The Potential Ways the Antioxidant Fisetin can be useful in the Treatment of Macular Degeneration.

Overview

Age-related Macular Degeneration (AMD) is the most common cause of vision loss in the United States, affecting over 10 million Americans. AMD impacts the retina, with an accumulation of unresolved oxidative stress as a by-product of metabolic processes. Diabetic complications such as Diabetic Nephropathy have been shown to have a strong association with AMD, and diabetic patients are three times as likely to develop AMD. While the connection between diabetes and AMD has been explored in previous research studies, little research has been done on the impact of the AGE-RAGE signaling pathway, a common thread in diabetic complications, in AMD. The AGE-RAGE pathway in diabetic complications has been shown to lead to an increase in oxidative stress and inflammation as a result of the production of advanced glycation end products (AGEs) and is irreversible. The production of AGEs results in a positive feedback loop through the RAGE receptor and oxidative stress, which exacerbates its negative impact on cells. The AGE-RAGE pathway is also associated with VEGF, TNF-α, and IL-1β, which result in inflammatory responses. This research examined the effect of the AGE-RAGE pathway in AMD on oxidative stress and the impact of the antioxidant Fisetin in reducing this oxidative stress. Fisetin is an antioxidant that is commonly found in fruits and vegetables such as cucumbers, strawberries, and persimmons. This interdisciplinary study identified common Differentially Expressed Genes (DEGs) in Fisetin-treated and AMD datasets by using GEO datasets GSE5258 and GSE103060. These DEGs were used to suggest the enrichment of pathways and protein-protein interactions using online tools. Subsequently, an in vitro model was made, using 661w murine photoreceptor cells which were treated with concentrations of fructose to model the diabetic microenvironment. This in vitro model was also treated with Fisetin. AGE-RAGE, VEGF, IL-1β, and TNF-α were studied in vitro through ELISAs. These ELISAs suggest a decreased secretion of TNF-α, IL-1β, and VEGF when cells were treated with higher concentrations of Fisetin, but an increased expression of the AGE-RAGE pathway and ROS. This research suggests that the AGE-RAGE pathway is connected to ROS production through oxidative stress, and TNF- α, IL-1β, and VEGF through inflammatory mechanisms. This paper suggests that Fisetin has anti-inflammatory properties which result in the potential to be considered as adjuvant therapy in lower concentrations for patients with AMD.