Nutrient Supplementation with n3 Polyunsaturated Fatty Acids, Lutein, and Zeaxanthin Decrease A2E Accumulation and VEGF Expression in the Retinas of Ccl2/Cx3cr1-Deficient Mice on Crb1(rd8) Background

Laboratory of Immunology.
Journal of Nutrition (Impact Factor: 3.88). 05/2013; 143(7). DOI: 10.3945/jn.112.169649
Source: PubMed


The Age-Related Eye Diseases Study 2 (AREDS2) clinical trial is assessing the effects of higher dietary xanthophyll (lutein and zeaxanthin) and long-chain n3 polyunsaturated fatty acid (LCPUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) intake on progression to advanced age-related macular degeneration (AMD). This study's purpose was to examine the retinal effects of the AREDS2 formulation on Chemokine (C-C motif) ligand 2 (Ccl2(-/-))/CX3C chemokine receptor 1 (Cx3cr1(-/-)) mice on Crumbs homolog 1 retinal degeneration phenotype 8 (Crb1(rd8)) background (DKO), which develop focal retinal lesions with certain features similar to AMD. DKO and C57BL/6N rd8 background mice (WT) were bred and randomized into 4 groups. Two groups, WT mice on AREDS2 diet (A-WT) and DKO mice on AREDS2 diet (A-DKO), were supplemented daily with 1.76 μmol of lutein, 35.1 μmol of zeaxanthin, 215 μmol EPA, and 107 μmol of DHA, and 2 control groups, WT mice on control diet (C-WT) and DKO mice on control diet (C-DKO), were fed an isocaloric diet. All mice had monthly fundus photos and were killed after 3 mo for biochemical and histologic analyses. After 3 mo, 81% of A-DKO mice had lesion regression compared with 25% of C-DKO mice (P < 0.05). Toxic retinal 2-[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetra-enyl]-1-(2-hydroxyethyl)-4-[4-methyl-6(2,6,6-trimethyl-1-cyclohexen-1-yl) 1E,3E,5E,7E-hexatrienyl]-pyridinium (A2E) concentrations were significantly lower in A-DKO compared with C-DKO mice. The outer nuclear layer thickness in A-DKO mice was significantly greater than that in C-DKO mice. Retinal expression of inducible nitric oxide synthase (iNos) tumor necrosis factor-α (Tnf-α), Cyclooxygenase-2 (Cox-2), interleukin1beta (IL-1β), and vascular endothelial growth factor (Vegf) was significantly lower in A-DKO compared with C-DKO mice. Xanthophylls and LCPUFAs have antiinflammatory, neuroprotective, and antiangiogenic properties. Our data provide potential mechanisms by which the AREDS2 formula has a protective effect on retinal lesions in DKO mice.

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    • "Histopathology confirmed these findings, where treatment of DKOrd8 mice prevented degeneration of retinal architecture and photoreceptor loss. Additionally, treated DKOrd8 mice showed similar levels of A2E biomarker as WT mice, which was significantly lower than the control DKOrd8 mice [32]. "
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    Full-text · Article · Oct 2013
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    • "Recent study conducted within the age-related eye disease study 2 (AREDS2) project manifested a high macular pigment optical density (MPOD), indicator of macula health, in individuals supplemented with 10 mg of lutein and 2 mg of zeaxanthin per day, when compared with control group not receiving this supplementation (Bernstein et al. 2012). Concordant results were obtained from the mouse model, DKO mice, which develop focal retinal lesions that had clinical, biochemical, and pathological features of AMD, including the degeneration and atrophy of focal photoreceptors and RPE (lipofuscin accumulation, hypertrophy, and hypotrophy) as well as the presence of some drusenoid deposits (Ramkumar et al. 2010, 2013; Tuo et al. 2007; Zhang et al. 2013). Although this model lacks a macula (like all nonprimate models), it adopts the accumulation of A2E and the degeneration of focal photoreceptor and RPE, which are found in AMD. "
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