Inhibition of Prostaglandins is Associated With Decreased Retinal VEGF Expression Levels in an Animal Model of AMD

Abstract

Purpose: : Choroidal neovascularization (CNV) is a common cause of severe vision loss in patients with age-related macular degeneration (AMD). While the etiology and pathogenesis of AMD remain poorly understood, there is considerable evidence that inflammatory events play a central role. Cyclooxygenase (COX) is an important enzyme in the inflammatory process and catalyzes the biosynthesis of prostaglandins, including PGE₂. It has been shown in a variety of experimental systems, that COX inhibition suppresses choroidal neovascularization (CNV). However, the specific mechanism of CNV suppression remains unclear. The intent of this study, therefore, was to determine the effect of prostaglandin inhibition on retinal vascular endothelial growth factor (VEGF) expression using a well established animal model of AMD.

Methods: : Laser photocoagulation was performed on 100g, male Brown Norway rats to induce CNV, using 50µm, 0.07s, 432nm, 360W laser settings. Animals were treated with either topical ketorolac or artificial tears four times per day until sacrifice. CNV leakage and lesion size were evaluated by fluorescein angiography (FA) and choroidal tissue mounts (CM) at three weeks. Retinal and vitreous levels of VEGF and PGE2 were measured at three and seven days after laser induction.

Results: : CNV lesions in the ketorolac treated eyes were 27% smaller on FA (p <0.00001), and 23% smaller on CM (p <0.00001), compared to control eyes at 3 weeks. Retinal PGE₂ levels in ketorolac treated eyes were 36% less at three days (p <0.05) and 31% less at seven days (p <0.0001) compared to control eyes. A 13% reduction (p <0.05) in vitreal PGE₂ levels was detected in ketorolac treated eyes seven days after laser induction compared to controls. Retinal VEGF levels in the ketorolac treated eyes were 20% less than controls (p <0.0001) seven days after laser induction.

Conclusions: : Topical ketorolac significantly inhibited CNV leakage on FA and lesion size on CM. The inhibition of CNV and PGE2 by ketorolac was associated with decreased retinal VEGF expression. These findings suggest that prostaglandins regulate VEGF expression in CNV.

Keywords: age-related macular degeneration • choroid: neovascularization • inflammation