Prevention of retinal capillary basement membrane thickening in diabetic dogs by a non-steroidal anti-inflammatory drug

Abstract

Aims/hypothesis. 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 (10 mg/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 polyol levels and antioxidant status. Results. Diabetes increased red blood cell sorbitol levels when compared to non-diabetic controls (p≤0.05), however, there was no difference in sorbitol levels between the untreated and the treated diabetic animals. No significant differences were found in red blood cell myoinositol levels between the three groups of animals. Pentosidine and other AGEs were increased two-to three-fold in the diabetic animals (p≤0.001) although treatment with Sulindac did not affect their accumulation in diabetic skin collagen or alter diabetesinduced rises in plasma malondialdehyde. Retinal capillary basement membrane volume was significantly increased in the untreated diabetic dogs compared to non-diabetic controls or Sulindac-treated diabetic animals (p≤0.0001). Conclusion/interpretation. 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. [Diabetologia (2003[Diabetologia ( ) 46:1269[Diabetologia ( -1275

Bovine Retinal Pericytes Are Resistant to Glucose-Induced Oxidative StressIn Vitro

“…In a recent 4-year study, the nonsteroidal antiinflammatory drug Sulindac was given to beagle dogs with STZ/alloxan-induced diabetes. Basement membrane thickening was prevented, an effect that was independent of inhibition of polyol pathway activity, advanced glycation, or oxidative stress, but the precise mode of action of this drug has to be further investigated (17). These results indicate that inflammation might be involved in the development of some of the pathologies of diabetic retinopathy.…”

The progress in understanding and treatment of diabetic retinopathy

“…Next to rodents, cats and dogs have been used most extensively as models of diabetic retinopathy and they provide excellent models of early-stage clinical disease (Budzynski et al, 2005;Gardiner et al, 2003b;Gardiner et al, 1994;Hatchell et al, 1995;Linsenmeier et al, 1998;Mansour et al, 1990). Dogs have been most extensively used for retinopathy studies with diabetes commonly induced using chemical induction of diabetes (Anderson et al, 1993) (Figure 6).…”

“…Since diabetic retinopathy in dogs is much closer to the clinical scenario, this species has been also used to assess drug efficacy (Gardiner et al, 2003b;Kador et al, 1990). The main disadvantages of the model are general objections against research in large mammals and the costs of the model.…”

Pathophysiology of Cyclooxygenase Inhibition in Animal Models

“…administration of flunixin meglumine significantly limited miosis and reduced the production of PGE 2 in the aqueous humor after acute inflammation induction in dogs (Millichamp et al 1991). In diabetic dogs, sulindac decreased retinal capillary basement membrane thickening and diabetic retinopathy (Gardiner et al 2003). In nonhuman primates, continuous infusion of indomethacin into the vitreous cavity reduced vascular leakage (Sakamoto et al 1995).…”