Bis-allylic Deuterated DHA Alleviates Oxidative Stress in Retinal Epithelial Cells
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...
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| Format: | Article |
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MDPI AG
2019-10-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/8/10/447 |
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| author | Mélissa Rosell Martin Giera Philippe Brabet Mikhail S. Shchepinov Michel Guichardant Thierry Durand Joseph Vercauteren Jean-Marie Galano Céline Crauste |
| author_facet | Mélissa Rosell Martin Giera Philippe Brabet Mikhail S. Shchepinov Michel Guichardant Thierry Durand Joseph Vercauteren Jean-Marie Galano Céline Crauste |
| author_sort | Mélissa Rosell |
| collection | DOAJ |
| description | 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 D<sub>2</sub>-DHA when incorporated at position 6 and D<sub>4</sub>-DHA when incorporated at the 6,9 <i>bis</i>-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. |
| first_indexed | 2024-03-12T05:42:39Z |
| format | Article |
| id | doaj.art-955b85fbbd214c10991f70434a9feb90 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-12T05:42:39Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-955b85fbbd214c10991f70434a9feb902023-09-03T05:54:03ZengMDPI AGAntioxidants2076-39212019-10-0181044710.3390/antiox8100447antiox8100447Bis-allylic Deuterated DHA Alleviates Oxidative Stress in Retinal Epithelial CellsMélissa Rosell0Martin Giera1Philippe Brabet2Mikhail S. Shchepinov3Michel Guichardant4Thierry Durand5Joseph Vercauteren6Jean-Marie Galano7Céline Crauste8IBMM, Univ Montpellier, CNRS, ENSCM, 34093 Montpellier, FranceLeiden University Medical Center, Center for Proteomics and Metabolomics, Albinusdreef 2, 2333ZA Leiden, The NetherlandsInstitute for Neurosciences of Montpellier, INSERM U1051-UM, Hospital St Eloi, 80 rue Augustin Fliche, 34091 Montpellier, FranceRetrotope, Inc., Los Altos, CA 94022, USAUniv-Lyon, Inserm UMR 1060, Inra UMR 1397 (CarMeN Laboratory), IMBL, INSA-Lyon, 69100 Villeurbanne, FranceIBMM, Univ Montpellier, CNRS, ENSCM, 34093 Montpellier, FranceIBMM, Univ Montpellier, CNRS, ENSCM, 34093 Montpellier, FranceIBMM, Univ Montpellier, CNRS, ENSCM, 34093 Montpellier, FranceIBMM, Univ Montpellier, CNRS, ENSCM, 34093 Montpellier, FranceOxidative 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 D<sub>2</sub>-DHA when incorporated at position 6 and D<sub>4</sub>-DHA when incorporated at the 6,9 <i>bis</i>-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.https://www.mdpi.com/2076-3921/8/10/447dhaoxidative stresskinetic isotope effectlipid peroxidationlipophenolphenolipid |
| spellingShingle | Mélissa Rosell Martin Giera Philippe Brabet Mikhail S. Shchepinov Michel Guichardant Thierry Durand Joseph Vercauteren Jean-Marie Galano Céline Crauste Bis-allylic Deuterated DHA Alleviates Oxidative Stress in Retinal Epithelial Cells Antioxidants dha oxidative stress kinetic isotope effect lipid peroxidation lipophenol phenolipid |
| title | Bis-allylic Deuterated DHA Alleviates Oxidative Stress in Retinal Epithelial Cells |
| title_full | Bis-allylic Deuterated DHA Alleviates Oxidative Stress in Retinal Epithelial Cells |
| title_fullStr | Bis-allylic Deuterated DHA Alleviates Oxidative Stress in Retinal Epithelial Cells |
| title_full_unstemmed | Bis-allylic Deuterated DHA Alleviates Oxidative Stress in Retinal Epithelial Cells |
| title_short | Bis-allylic Deuterated DHA Alleviates Oxidative Stress in Retinal Epithelial Cells |
| title_sort | bis allylic deuterated dha alleviates oxidative stress in retinal epithelial cells |
| topic | dha oxidative stress kinetic isotope effect lipid peroxidation lipophenol phenolipid |
| url | https://www.mdpi.com/2076-3921/8/10/447 |
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