Pharmacological Inhibition of Diabetic Retinopathy

Abstract

Effects of aminoguanidine and aspirin on the development of retinopathy have been examined in 5-year studies of diabetic dogs. Either agent was administered daily in doses of 20 -25 mg ⅐ kg ؊1 ⅐ day ؊1 . Because severity of hyperglycemia greatly influences development of the retinopathy, special effort was devoted to maintaining comparable glycemia in experimental and control groups. The retinal vasculature was isolated by the trypsin digest method, and retinopathy was assessed by light microscopy. Diabetes for 5 years resulted, as expected, in saccular capillary aneurysms, pericyte ghosts, acellular capillaries, retinal hemorrhages, and other lesions. Administration of aminoguanidine essentially prevented the retinopathy, significantly inhibiting the development of retinal microaneurysms, acellular capillaries, and pericyte ghosts compared with diabetic controls. Aspirin significantly inhibited the development of retinal hemorrhages and acellular capillaries over the 5 years of study, but had less effect on other lesions. Although diabetes resulted in significantly increased levels of advanced glycation end products (AGEs) (namely, pentosidine in tail collagen and aorta, and Hb-AGE), aminoguanidine had no significant influence on these parameters of glycation. Nitration of a retinal protein was significantly increased in diabetes and inhibited by aminoguanidine. The biochemical mechanism by which aminoguanidine has inhibited retinopathy thus is not clear. Aminoguanidine (but not aspirin) inhibited a diabetesinduced defect in ulnar nerve conduction velocity, but neither agent was found to influence kidney structure or albumen excretion.

Diabetic retinopathy

“…Hence, PDR is not a contra-indication to anti-aggregating treatment for the prevention of cardio-vascular events. Studies of aminoguanidine [116,117], soluble anti-VEGF receptors and anti-oxidants or free-radical scavengers are at present preliminary in nature and/or confined to animal models of retinopathy.…”

Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes

“…Quantification of vascular histopathology The retinal vasculature was isolated by the trypsin digest method as described by us previously [8,17]. Briefly, freshly isolated eyes were fixed with buffered formalin (4% [wt/vol.]…”

“…Aminoguanidine is a relatively selective inhibitor of iNOS [7] and has been found to inhibit the diabetes-induced increase in iNOS levels and nitric oxide production in retina [4]. Importantly, aminoguanidine has also been found to inhibit development of the microvascular lesions of diabetic retinopathy in diabetic dogs [8], rats [9,10] and mice (T. S. Kern, unpublished data). However, results from these aminoguanidine studies did not suffice to prove that iNOS plays a critical role in diabetes-induced retinal pathology, since aminoguanidine has also been shown to inhibit dicarbonylmediated cross-linking and protein modification [11] and can even inhibit eNOS level under some circumstances [12].…”

Comparative Trial of N-Acetyl-Cysteine, Taurine, and Oxerutin on Skin and Kidney Damage in Long-Term Experimental Diabetes

“…Several compounds with putative properties against AGE accumulation have been investigated in both clinical and experimental settings (8,9). In most instances, the results have been only partially satisfactory, possibly because the drugs being tested inhibited either glycation or oxidation but not both processes.…”