A Systematic Pharmacology Analysis of the Age-Related Eye Disease Study 2 (AREDS2) formula and its role in preventing Age-Related Macular Degeneration (AMD)

Purpose: According to the major clinical trial sponsored by the National Eye Institute (NEI), oral supplementation with the Age-Related Eye Disease Study 2 (AREDS2) formulation (vitamins C and E, zinc, copper, lutein, and zeaxanthin) has been shown to delay the progression of advanced age- related macular degeneration (AMD). However, the detailed pharmacological mechanisms of AREDS2 are not fully understood at the molecular level. In this study, we intend to develop a systematic approach to predict AREDS2-associated targets and to map the drug-disease-target network. Methods: Genes of interest were identified via the NCBI database for compounds in the AREDS2 formula. Cytoscape software was used to visually create a network of source and target nodes to analyze the similarities between them. The formula's relation to AMD was analyzed via the Gene2Function and GeneCard databases. Results: A total of 158 genes were identified as the targets of the AREDS2 formula. 27 of these genes were a result of multiple components of the AREDS2 formula. The main pathways that these genes affect were identified and mapped out to include lipid metabolism, DNA damage responses, and oxidative stress. The top 5 genes regulated by the most components of the AREDS2 formula are GSTP1, Nrf2, VEGFA, HIF1A, and CXCL8. Conclusions: A systematic pharmacology-based approach provides beneficial information for elucidating the potential mechanisms of action of the AREDS2 formula in treating AMD. Furthermore, it provides future direction for AMD treatment which may focus on anti-adipogenic, anti-inflammatory, and anti-oxidant pathways.