Diabetic Retinal Microvascular Pathology is Prevented by Sulindac, a Non-steroidal Anti-inflammatory Drug, without Inhibition of Advanced Glycation, Polyol Pathway Activity or Oxidative Stress

Abstract

Abstract: : Purpose: To investigate the effect of treatment with the non-steroidal anti-inflammatory drug Sulindac on the early vascular pathology of diabetic retinopathy in the dog, and it’s effect on recognised biochemical indices of hyperglycaemia-related pathophysiology. Methods: Experimental diabetes (streptozotocin/alloxan) was induced in 22 male beagle dogs and 12 of the animals were assigned at random to receive oral Sulindac (10mg/kg daily). Age and sex-matched control animals were maintained as non-diabetic controls. After 4 years, several morphological parameters were quantified in the retinal microvasculature of each animal group using an established stereological method. Also, the following diabetes-associated biochemical parameters were analysed: accumulation of advanced glycation end products (AGEs), red blood cell sorbitol and fructose levels, and antioxidant status as assessed by plasma malondialdehyde (MDA), total antioxidant capacity (TAC) and alpha tocopherol. Results: Diabetes increased red blood cell (RBC) sorbitol and fructose levels when compared to non-diabetic controls (p≤0.05), however, there was no difference between untreated and Sulindac-treated diabetic animals. Pentosidine, fructoselysine, N-(carboxymethyl)lysine and N-(carboxyethyl)lysine were increased 2-3 fold in the skin collagen of diabetic animals (p≤0.001) although Sulindac did not affect the levels of any of these products. Likewise diabetes significantly increased plasma MDA and depleted the TAC, although alpha tocopherol was not affected; none of these indices were altered by Sulindac. Retinal capillary basement membrane volume (BMV) was significantly increased in the untreated diabetic dogs compared to non-diabetic controls or Sulindac-treated diabetic animals (p≤0.0001). There was no significant difference in the retinal capillary BMV between Sulindac-treated diabetics and control dogs (p≤0.0001). Conclusions: This study has confirmed the beneficial effect of a non-steroidal anti-inflammatory drug on the early vascular pathology of diabetic retinopathy. However the treatment benefit was not dependent on inhibition of polyol pathway activity, advanced glycation, or oxidative stress. We conclude that the beneficial effect of Sulindac in diabetes-related retinal capillary BM accumulation is attributable to its NSAID activity.

Keywords: retina • diabetic retinopathy • animal model