Abstract
Oxidative stress plays a crucial role in developing and accelerating retinal diseases including age-related macular degeneration (AMD). Docosahexaenoic acid (DHA, C22:6, n-3), the main lipid constituent of retinal epithelial cell membranes, is highly prone to radical and enzymatic oxidation leading to deleterious or beneficial metabolites for retinal tissue. To inhibit radical oxidation while preserving enzymatic metabolism, deuterium was incorporated at specific positions of DHA, resulting in D2-DHA when incorporated at position 6 and D4-DHA when incorporated at the 6,9 bis-allylic positions. Both derivatives were able to decrease DHAs’ toxicity and free radical processes involved in lipid peroxidation, in ARPE-19 cells (Adult Retinal Pigment Epithelial cell line), under pro-oxidant conditions. Our positive results encouraged us to prepare lipophenolic-deuterated-DHA conjugates as possible drug candidates for AMD treatment. These novel derivatives proved efficient in limiting lipid peroxidation in ARPE-19 cells. Finally, we evaluated the underlying mechanisms and the enzymatic conversion of both deuterated DHA. While radical abstraction was affected at the deuterium incorporation sites, enzymatic conversion by the lipoxygenase 15s-LOX was not impacted. Our results suggest that site-specifically deuterated DHA could be used in the development of DHA conjugates for treatment of oxidative stress driven diseases, or as biological tools to study the roles, activities and mechanisms of DHA metabolites.
Highlights
Docosahexaenoic acid, (DHA, C22:6, n-3) is a polyunsaturated fatty acid that belongs to the omega-3 family
In view of therapeutic applications on age-related macular degeneration (AMD) and Stargardt disease, we evaluated the impact of deuterium on lipid peroxidation when incorporated in the lipid part of IP-docosahexaenoic acid (DHA) (Scheme 2), a lipophenol molecule already highlighted for its anti-carbonyl stress properties [21,30,31]
Our work demonstrates the efficiency of selective deuterium incorporation at bis-allylic positions of DHA, to decrease toxicity and lipid peroxidation in a retina cell line, under oxidative conditions
Summary
Docosahexaenoic acid, (DHA, C22:6, n-3) is a polyunsaturated fatty acid that belongs to the omega-3 family. Several biological functions have been assigned to DHA, including anti-inflammatory [1], anti-angiogenesis [2] and anti-apoptotic roles [3]. DHA is the most abundant polyunsaturated fatty acid (PUFA) of the retina cell membrane, representing more than 50% of the total fatty acid content within the rod outer segments of photoreceptors [4,5]. For this reason, this lipid is indispensable for retina development and for visual acuity. DHA plays a crucial role in preserving retina integrity and function. DHA ensures fluidity of photoreceptor membranes, maintaining bilayer flexibility, thereby providing an adequate
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