Diyabetin geç komplikasyonlarının önlenmesinde antioksidanlar ve aldoz redüktaz inhibisyonu: Yeni pridoindol bileşikleri üzerinde çalışmalar

Diabetes mellitus is associated with an increased production of reactive oxygen species (ROS) and a reduction in antioxidant defenses. Autoxidation of glucose and the activation of polyol pathway were postulated as two main sources of excess production of reactive oxygen species in diabetic tissues. Oxidative stress, which is responsible for impaired cellular homeostasis, leads to multiple organ deficiency and diabetic complications. Although, tight glycemic control is the most effective way of preventing or decreasing these complications, it remains insufficient in long-term treatment of diabetes. Previous studies showed that antioxidants compounds may have some beneficial effects in the preventing and treating diabetic complications. As a new pyridoindole derivative, stobadine, together with high oral bioavailibility, efficient detoxification pathways, and toxic safety, has been found to protect tissues against destructive effects of ROS. Hence, we investigated the effects of stobadine in the prevention or treatment of late complications of diabetes in an animal model of diabetes mellitus. We also compared the various effects of stobadine treatment alone with the effects of treatment with another antioxidant vitamin E and stobadine plus vitamin E in heart, brain, aorta, liver, kidney, eye and vas deferens. Combined treatment with stobadine and vitamin E provided more benefits in the reduction of hyperglycemia and lipid peroxidation, retinal capillary basement membrane thickening, hemoglobin glycosylation, lipid abnormalities and VEGF immunoreactivity in diabetic animals. Glucose-6-phosphate dehydrogenase activity but not 6-phosphogluconate dehydrogenase activity were markedly increased in diabetic brain; only combined treatment with stobadine and vitamin E produced a partial prevention on this alteration. Decreased pentose phosphate enzyme activities in diabetic aorta unchanged with either single or combination treatments. Diabetes-induced disturbtions in tissue glutathione-dependent enzymes and catalase activities, and phenylephrine and Bay K-8644 stimulated aortic contractions were comletely prevented by stobadine treatment alone. The treatment with each antioxidant completely prevented calcium accumulation in diabetic tissues. Neither treatment with stobadine nor vitamin E alone, nor their combination did not effectively ameliorated Ca2+Mg2+-ATPase activity in diabetic tissues. Single therapies with each antioxidant partly prevented the abnormalities observed in tissue protein glycation, tissue aldose reductase and Na+,K+-ATP'ase activities and leukocyte function. Combination of two antioxidants was found to be beter for the therapy of reproductive system disabilities in male diabetic rats. Stobadine protected kidney morphology, relaxation capasity of vessels and normal blood pressure in diabetic animals. Our studies provided further evidence that pharmacological intervention of different antioxidants and antioxidant combinations may have significant implications in the prevention of oxidative feature of diabetes, and described the cellular mechanisms of stobadine that may inhibit the development of late diabetic complications.