rhodanine and Diabetic-Angiopathies

Topics: Aldehyde Reductase; Animals; Clinical Trials as Topic; Diabetic Angiopathies; Drug Design; Humans; Imidazolidines; Polymers; Polymorphism, Genetic; Pyrazines; Rhodanine; Spiro Compounds; Thiazolidines

Topics: Aldehyde Reductase; Animals; Binding Sites; Blood Glucose; Cataract; Chemical Phenomena; Chemistry; Corneal Diseases; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Disease Models, Animal; Fluorenes; Galactose; Humans; Hydantoins; Imidazoles; Imidazolidines; Models, Molecular; Naphthalenes; Phthalazines; Rhodanine; Sorbitol; Structure-Activity Relationship; Substrate Specificity; Sugar Alcohol Dehydrogenases; Thiazolidines; Tissue Distribution

We sought to evaluate the long-term efficacy and safety of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy.. Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) >or=40 m/s, and HbA(1c)

Topics: Adult; Aged; Aldehyde Reductase; Blood Glucose; Diabetic Angiopathies; Diabetic Neuropathies; Enzyme Inhibitors; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Neural Conduction; Rhodanine; Thiazolidines

Although increased polyol pathway activity has been implicated in the pathogenesis of diabetic microangiopathy, the relation with diabetic macroangiopathy remains unclear. Galactose feeding is known to stimulate the polyol pathway and to develop abnormalities similar to those in diabetic microangiopathy. Our study was conducted to investigate whether an activation of polyol pathway by long-term treatment with galactose produced morphological changes in coronary arteries of dogs and the effect of an aldose reductase inhibitor, epalrestat, was also studied.. Dogs received either normal chow or chow containing 30% galactose with or without epalrestat given orally (20 or 50 mg x kg(-1)). After 44 months, morphometric analyses of coronary arteries were carried out and the galactitol contents in aortas were measured.. The ratio of areas of the intimal layer to those of the medial layer, an indicator of intimal thickening, was statistically significantly increased in galactose-fed dogs compared with control dogs. Galactose-fed dogs had a remarkable accumulation of galactitol in their aortas. These morphological and biochemical deficits were reduced by treatment with epalrestat.. This report morphologically shows diabetes-like macrovascular abnormalities in galactosaemic animals, suggesting that polyol pathway hyperactivity is closely related to the development of diabetic macroangiopathy, which could be prevented by aldose reductase inhibition.

Topics: Aldehyde Reductase; Animals; Aorta; Blood Glucose; Body Weight; Coronary Vessels; Diabetic Angiopathies; Dogs; Enzyme Inhibitors; Erythrocytes; Galactitol; Galactose; Glycated Hemoglobin; Male; Polymers; Rhodanine; Thiazolidines

The effects of aldose reductase inhibitors (ARIs) on the synthesis of prostacyclin (PGI2) by aortic rings from diabetic rats were examined. The ARIs studied were ONO-2235 and isoliquiritigenin, a new compound extracted from glycyrrhizae radix. The content of sorbitol in the sciatic nerve of diabetic rats induced by streptozotocin was significantly increased as compared with that of controls. This increase was significantly inhibited by the administration of an ARI. On the other hand, there was a marked decrease in the synthesis of PGI2 by the diabetic rats compared with the control rats. The decrease in PGI2 synthesis was significantly reversed by the administration of an ARI. Furthermore, the synthesis of PGI2 by the aortic rings was inversely correlated with the content of sorbitol in sciatic nerves. Those observations suggest that an ARI may have a beneficial effect on the vascular synthesis of PGI2 in diabetes mellitus.

Topics: Aldehyde Reductase; Animals; Aorta, Thoracic; Blood Glucose; Chalcone; Chalcones; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Epoprostenol; Male; Rats; Rats, Inbred Strains; Rhodanine; Sciatic Nerve; Sorbitol; Streptozocin; Sugar Alcohols; Thiazolidines

Wistar strain rats were made diabetic by injection of streptozotocin and divided into three groups fed on different diets: conventional solid foods, a fructose-rich diet and a fructose-rich diet mixed with ONO 2235, an aldose reductase inhibitor. The retinas of these rats were examined in flat mount preparations after trypsinization. Microvascular changes such as capillary tortuosity, microaneurysms, pericyte loss, that are typical of diabetic retinal microangiopathy, were seen most frequently in the rats fed on the fructose-rich diet. The rats fed on the fructose-rich diet with ONO 2235 showed much less vascular change than the diabetic rats fed on the conventional food. Electron microscopy of the retina revealed localized thickening of the basement membrane of the retinal capillaries, and this was most frequent in the fructose-fed rats. However, in rats fed on fructose with ONO 2235 the changes of the basement membrane were slight. It was concluded that the aldose reductase inhibitor, ONO 2235, prevented development of diabetic microangiopathy, probably by suppressing the enzymatic activation of aldose reductase in the retina.

Topics: Aldehyde Reductase; Animals; Basement Membrane; Blood Glucose; Body Weight; Capillaries; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Male; Microscopy, Electron; Rats; Rats, Inbred Strains; Retinal Vessels; Rhodanine; Streptozocin; Sugar Alcohol Dehydrogenases; Thiazoles; Thiazolidines