Molecular identified as key to suppress inflammation in brain
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SAN FRANCISCO, Sept. 24 (Xinhua) -- New research at the University of California, San Francisco, or UCSF, has discovered a molecular key to the ketogenic diet's apparent effects on patients with epilepsy and other neurological illnesses.
The diet, namely extreme low-carbohydrate, high-fat regimen, may work by lowering inflammation in the brain.
"It's a key issue in the field - how to suppress inflammation in brain after injury," said Raymond Swanson, a professor of neurology at UCSF and senior author of the new study published online in the journal Nature Communications.
Swanson and his colleagues found the previously undiscovered mechanism by which a low carbohydrate diet reduces inflammation in the brain, and identified a pivotal protein that links the diet to inflammatory genes, which, if blocked, could mirror the anti-inflammatory effects of ketogenic diets, which are known to change the way the body uses energy.
In response to the shortage of carb-derived sugars such as glucose, the body begins breaking down fat into ketones and ketoacids, which it can use as alternative fuels.
In rodents, ketogenic diets are known to reduce inflammation, improve outcomes after brain injury and extend lifespan. However, these benefits are less well-established in humans because of the difficulty in maintaining a ketogenic state. In addition, it has been difficult to tease out the molecular nuts and bolts by which these diets influence the immune system.
In the new study, the researchers used a small molecule called 2-deoxyglucose, or 2DG, to block glucose metabolism and produce a ketogenic state in rats and controlled laboratory cell lines, leading to the discovery that 2DG could bring inflammation levels down to almost control levels. They further found that reduced glucose metabolism lowered a key barometer of energy metabolism, namely the NADH/NAD+ ratio, which in turn activated a protein called CtBP that acts to suppress activity of inflammatory genes.
In an experiment, the researchers designed a drug-like peptide molecule that blocks the ability of CtBP to enter its inactive state, forcing the protein to constantly block inflammatory gene activity and mimicking the effect of a ketogenic state.
Peptides, which are small proteins, don't work well as drugs because they are unstable, expensive, and people make antibodies against them. But other molecules that act the same way as the peptide could provide ketogenic benefits without requiring extreme dietary changes, Swanson was quoted as saying in a news release.
The findings may open the door for new therapies that could reduce brain inflammation following stroke and brain trauma by mimicking the beneficial effects of an extreme low-carb diet, and also provide a way of interfering with the relationship between the extra glucose in patients with diabetes and this inflammatory response.