title: 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 Crb1rd8 background.
abstract: 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.
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Hema L
authors.initials: HL
authors.lastname: Ramkumar
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Tuo
authors.forename: De F
authors.initials: DF
authors.lastname: Shen
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Cao
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Chew
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D000073883:CX3C Chemokine Receptor 1; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D019587:Dietary Supplements; D004281:Docosahexaenoic Acids / Q000008:administration & dosage*; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage*; D020869:Gene Expression Profiling; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D014975:Lutein / Q000008:administration & dosage*; D008268:Macular Degeneration / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011726:Pyridinium Compounds / Q000493:pharmacokinetics; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D012162:Retinal Degeneration / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D012176:Retinoids / Q000493:pharmacokinetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D024341:Xanthophylls / Q000008:administration & dosage*; D065146:Zeaxanthins
chemical_list: C112040:A2-E (N-retinylidene-N-retinylethanolamine); D020533:Angiogenesis Inhibitors; D000893:Anti-Inflammatory Agents; D000073883:CX3C Chemokine Receptor 1; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C471885:Cx3cr1 protein, mouse; D053583:Interleukin-1beta; D011726:Pyridinium Compounds; D019707:Receptors, Chemokine; D012176:Retinoids; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D024341:Xanthophylls; D065146:Zeaxanthins; C467480:vascular endothelial growth factor A, mouse; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D014975:Lutein