Resveratrol's molecular formula is C14H12O3.
The authors believe their findings may lay the foundations for research into medications based on resveratrol, as well as settling the debate on its biochemistry. Resveratrol has become the focus of interest for drug companies because of its anti-cancer, anti-inflammation and diabetes prevention properties.
Lead author Jay H. Chung, M.D., Ph.D., said:
"Resveratrol has potential as a therapy for diverse diseases such as type 2 diabetes, Alzheimer's disease, and heart disease. However, before researchers can transform resveratrol into a safe and effective medicine, they need to know exactly what it targets in cells."
Researchers had supposed that resveratrol mainly targeted sirtuin 1, a protein linked to aging. However, Chung and team wondered whether resveratrol might work in a different way when they discovered that it requires AMPK (another protein) in order to become active. If resveratrol interacted with sirtuin 1, this could not happen.
Chung and colleagues traced out cells' metabolic activity which had been treated with resveratrol and found that PDE4 in the skeletal muscle was the main target for resveratrol's health benefits. It inhibits PDE4, triggering a cascade of events with the cell, including the indirect activation of sirtuin 1.
The scientists wanted to make sure resveratrol attaches to and inhibits PDE proteins, so they gave laboratory mice rolipram, a medication known to inhibit PDE4. The drug reproduced all the health benefits and biochemical effects of resveratrol, including the prevention of obesity (due to diet), enhanced glucose tolerance, and better physical endurance.
However, Chung stressed that we still don't know what toxic effects resveratrol as a drug might have - it interacts with other proteins, apart from PDEs.
Resveratrol does not exist in wine or grapes in a high-enough amount to provide any significant health benefits or problems, the authors explained. Human trials with any relevant findings have used resveratrol doses equivalent to 667 bottles of red wine (1gm of resveratrol).
PDE4 inhibitors might offer resveratrol's benefits without the negative risks, because they do not react with other proteins. Roflumilast, a PDE4 inhibitor, has already been approved by US regulatory authorities for COPD (chronic obstructive pulmonary disease) therapy.
Robert Balaban, Ph.D., director of the NHLBI Division of Intramural Research, said:
"This result underscores the need for careful, well-controlled studies to illuminate how these natural products operate. As Dr. Chung's work suggests, the effects of resveratrol seem to be more complicated than originally thought. However, this new insight into the phosphodiesterases might prove an interesting avenue to pursue."
Written by Christian Nordqvist