Abstract
Age-related macular degeneration (AMD) is a multifactorial pathology and its progression is exacerbated by oxidative stress. Oxidation and photo-oxidation reactions modify lipids in retinal cells, contribute to tissue injury, and lead to the formation of toxic adducts. In particular, autofluorescent pigments such as N-retinylidene-N-retinylethanolamine (A2E) accumulate as lipofuscin in retinal pigment epithelial cells, contribute to the production of additional reactive oxygen species (ROS), and lead to cell degeneration. In an effort to develop efficient antioxidants to reduce damage caused by lipid oxidation, various natural polyphenols were structurally modified to increase their lipophilicity (lipophenols). In this study, resveratrol, phloroglucinol, quercetin and catechin were selected and conjugated to various polyunsaturated fatty acids (PUFAs) using classical chemical strategies or enzymatic reactions. After screening for cytotoxicity, the capacity of the synthesized lipophenols to reduce ROS production was evaluated in ARPE-19 cells subjected to H2O2 treatment using a dichlorofluorescein diacetate probe. The positions of the PUFA on the polyphenol core appear to influence the antioxidant effect. In addition, two lipophenolic quercetin derivatives were evaluated to highlight their potency in protecting ARPE-19 cells against A2E photo-oxidation toxicity. Quercetin conjugated to linoleic or α-linolenic acid were promising lipophilic antioxidants, as they protected ARPE-19 cells from A2E-induced cell death more effectively than the parent polyphenol, quercetin.
Highlights
Nowadays, the interest in natural or synthetic substances to counteract damages produced by oxidative stress (OS) has risen sharply
Cytotoxicity evaluation of the derivatives in this study showed that the linoleic acid (LA) introduced in phloroglucinol and resveratrol series had no enhanced toxicity in ARPE-19 cells compared to their natural homologue
Most of the reactive oxygen species (ROS) inhibition tests performed on lipophenol derivatives as described in the literature are performed on non-cellular assay and frequently showed a decrease in the antioxidant properties of lipophenols
Summary
The interest in natural or synthetic substances to counteract damages produced by oxidative stress (OS) has risen sharply. For cosmetic, agricultural food or pharmaceutical purposes, hydrophobic antioxidants are developed, either to protect lipid food matrices, for better absorption by the skin or to protect cell membranes against lipid peroxidation. In retina pathologies such as age-related macular degeneration (AMD, the leading cause of vision loss in the elderly), OS plays a significant role in the development and aggravation of the pathology. AMD is a multifactorial, chronic and age-related disease that is influenced by both environmental and genetic factors. In the dry form of the pathology [1,2], oxidative stress is involved in the toxification mechanisms leading to N-retinylidene-N-retinylethanolamine (A2E) accumulation and degradation.
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