Hebrew U.: Molecule developed to lower risk of dementia connected to diabetes

Mechanism of action that may be responsible for changes in the brain due to high sugar levels examined in rats.

Elderly woman looks out of window [illustrative] (photo credit: Ivan Alvarado / Reuters)
Elderly woman looks out of window [illustrative]
(photo credit: Ivan Alvarado / Reuters)
Having a high level of blood sugar, including having diabetes, has been known in recent years to increase the risk of eventually developing impaired cognition, reduced brain function, and dementia, including its most common form – Alzheimer’s disease. But now, researchers at the Hebrew University of Jerusalem have created a molecule that could reduce the danger in such people.
Prof. Daphne Atlas of the biological chemistry department in the Alexander Silberman Institute of Life Science has found a potential neuro-inflammatory pathway that could be responsible for diabetics’ increased risk of Alzheimer’s and dementia. They also reveal a potential treatment to reverse this process.
The study, “Thioredoxin-Mimetic peptide CB3 Lowers MAPKinsase activity in the Zucker Rat Brain,” appeared in the journal Redox Biology, the official journal of the Society for Free Radical Biology and Medicine and the Society for Free Radical Research-Europe. The molecule is protected by a patent registered by the Yissum Research Development Company, HU’s technology transfer arm.
She and her team experimented with diabetic rats to examine the mechanism of action that may be responsible for changes in the brain due to high sugar levels. The researchers found that diabetic rats displayed high activity of enzymes, called MAPK kinases, which are involved in facilitating cellular responses to a variety of stimuli, leading to inflammatory activity in brain cells and the early death of cells.
Diabetic rats were given a daily injection of the sugar-lowering drug rosiglitazone (commercially known as Avandia (made by GlaxoSmithKline), an anti-diabetic drug in the thiazolidinedione class of drugs, for a month. At the end, the rats were shown to have a significant decrease in MAPK enzyme activity, accompanied by a decrease in the inflammatory processes in the brain.
According to the researchers, this finding represents the first unequivocal evidence of a functional link between high blood sugar and the activation of this specific inflammatory pathway in the brain.
Using the diabetic rat model, they explored a novel approach that would lower the activation of these enzymes in the brain and decrease neuronal cell death. In the last few years, Atlas developed a series of molecules that mimic the action of thioredoxin, called thioredoxin- mimetic peptides (TXM), whose role is to protect the cells from early death through activating inflammatory pathways.
The TXM peptides were effective in different animal models and were able to prevent the activation of the damaging MAPK kinases.
Applied to the diabetic Zucker rats, one of the molecules – called TXM-CB3 – significantly reduced the activity of these enzymes and the accelerated brain cell death. These results indicate that the molecule managed to cross the bloodbrain barrier and improve the condition of the brain cells, through lowering the inflammatory processes in the rats’ brains, despite the high glucose levels afflicting the rats.
“This study paves the way for preventive treatment of damage caused by high sugar levels and for reducing the risk of dementia and Alzheimer’s disease in diabetics or people with elevated blood sugar levels,” Atlas said on Tuesday. Following the successful animal testing of the molecule we developed, we hope to explore its potential benefit for treating cognitive and memory impairments caused by diabetes on humans.”