Inhibition of Hypoxia-Inducible Factor-1alpha and Vascular Endothelial Growth Factor by Chrysin in a Rat Model of Choroidal Neovascularization

Abstract

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss among the elderly population. Vascular endothelial growth factor (VEGF) is essential for choroidal neovascularization (CNV) development in advanced, wet AMD. Chrysin (5,7-dihydroxyflavone) is a natural flavonoid with anti-inflammatory, anti-oxidative, and anti-angiogenic effects. We hypothesized that intravitreally injected chrysin may inhibit CNV due to its inhibitory effect on angiogenesis. To determine the effects of chrysin on an experimental CNV model, we induced CNV in Brown Norway rats with a diode laser. One week later, rats were injected intravitreally with chrysin in the right eye and vehicle in the left eye. The following week, we evaluated chrysin's effects via the CNV grade assessed with fluorescein angiography and histologic analyses. Hypoxia-inducible factor-1 alpha (HIF-1alpha) and VEGF expression in the retina/choroid complex were also measured in both eyes. The mean CNV grade was significantly lower in chrysin-treated vs. control eyes (2.34 +/- 1.14 vs. 2.97 +/- 1.05, p < 0.001), as was the mean CNV thickness (33.90 +/- 4.89 vs. 38.50 +/- 5.43 mum, p < 0.001) and mean HIF-1alpha and VEGF levels (both p < 0.001). Compared to chrysin-treated eyes, the relative risk of control eyes developing high-leakage lesions was 2.03 (95% confidence interval: 1.46-2.83). Since chrysin inhibited laser-induced CNV and downregulated HIF-1alpha and VEGF expression, it is a candidate for treating wet AMD and other CNV-associated conditions.