2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure.
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.
Garriga-Canut
Mireia
M
Department of Neurology, Medical Science Center, Room 1715, University of Wisconsin-Madison, 1300 University Avenue, Madison, Wisconsin 53706, USA.
Schoenike
Barry
B
Qazi
Romena
R
Bergendahl
Karen
K
Daley
Timothy J
TJ
Pfender
Rebecca M
RM
Morrison
John F
JF
Ockuly
Jeffrey
J
Stafstrom
Carl
C
Sutula
Thomas
T
Roopra
Avtar
A
D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D002843:Chromatin / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D003847:Deoxyglucose / Q000494:pharmacology*; D004032:Diet; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D004734:Energy Metabolism / Q000502:physiology; D004827:Epilepsy / Q000178:diet therapy / Q000188:drug therapy* / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007696:Kindling, Neurologic / Q000502:physiology; D009243:NAD / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects; D051381:Rats; D020813:Receptor, trkB / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000099229:RE1-Silencing Transcription Factor
D000429:Alcohol Oxidoreductases; D000963:Antimetabolites; D002843:Chromatin; D004268:DNA-Binding Proteins; D003847:Deoxyglucose; D009243:NAD; D020813:Receptor, trkB; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C096794:C-terminal binding protein