1. 2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure.
- Author
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Garriga-Canut M, Schoenike B, Qazi R, Bergendahl K, Daley TJ, Pfender RM, Morrison JF, Ockuly J, Stafstrom C, Sutula T, and Roopra A
- Subjects
- Alcohol Oxidoreductases genetics, Animals, Chromatin drug effects, DNA-Binding Proteins genetics, Diet, Disease Progression, Down-Regulation drug effects, Energy Metabolism physiology, Epilepsy diet therapy, 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, Transcription Factors genetics, Alcohol Oxidoreductases physiology, Antimetabolites pharmacology, Chromatin physiology, DNA-Binding Proteins physiology, Deoxyglucose pharmacology, Epilepsy drug therapy, Epilepsy metabolism, Repressor Proteins physiology, Transcription Factors physiology
- 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.
- Published
- 2006
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