Topical Administration of Nepafenac Inhibits the Early Stages of Diabetic Retinopathy

Abstract

Abstract: : Purpose: Pharmacologic treatment of diabetic retinopathy via eyedrops would have important advantages, but has not been successful to date. We explored the ability of Nepafenac, an anti–inflammatory drug known to reach the retina when administered via eyedrops, on the development of early stages of diabetic retinopathy. Nepafenac activity is especially directed towards cyclooxygenase–2 Methods: Streptozotocin (STZ)–diabetic rats were assigned to 3 groups (untreated control, Nepafenac eyedrops, and vehicle eyedrops) for comparison to nondiabetic controls. Eyedrops were administered 4 times/day for 9 mos. Vascular lesions of diabetic retinopathy were quantitated after isolation of the retinal vasculature by the trypsin digest technique, and loss of cells in the ganglion cell layer was evaluated in retinal cross–sections. Retinal activity was assessed by measuring electroretinograms (ERGs) under dark and light adapted conditions to evaluate rod and cone pathways, respectively. Results: A significant increase in the number of TUNEL–positive capillary cells, acellular capillaries, and pericyte ghosts was measured at 9 months of diabetes. Topical administration of Nepafenac significantly inhibited all of these retinal abnormalities in diabetic rats. Diabetes–induced activation of caspases 3 and 6 in retina was partially inhibited by Nepafenac, but the drug had no effect on diabetes–induced loss of cells in the ganglion cell layer or alterations in retinal function as assessed by ERG. Conclusions: Nepafenac eyedrops achieve sufficient drug delivery to the retina that many diabetes–induced alterations in vascular function and histopathology are inhibited. In contrast, little or no effect was observed on diabetes–induced alterations in neural cell function or retinal ganglion cell survival. Local inhibition of inflammatory pathways in the eye offers a novel therapeutic approach towards inhibiting the development of diabetic retinopathy.

Keywords: diabetic retinopathy • cell death/apoptosis