Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy.

Abstract

Retinal capillary closure induced by hyperglycemia is the principal pathophysiologic abnormality underlying diabetic retinopathy, but the mechaniss by which this induction occurs are not clear. Treatment of diabetic rats for 26 weeks with aminouanidine, an inhibitor of advanced glycosylation product formation, prevented a 2.6-fold accumulation of these products at branching sites of precapillary arterioles where abnormal periodic acid/Schiff reagentpositive deposits also occurred. A dine treatment completely prevented abnormal endothelial cell proliferation and signiflcantiy diminshed pericyte dropout. After 75 weeks, untreated diabetic animals developed an 18.6-fold increase in the number of acellular capillaries and formed capillary microaneurysms, characteristic pathologic features of background diabetic retinopathy. In contrast, aminoguanidinetreated diabetic animals had only a 3.6-fold increase in acellular capillaries and no microaneurysms. These findings indicate that advanced glycosylation product accumulation contributes to the development of diabetic retinopathy and suggest that a anqidine may have future therapeutic use in this disorder.Pathologic retinal changes are found in virtually 100%o of patients having type I diabetes for 15 yr or longer (1). Underlying the complex clinical manifestations of diabetic retinopathy are two fundamental abnormalities: increased retinal vascular permeability and progressive retinal vessel closure (2, 3). Digested retinal vasculature preparations from diabetic patients and animals characteristically show early pericyte loss which is followed by acellular capillary development and microaneurysm formation (4,5). The severity of these changes is associated with the degree of chronic hyperglycemia to which the diabetic retina has been exposed, but the mechanisms by which elevated glucose levels cause retinal damage are currently not known (6, 7). Potentially important mechanisms include increased polyol pathway activity, activation of protein kinase C by de novo diacylglycerol synthesis, and altered cell/matrix functions induced by accumulated advanced glycosylation end products (8-11).Recently the nucleophilic hydrazine compound aminoguanidine has been shown to inhibit the formation of advanced glycosylation products on collagen and basement membrane both in vitro and in vivo (12,13 pepsin/0.2% HCL. After 10 min in a water bath at room temperature, the retina was subjected to digestion by 3% trypsin/0.2 M Tris for 3.5 hr at 370C to remove the inner limiting membrane. The sample was then placed on a glass slide, and further digestion with trypsin was monitored under a dissecting microscope. The intact isolated retinal vessel preparation was washed with distilled H20 and air-dried. Retinal vessel preparations were stained with periodic acid/ Schiff reagent/hematoxylin (15) and photographed using a

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.…”

Toxic action of advanced glycation end products on cultured retinal capillary pericytes and endothelial cells: relevance to diabetic retinopathy

“…Results from numerous investigations have already suggested a strong link between the deposition of AGE in tissues and the pathogenesis of diabetic complications [29]. The work of Hammes et al [37] demonstrating, (i) the presence of AGE products in retinal capillaries of 26-week diabetic rats, and (ii) significant reduction in the number of diabetes-induced acellular capillaries and pericyte loss when the formation of AGE is inhibited with aminoguanidine, seems to suggest a possible link between excessive accumulation of AGE and the pathogenesis of diabetic retinopathy. There does appear to be a good correlation between the extent to which AGE accumulates on patients' dermal collagen and the degree of diabetic retinopathy [38].…”

Functional Hyperemia and Mechanisms of Neurovascular Coupling in the Retinal Vasculature

“…Indeed, aminoguanidine has been shown to dramatically slow the progression of diabetic retinopathy in animal models of diabetes. [108][109][110][111][112] A human trial of aminoguanidine also demonstrates a slowing of diabetic retinopathy progression, although the trial was terminated early due to side effects of aminoguanidine when administered at high doses. 113 In addition to inhibiting iNOS, aminoguanidine also blocks formation of advanced glycation endproducts and its beneficial effect on diabetic retinopathy could be due to this effect on advanced glycation endproducts.…”