Aspirin at Low-Intermediate Concentrations Protects Retinal Vessels in Experimental Diabetic Retinopathy Through Non–Platelet-Mediated Effects

Abstract

The prevention of diabetic retinopathy requires drugs that leverage the benefits of glycemic control without adding the burden of side effects. Aspirin at dosages of 1-1.5 g/day has prevented manifestations of diabetic retinal microangiopathy in a clinical trial as well as in studies with dogs. Because lower and safer doses of aspirin could be used if its beneficial effects on retinopathy were due to antithrombotic effects, we compared the effects of a selective antiplatelet drug (clopidogrel) to those of aspirin in streptozotocin-induced diabetic rats. Clopidogrel did not prevent neuronal apoptosis, glial reactivity, capillary cell apoptosis, or acellular capillaries in the retina of diabetic rats. Aspirin, at doses yielding serum levels (<0.6 mmol/l) well below the anti-inflammatory range for humans, prevented apoptosis of capillary cells and the development of acellular capillaries but did not prevent neuroglial abnormalities. The aldose reductase inhibitor sorbinil, used as the benchmark for the effect of the other drugs, prevented all abnormalities. The diabetic rat retina showed increased expression of the transcription factor CCAAT/enhancerbinding protein-␤, one of the known targets of low-intermediate concentrations of aspirin. Thus we found a spectrum of drug efficacy on the prevention of experimental diabetic retinopathy, ranging from the absent effect of a selective antiplatelet drug to the prevention of all abnormalities by an aldose reductase inhibitor. Aspirin at low-intermediate concentrations selectively prevented microangiopathy. The minimal effective dose of aspirin should now be sought. Diabetes 54:3418 -3426, 2005 D iabetic retinopathy remains a sight-threatening complication of diabetes despite decades of efforts to identify drugs that can leverage the prevention afforded by glycemic control. Aspirin has been studied several times in this context, with results that may appear inconsistent but actually are worthy of scrutiny in light of evolving knowledge. The Early Treatment Diabetic Retinopathy Study (ETDRS), the largest of the clinical trials testing aspirin, concluded that aspirin (650 mg/day) has no clinically important beneficial effects on the progression of retinopathy (1). The trial was performed in patients with mild to severe nonproliferative or early proliferative diabetic retinopathy. Having learned from the Diabetes Control and Complications Trial that intervening after retinopathy is clinically evident is much less successful than primary prevention (2), it is safe not to extrapolate the EDTRS results to prevention. The Dipyridamole Aspirin Microangiopathy of Diabetes Study, which enrolled patients with early diabetic retinopathy (a lesssevere degree of retinopathy than that seen in the ETDRS), showed that aspirin (990 mg/day) was able to slow the progression of microaneurysms by Ͼ50% over the 3-year duration of the study (3). Microaneurysms are only a surrogate end point of diabetic retinopathy, but they have high predictive value for worsening retinopathy (4,5). When aspirin ...

Topical Administration of Nepafenac Inhibits Diabetes-Induced Retinal Microvascular Disease and Underlying Abnormalities of Retinal Metabolism and Physiology

“…Aspirin and other anti-inflammatory agents that inhibit PGs also have been found to inhibit diabetesinduced alterations in retinal metabolism and physiology in animal models (9,24,32,33). Clinical trials to determine whether low-dose aspirin might be a potentially effective therapy against diabetic retinopathy have yielded contradictory results (4,5), but chronic treatment of diabetic dogs (3) or rats (34,35) with higher doses of aspirin significantly reduced capillary degeneration and development of other lesions characteristic of diabetic retinopathy. In contrast to aspirin, clopidogrel, a different antiplatelet drug, has not been found to inhibit the development of early stages of diabetic retinopathy in rats (35).…”

A Selective Aldose Reductase Inhibitor of a New Structural Class Prevents or Reverses Early Retinal Abnormalities in Experimental Diabetic Retinopathy

“…ARIs are only one of several types of drugs that have shown prevention of late, irreversible vascular damage in experimental diabetic retinopathy (3,(31)(32)(33), and they are candidate adjunct treatments for retinopathy and other complications of diabetes in humans. It is valuable and desirable that more than one candidate drug be developed because prevention of the complications of diabetes will require drugs that can be used effectively and safely over many years in the context of the unique requirements and sensitivities of individual patients.…”

“…ARI-809 is a highly selective (1:930) (7) inhibitor of aldose reductase relative to aldehyde reductase, and such selectivity distinguishes it from sorbinil, which inhibits aldose and aldehyde reductase to a comparable extent (11). Sorbinil was previously shown to prevent the development of experimental diabetic retinopathy (1,3,9). The structural uniqueness and high selectivity of ARI-809 now presented an important opportunity to critically target the role of the polyol pathway in the early stages of the development of experimental diabetic retinopathy.…”

PGE2, Kidney Disease, and Cardiovascular Risk

“…58 COX-2 has long been implicated in the retinal damage associated with diabetes. [59][60][61][62][63][64][65] In the earliest stages of Figure 2. PGE 2 contributes to renal insufficiency and injury leading to increased cardiovascular (CV) risk.…”