Abstract
Background: Age-related macular degeneration (AMD) is the leading cause of blindness and can be classified into two types called atrophic AMD (dry AMD) and neovascular AMD (wet AMD). Dry AMD is characterized by cellular degeneration of the retinal pigment epithelium, choriocapillaris, and photoreceptors. Wet AMD is characterized by the invasion of abnormal vessels from the choroid. Although anti-vascular endothelial growth factor (VEGF) therapy has a potent therapeutic effect against the disease, there is a possibility of chorio-retinal atrophy and adverse systemic events due to long-term robust VEGF antagonism. We focused on hypoxia-inducible factor (HIF) regulation of VEGF transcription, and report the suppressive effects of HIF inhibition against ocular phenotypes in animal models. Many of the known HIF inhibitors are categorized as anti-cancer drugs, and their systemic side effects are cause for concern in clinical use. In this study, we explored food ingredients that have HIF inhibitory effects and verified their effects in an animal model of AMD. Methods: Food ingredients were screened using a luciferase assay. C57BL6/J mice were administered the Garcinia cambogia extract (Garcinia extract) and hydroxycitric acid (HCA). Choroidal neovascularization (CNV) was induced by laser irradiation. Results: Garcinia extract and HCA showed inhibitory effects on HIF in the luciferase assay. The laser CNV model mice showed significant reduction of CNV volume by administering Garcinia extract and HCA. Conclusions: Garcinia extract and HCA showed therapeutic effects in a murine AMD model.
Highlights
Age-related macular degeneration (AMD) is the leading cause of blindness worldwide [1,2]
By inhibiting hypoxia-inducible factor (HIF), we reported that the volume of choroidal neovascularization (CNV) is reduced in a wet AMD animal model known as a laser-induced Choroidal neovascularization (CNV) mouse model [14]
The murine retinal cone cell line (661W) and the human retinal pigment epithelium (RPE) cell line (ARPE19) were used to evaluate HIF activity with a luciferase assay since photoreceptors and RPE cells significantly contribute the pathogenesis of AMD even though organoids or differentiated cells derived from iPS cells of AMD patients may be considered for better in vitro systems
Summary
Age-related macular degeneration (AMD) is the leading cause of blindness worldwide [1,2]. Wet AMD is characterized by the invasion of abnormal vessels from the choroid into the outer retinal layers, which causes leakage, a hemorrhage, and fibrosis. In diabetic retinopathy (DR) and wet AMD, abnormal blood vessel growth is largely caused by a vascular endothelial growth factor (VEGF) [5,6,7]. Age-related macular degeneration (AMD) is the leading cause of blindness and can be classified into two types called atrophic AMD (dry AMD) and neovascular AMD (wet AMD). Anti-vascular endothelial growth factor (VEGF) therapy has a potent therapeutic effect against the disease, there is a possibility of chorio-retinal atrophy and adverse systemic events due to long-term robust VEGF antagonism. Results: Garcinia extract and HCA showed inhibitory effects on HIF in the luciferase assay. Conclusions: Garcinia extract and HCA showed therapeutic effects in a murine AMD model
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