Experimental Drug Reduces Brain Inflammation in Diabetic Rat Model

A recent paper reported that peptides that mimic the activity of thioredoxin were able to inhibit the development of inflammation in the brains of Zucker diabetic fatty (ZDF) rats.

Recent studies have linked the high levels of sugar in the blood of diabetics to the development of dementia, impaired cognition, and a decline of brain function. Diabetics have also been found to have twice the risk of developing Alzheimer's disease compared to non-diabetics.

Male Zucker diabetic fatty (ZDF) rats are a highly regarded model system for the study of diabetes. These animals develop obesity and insulin resistance at a young age, and then with aging, progressively develop hyperglycemia. This hyperglycemia is associated with impaired pancreatic beta-cell function, loss of pancreatic beta-cell mass, and decreased responsiveness of liver and extrahepatic tissues to the actions of insulin and glucose.

The ZDF model system was chosen by investigators at the Hebrew University of Jerusalem (Israel) to elucidate the underlying mechanisms linking inflammatory events elicited in the brain during oxidative stress and diabetes.

The investigators monitored the anti-inflammatory effects of the thioredoxin mimetic (TxM) peptides, Ac-Cys-Pro-Cys-amide (CB3) and Ac-Cys-Gly-Pro-Cys-amide (CB4) in the brains of ZDF rats and in an in vitro culture system based on human neuroblastoma SH-5HY5 cells. Thioredoxins are proteins that act as antioxidants by facilitating the reduction of other proteins by cysteine thiol-disulfide exchange. They are found in nearly all known organisms and are essential for life in mammals.

Results published in the January 9, 2014, online edition of the journal Redox Biology revealed that despite high glucose levels in the blood of the ZDF rats, the TXM peptide CB3 significantly reduced the activity of proapoptotic MAPK kinases and retarded premature brain cell death. These results indicated that the CB3 was able to cross the blood-brain barrier and improve the condition of the brain cells by inhibiting various inflammatory processes. Furthermore, CB3 prevented apoptosis in human neuroblastoma SH-SY5Y cells.

Senior author Dr. Daphne Atlas, professor of neurochemistry at the Hebrew University of Jerusalem, said, "This study paves the way for preventive treatment of damages 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. 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.”

Use of the CB3 molecule has been protected by a patent registered by the Yissum Research Development Company, the technology transfer arm of the Hebrew University of Jerusalem.

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