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: Hema L Ramkumar, Jingsheng Tuo, De F Shen, Jun Zhang, Xiaoguang Cao, Emily Y Chew, Chi-Chao Chan
• Journal: The Journal of nutrition (J Nutr) Vol. 143 Issue 7 Pg. 1129-35 (07 2013) ISSN: 1541-6100 [Electronic] United States
• PMID: 23677863 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• A2-E (N-retinylidene-N-retinylethanolamine)
• Angiogenesis Inhibitors
• Anti-Inflammatory Agents
• CX3C Chemokine Receptor 1
• Ccl2 protein, mouse
• Chemokine CCL2
• Cx3cr1 protein, mouse
• Interleukin-1beta
• Pyridinium Compounds
• Receptors, Chemokine
• Retinoids
• Tumor Necrosis Factor-alpha
• Vascular Endothelial Growth Factor A
• Xanthophylls
• Zeaxanthins
• vascular endothelial growth factor A, mouse
• Docosahexaenoic Acids
• Eicosapentaenoic Acid
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Lutein

Topics

• Angiogenesis Inhibitors (administration & dosage)
• Animals
• Anti-Inflammatory Agents (administration & dosage)
• CX3C Chemokine Receptor 1
• Chemokine CCL2 (genetics, metabolism)
• Cyclooxygenase 2 (genetics, metabolism)
• Dietary Supplements
• Docosahexaenoic Acids (administration & dosage)
• Eicosapentaenoic Acid (administration & dosage)
• Gene Expression Profiling
• Interleukin-1beta (genetics, metabolism)
• Lutein (administration & dosage)
• Macular Degeneration (drug therapy, genetics, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Electron, Transmission
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Phenotype
• Pyridinium Compounds (pharmacokinetics)
• Receptors, Chemokine (genetics, metabolism)
• Retina (drug effects, metabolism)
• Retinal Degeneration (drug therapy, genetics, pathology)
• Retinoids (pharmacokinetics)
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Xanthophylls (administration & dosage)
• Zeaxanthins