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.

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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.

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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

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)

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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

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