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| Longitudinal sections of two injured nerves with regenerating nerve fibers. Both specimens are from diabetic animals; in the lower image, the animal was treated with a peptide. Regeneration can be seen in the green-stained nerve fibers. Image Credit: Dietmar Fischer / University of Cologne |
Researchers have decoded the signaling pathway that inhibits nerve regeneration in diabetes and have developed a therapeutic peptide that could transform the treatment—and possibly even the prevention—of diabetic nerve damage.
Nerve damage is one of the most common and burdensome complications of diabetes. Millions of patients worldwide suffer from pain, numbness, and restricted movement, largely because damaged nerve fibers do not regenerate sufficiently. The reasons for this are unclear. A research team led by Professor Dr Dietmar Fischer, Professor of Pharmacology at the University of Cologne’s Faculty of Medicine, and Director of the Center for Pharmacology at University Hospital Cologne, has now identified a central mechanism that explains limited regeneration in diabetes. Building on this, the researchers have developed a promising therapeutic approach that can be used to increase regeneration. Their findings were published in the ‘Science Translational Medicine’ journal under the title ‘Failure of nerve regeneration in mouse models of diabetes is caused by p35-mediated CDK5 hyperactivity’.
Using mouse models of type 1 and type 2 diabetes mellitus, the team demonstrated a high accumulation of the p35 protein in nerve cells. This protein activates an enzyme that triggers a signaling cascade, which in turn blocks the regrowth of nerve fibers. This considerably restricts the nerves’ natural regenerative capacity. Through targeted interventions in this signaling pathway – either using genetic methods or, pharmacologically, with newly developed small protein building blocks (peptides) that can be administered systemically – the scientists succeeded in removing the block. In the preclinical models, the nerve fibers then grew again at a similar rate to those observed in healthy animals. This was accompanied by significant motor and sensory improvements.“For the first time, our results show that diabetic nerve healing can be brought back to a level that compares with that of healthy animals if the excessive activation of the signaling pathway is inhibited,” says Professor Fischer. “Even when diabetic neuropathy has already manifested, an improvement in regeneration occurs.” A peptide developed and patented by his research group shows promise in this respect, as it targets the underlying cause directly and could, in principle, be developed into a drug.
It is also worth noting that the regeneration weakness caused by diabetes occurs even before the onset of diabetic neuropathy, a common complication that affects almost half of all patients. In a further study, Professor Fischer and his team are currently investigating whether the mechanism they discovered contributes directly to the development of this nerve disease, or whether the risk can be reduced through the new treatment options.
The current study thus opens new perspectives for the treatment and, potentially, the prevention of diabetic nerve damage, also known as diabetic neuropathy, which is one of the most common and currently incurable secondary diseases worldwide.
Published in journal: Science Translational Medicine
Authors: Philipp Gobrecht, Jeannette Gebel, Günter Gisselmann, Kirsten Haastert-Talini, and Dietmar Fischer
Source/Credit: University of Cologne
Reference Number: bmed112725_01