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Identification of Signaling Pathway Involved in Diabetic Nerve Damage Leads to Discovery of Promising New Therapy

Researchers have discovered that blocking a signaling pathway involved in diabetic nerve damage with a drug already being given to people for other conditions could prevent or reverse that damage in mice. People with diabetes can, over time, develop nerve damage throughout the body. The most common type of diabetic nerve damage, called peripheral diabetic neuropathy, causes pain or loss of feeling in the feet, legs, hands, and arms and is a major risk factor for amputation. Currently, people with diabetic nerve damage may be treated with medications to manage pain, but there is great need to find therapies to prevent and reverse this serious complication to reduce its significant health burden.

Toward this goal, scientists screened a library of molecules for those that could enhance repair of male rat nerve cells in laboratory culture by stimulating the outgrowth of neurites, which project from nerve cell bodies and connect the cells to other nerve cells. The more neurite outgrowth the better, in terms of repairing nerve damage. They found that molecules that blocked “muscarinic acetylcholine type 1 receptors” (M1R) stimulated neurite outgrowth. Further experiments confirmed a key role for M1R in regulating neurite outgrowth: neurite outgrowth was inhibited when M1R protein levels were experimentally increased in cultured rat nerve cells, whereas neurite outgrowth was higher in nerve cells from an experimental mouse model lacking M1R compared to control mice. To take these observations a step further, the researchers studied an M1R -blocking drug in mouse models of diabetes, focusing on a drug called pirenzepine because it is already used clinically for other conditions. They found that pirenzepine treatment prevented and reversed diabetic nerve damage in male and female mouse models of type 1 and type 2 diabetes. The drug also prevented nerve damage associated with other conditions, such as chemotherapy, suggesting that blocking M1R with pirenzepine stimulates nerve repair/regeneration even when the underlying cause of the damage varies in animals.

This research suggests that M1R plays a key role in the nerve damage associated with diabetes and other conditions in mice, and that blocking its activity with pirenzepine could prevent or reverse that damage. Interestingly, the scientists found no evidence that the normal M1R signaling pathway is altered in diabetes, so the mechanism by which pirenzepine is exerting its effects is not clear. Nonetheless, the promising results of the study are already being translated to people: the NIDDK is funding a pilot clinical trial to test whether another drug (topical oxybutynin) that blocks M1R can reverse diabetic neuropathy.


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