabolic Regulation of Chromatin Structure

Nat Neurosci. 2006 Nov;9(11):1382-7. doi: 10.1038/nn1791. Epub 2006 Oct 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Oxidoreductases / genetics
  • Alcohol Oxidoreductases / physiology*
  • Animals
  • Antimetabolites / pharmacology*
  • Chromatin / drug effects
  • Chromatin / physiology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Deoxyglucose / pharmacology*
  • Diet
  • Disease Progression
  • Down-Regulation / drug effects
  • Energy Metabolism / physiology
  • Epilepsy / diet therapy
  • Epilepsy / drug therapy*
  • Epilepsy / metabolism*
  • Gene Expression / drug effects
  • Glycolysis / drug effects
  • Glycolysis / physiology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Kindling, Neurologic / physiology
  • NAD / physiology
  • Neuronal Plasticity / drug effects
  • Rats
  • Receptor, trkB / biosynthesis
  • Receptor, trkB / genetics
  • Repressor Proteins / genetics
  • Repressor Proteins / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / physiology*

Substances

  • Antimetabolites
  • Chromatin
  • DNA-Binding Proteins
  • RE1-silencing transcription factor
  • Repressor Proteins
  • Transcription Factors
  • NAD
  • Deoxyglucose
  • Alcohol Oxidoreductases
  • C-terminal binding protein
  • Receptor, trkB