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 factor in the development of diabetic microvascular complications. The effects of a novel inhibitor of AGE formation, NNC39-0028 (2,3-diaminophenazine), and a breaker of already formed AGE cross-links, N-phenacylthiazolium bromide (PTB), were investigated in streptozotocin-diabetic female Wistar rats. Diabetes for 24 weeks resulted in decreased tail collagen pepsin solubility, reflecting the formation of AGE cross-linking. Collagen solubility was significantly ameliorated by treatment with NNC39-0028, whereas PTB had no effect. Increased urinary albumin excretion (UAE) in diabetic rats was observed in serial measurements throughout the study period, and was not reduced by any treatment. Vascular dysfunction in the eye, measured as increased clearance of 125I-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 in this study.
Oturai
P S
PS
Novo Nordisk, Health Care Discovery, Bagsvaerd, Denmark.
Christensen
M
M
Rolin
B
B
Pedersen
K E
KE
Mortensen
S B
SB
Boel
E
E
D000419:Albuminuria / Q000652:urine; D000818:Animals; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000097:blood; D004326:Drinking / Q000187:drug effects; D005123:Eye / Q000098:blood supply; D005260:Female; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007668:Kidney / Q000033:anatomy & histology / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010619:Phenazines / Q000494:pharmacology*; D019275:Radiopharmaceuticals; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000378:metabolism; D012711:Serum Albumin, Radio-Iodinated; D012995:Solubility; D013623:Tail; D013710:Tendons / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
D017127:Glycation End Products, Advanced; C101705:N-phenacylthiazolium bromide; D010619:Phenazines; D019275:Radiopharmaceuticals; D012709:Serum Albumin; D012711:Serum Albumin, Radio-Iodinated; D013844:Thiazoles; C054312:2,3-diaminophenazine; D003094:Collagen