Long-term treatment with fidarestat suppresses the development of diabetic retinopathy in STZ-induced diabetic rats.
It is important to suppress retinal vascular changes for prevention of the onset and progression of diabetic retinopathy. In the present study, we investigated the dose-response effect of an aldose reductase (AR) inhibitor, fidarestat, on retinal vascular changes in the retinas of streptozotocin (STZ)-induced diabetic rats. Fidarestat (0.5, 1, and 2 mg/kg) was administered once a day, from 4 days after STZ injection, for 15 months. Microaneurysms and thickness of the basement membrane were frequently observed in the untreated diabetic group as compared to the nondiabetic control group. In addition, the number of pericytes decreased in the untreated diabetic group. Fidarestat diminished the prevalence rate of microaneurysms, basement membrane thickness and decrease in the number of pericytes, and complete suppression was observed at a dose of 2 mg/kg. Fidarestat also dose-dependently inhibited sorbitol accumulation in the retina. Furthermore, a close correlation was observed between the prevalence rate of microaneurysms and the decrease in the number of pericytes, which indicated that damage to pericytes triggers retinal vascular changes. These results suggest that fidarestat, by virtue of its long-term correction of the accelerated polyol pathway, has a potential role in preventing the progression of diabetic retinopathy.
Kato
Noriaki
N
Central Research Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd., 363 Shiosaki, Hokusei, Mie 511-0406, Inabe, Japan.
Yashima
Satomi
S
Suzuki
Takeshi
T
Nakayama
Yukiharu
Y
Jomori
Takahito
T
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000783:Aneurysm / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D007093:Imidazoles / Q000008:administration & dosage*; D048289:Imidazolidines; D008297:Male; D020286:Pericytes / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013311:Streptozocin
D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D013311:Streptozocin; C077139:fidarestat; D000449:Aldehyde Reductase