Effects of advanced glycation end-product inhibition and cross-link breakage in diabetic rats

The accelerated formation of advanced glycation end-products (AGEs) due to elevated glycemia has repeatedly been reported as a central pathogenic fact or in the development of diabetic microvascular complications. The effects of a novel inhibitor of AGE formation, NNC39-0028 (2,3-diaminophenazine), a nd a breaker of already formed AGE cross-links, N-phenacylthiazolium bromid e (PTB), were investigated in streptozotocin-diabetic female Wistar rats. D iabetes for 24 weeks resulted in decreased tail collagen pepsin solubility, reflecting the formation of AGE cross-linking. Collagen solubility was sig nificantly ameliorated by treatment with NNC39-0028, whereas PTB had no eff ect. Increased urinary albumin excretion (UAE) in diabetic rats was observe d in serial measurements throughout the study period, and was not reduced b y any treatment. Vascular dysfunction in the eye, measured as increased cle arance of I-125-albumin, was induced by diabetes. NNC39-0028 did not affect this abnormality. This study demonstrated a pharmacological inhibition of collagen solubility alterations in diabetic rats without affecting diabetes -induced pathophysiology such as the increase in UAE or albumin clearance. Treatment with PTB, a specific breaker of AGE cross-links, had no effects i n this study. Copyright (C) 2000 by W.B. Saunders Company.