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New lipophenols prevent carbonyl and oxidative stresses involved in macular degeneration
Espérance Moine1, Manel Boukhallat1, David Cia2
1Institut des Biomolécules Max Mousseron (IBMM), Université de Montpellier, CNRS, ENSCM, Montpellier, 34093, France.
Abstract:
Dry age-related macular degeneration and Stargardt disease undergo a known toxic mechanism caused by carbonyl and oxidative stresses (COS). This is responsible for accumulation in the retinal pigment epithelium (RPE) of A2E, a main toxic pyridinium bis-retinoid lipofuscin component. Previous studies have shown that carbonyl stress in retinal cells could be reduced by an alkyl-phloroglucinol-DHA conjugate (lipophenol). Here, we performed a rational design of different families of lipophenols to conserve anti-carbonyl stress activities and improve antioxidant properties. Five synthetic pathways leading to alkyl-(poly)phenol derivatives, with phloroglucinol, resveratrol, catechin and quercetin as the main backbone, linked to poly-unsaturated fatty acid, are presented. These lipophenols were evaluated in ARPE-19 cell line for their anti-COS properties and a structure-activity relationship study is proposed. Protection of ARPE-19 cells against A2E toxicity was assessed for the four best candidates. Finally, interesting anti-COS properties of the most promising quercetin lipophenol were confirmed in primary RPE cells.
Insights
New lipophenols were designed to combat carbonyl and oxidative stresses (COS) linked to macular degeneration and Stargardt disease. The most effective quercetin lipophenol protected retinal cells from toxic A2E accumulation.
Area of Science:
- Ophthalmology
- Neuroscience
- Medicinal Chemistry
Background:
- Dry age-related macular degeneration and Stargardt disease involve toxic mechanisms from carbonyl and oxidative stresses (COS).
- These stresses lead to the accumulation of A2E, a toxic lipofuscin component, in retinal pigment epithelium (RPE) cells.
- Previous research indicated that alkyl-phloroglucinol-DHA conjugates (lipophenols) can reduce carbonyl stress in retinal cells.
Purpose of the Study:
- To rationally design novel lipophenols with enhanced anti-carbonyl stress and antioxidant properties.
- To synthesize and evaluate various alkyl-(poly)phenol derivatives linked to poly-unsaturated fatty acids.
- To investigate the structure-activity relationships of these compounds for potential therapeutic applications.
Main Methods:
- Five synthetic pathways were employed to create alkyl-(poly)phenol derivatives using phloroglucinol, resveratrol, catechin, and quercetin backbones.
- Lipophenols were evaluated for anti-COS properties in the ARPE-19 cell line.
- The protective effects of the most promising candidates against A2E toxicity were assessed in ARPE-19 and primary RPE cells.
Main Results:
- Several families of lipophenols were synthesized, demonstrating conserved anti-carbonyl stress activities and improved antioxidant properties.
- A structure-activity relationship study was conducted to identify key molecular features for efficacy.
- The four best lipophenol candidates showed protection against A2E toxicity in ARPE-19 cells.
- The most promising quercetin lipophenol exhibited significant anti-COS properties in primary RPE cells.
Conclusions:
- Novel lipophenols, particularly those based on quercetin, show promise in mitigating the toxic effects of carbonyl and oxidative stresses in retinal cells.
- These findings suggest a potential therapeutic strategy for conditions like dry age-related macular degeneration and Stargardt disease.
- Further research into lipophenols could lead to new treatments for retinal degenerative diseases.
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