Commentary Cellscience Reviews Vol 3 No 3 ISSN 1742-8130

Inhibition of glycolysis: a new strategy for treating epilepsy?

The ketogenic diet (KD) is a remarkably effective treatment for medically refractory epilepsy, but the mechanisms underlying such clinical efficacy are unknown. Patients treated with the KD exhibit modestly reduced serum glucose levels, suggesting that decreased glycolytic flux may play a role in seizure control. In support of this, Garriga-Canut et al. (2006) found that 2-deoxyglucose (2-DG) - an inhibitor of phosphoglucose isomerase - potently inhibited seizure progression in the rat kindling model of temporal lobe epilepsy. They provide compelling evidence that 2-DG decreases the expression of brain-derived neurotrophic factor (BDNF) and its principal receptor, TrkB, via induction of the transcription factor NRSF (neuron restrictive silencing factor), a master negative regulator of neuronal genes. The authors hypothesize that NSRF interacts with the NADH-binding co-repressor CtBP (C-terminal binding protein) to establish a repressive chromatin environment around the BDNF promoter to decrease BDNF mRNA levels and to reduce the hyperexcitability associated with its overexpression (Binder et al., 2001). This novel and provocative report clearly establishes the important role that glycolysis plays in the development of epilepsy, and helps lay the foundation for a new class of antiepileptic drugs based on direct modulation of bioenergetic pathways.

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