It's been know since Hippocrates' times that starvation diets can stave off epilepsy. In a Nature Neuroscience paper now available online, researchers show why - and show that 2-deoxyglucose, or 2DG, a sugar derivative that has long been administered to humans in research studies, might achieve the same effect.

"At the moment, when people use diet to control their epilepsy, they use ketogenic diet, which is hard to maintain," senior author Avtar Roopra told BioWorld Today. "We hope [2DG] could be used on top of a fairly normal diet - though probably your doctor will still tell you, No Twinkies for breakfast.'"

The reason that epileptics, if the approach pans out, would not need to replace all their glucose with the 2-deoxyglucose variety - which is glucose that is missing a single atom - is its mechanism of action. 2DG competes for the active site of an enzyme that metabolizes glucose, but once it occupies that active site, it refuses to move on. So rather than replacing all dietary glucose with 2DG, a patient would need only enough to throw a wrench into the enzyme. "In the perfect world, in my most optimistic scenario, you would just use a little bit of it as is - you could sprinkle it in your coffee," said Roopra, an assistant professor of neurology at the University of Wisconsin-Madison.

Despite the fact that the discovery might be a highly practical one, Roopra and his colleagues actually were trying to solve quite a different puzzle when they made it: What controls expression levels, and specificity, of genes that are expressed in the brain?

They were studying the transcription factor NRSF, which fine-tunes gene expression in the brain, and found a link between NRSF and two other molecules: NADH, a molecule produced by glucose consumption, and the transcriptional repressor CtBP.

NRSF can bind CtBP - but only when glucose is low. If glucose levels are high, levels of NADH also will increase. And "because NADH binds CtBP, CtBP won't bind to NRSF, and NRSF can't repress its genes very well," Roopra said.

When CtBP does bind NRSF, on the other hand, the combination recruits histone-modifying proteins to the DNA that essentially close down the chromatin, making them much more difficult to transcribe.

In the paper, Roopra and his colleagues tested whether their finding might be used practically. They found that in rats that are subjected to epilepsy-inducing stimuli, inhibiting sugar metabolism by giving animals 2DG slowed down the development of seizures. At the molecular level, by inhibiting sugar metabolism and lowering NADH levels in the brain, 2DG promotes the binding of NRSF and CtBP. This is turn represses brain-derived neurotrophic factor and its receptor, TrkB. Both of those genes contribute to the development of epilepsy if they are expressed, and both are regulated by NRSF.

Roopra said that the key finding that allowed them to link sugar metabolism to epilepsy development was their discovery of the relationship between NADH and NRSF.

"That's when we got really happy, and went to the local bar to celebrate," he said. "Because that's when we knew we had found a link between metabolism and gene expression."

The Wisconsin Alumni Research Foundation has filed a patent application on the use of 2DG to treat seizure disorders via the inhibition of sugar-metabolizing enzymes. The patents, in turn, are licensed to Malvern, Pa.-based NeurogenomeX Inc. Roopra said he hopes that clinical trials on the compound for the treatment of epilepsy will begin sometime next year.

Despite the fact that his discoveries may turn out to be very practical indeed, Roopra put in a plug for basic research funding: "We didn't set out to discover a drug," he said, "but that was the endpoint." And because the work began as basic research, "we have a paper that goes all the way from basic mechanisms of how genes are regulated to a drug that might benefit a lot of people quite soon."