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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alcohol Oxidoreductases / genetics
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Alcohol Oxidoreductases / physiology*
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Animals
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Antimetabolites / pharmacology*
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Chromatin / drug effects
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Chromatin / physiology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Deoxyglucose / pharmacology*
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Diet
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Disease Progression
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Down-Regulation / drug effects
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Energy Metabolism / physiology
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Epilepsy / diet therapy
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Epilepsy / drug therapy*
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Epilepsy / metabolism*
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Gene Expression / drug effects
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Glycolysis / drug effects
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Glycolysis / physiology
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Hippocampus / drug effects
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Hippocampus / metabolism
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Kindling, Neurologic / physiology
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NAD / physiology
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Neuronal Plasticity / drug effects
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Rats
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Receptor, trkB / biosynthesis
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Receptor, trkB / genetics
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Repressor Proteins / genetics
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Repressor Proteins / physiology*
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Transcription Factors / genetics
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Transcription Factors / physiology*
Substances
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Antimetabolites
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Chromatin
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DNA-Binding Proteins
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RE1-silencing transcription factor
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Repressor Proteins
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Transcription Factors
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NAD
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Deoxyglucose
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Alcohol Oxidoreductases
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C-terminal binding protein
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Receptor, trkB