Topical Nepafenac: Effects on Diabetes-Induced Increases in Retinal Leukostasis and Superoxide Production

Abstract

Abstract: : Purpose: We reported previously that high-dose aspirin significantly inhibits the development of diabetic retinopathy in a 5-year study of dogs, but the mechanism of action was not clear. In the current study, we were exploring the possible role of cyclo-oxygenase in diabetes-induced alterations of retinal biochemistry and function using a topical inhibitor of COX1/2, Nepafenac (Alcon Research, Ltd). Methods: Rats were made diabetic with streptozotocin, and representative diabetics and normal controls received topical ocular administration of 0.3% Nepafenac or mannitol vehicle (4 times per day) for 2 months. Retinal PGE2 was measured by commercially available ELISA. Leukostasis was determined by counting fluorescent cells remaining in the retinal vasculature after perfusing the animal with buffer and then with conconavalin A-FITC. Superoxide was measured by adding fresh retina to buffer containing luciginen, and measuring luminescence. Results: After 2 months, insulin-deficient diabetic control rats had significant increases in leukostasis within retinal vessels, and in production of retinal superoxide and PGE2, compared to nondiabetic controls. Topical ocular administration of Nepafenac significantly inhibited all 3 of these retinal abnormalities in diabetic rats, but had no significant effects in nondiabetic animals. Conclusions: Topical ocular administration of Nepafenac in rats achieves sufficient drug delivery to the posterior segment such that diabetes-induced alterations in retinal function and metabolism are inhibited. Local inhibition of COX1/2 in the eye might offer a novel therapeutic approach towards inhibiting the development of human diabetic retinopathy.

Keywords: diabetic retinopathy • oxidation/oxidative or free radical damage