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

Mireia Garriga-Canut; Barry Schoenike; Romena Qazi; Karen Bergendahl; Timothy J. Daley; Rebecca M. Pfender; John F. Morrison; Jeffrey Ockuly; Carl Stafstrom; Thomas Sutula; Avtar Roopra

doi:10.1038/nn1791

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

Mireia Garriga-Canut, Barry Schoenike, Romena Qazi, Karen Bergendahl, Timothy J. Daley, Rebecca M. Pfender, John F. Morrison, Jeffrey Ockuly, Carl Stafstrom, Thomas Sutula, Avtar Roopra

Research output: Contribution to journal › Article › peer-review

314 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1382-1387
Number of pages	6
Journal	Nature neuroscience
Volume	9
Issue number	11
DOIs	https://doi.org/10.1038/nn1791
State	Published - Nov 2006
Externally published	Yes

ASJC Scopus subject areas

General Neuroscience

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title = "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.",

author = "Mireia Garriga-Canut and Barry Schoenike and Romena Qazi and Karen Bergendahl and Daley, {Timothy J.} and Pfender, {Rebecca M.} and Morrison, {John F.} and Jeffrey Ockuly and Carl Stafstrom and Thomas Sutula and Avtar Roopra",

note = "Funding Information: 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.",

year = "2006",

month = nov,

doi = "10.1038/nn1791",

language = "English (US)",

volume = "9",

pages = "1382--1387",

journal = "Nature neuroscience",

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T1 - 2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure

AU - Garriga-Canut, Mireia

AU - Schoenike, Barry

AU - Qazi, Romena

AU - Bergendahl, Karen

AU - Daley, Timothy J.

AU - Pfender, Rebecca M.

AU - Morrison, John F.

AU - Ockuly, Jeffrey

AU - Stafstrom, Carl

AU - Sutula, Thomas

AU - Roopra, Avtar

N1 - Funding Information: 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.

PY - 2006/11

Y1 - 2006/11

N2 - 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.

AB - 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.

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

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