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Hema L. Ramkumar, Jingsheng Tuo, De Fen Shen, Jun Zhang, Xiao-Guang Cao, Emily Y. Chew, Chi-Chao Chan; Nutrient Supplementation Improves Retinal Lesions of Ccl2 /Cx3cr1 Deficient Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4013.
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"Age-related eye diseases study" (AREDS) participants with high dietary intake of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), lutein, and zeaxanthin had lower rates of age-related macular degeneration (AMD). This finding led to the AREDS2 clinical trial with this nutrient combination. We evaluated the retinal effects of feeding AREDS2 formula to Ccl2 -/-/Cx3cr1-/- mice, which develop lesions mimicking AMD, including focal RPE degeneration and photoreceptor loss.
At 1 month of age, Ccl2 -/-/Cx3cr1-/- (n=36) and wild type (n= 34) mice were evenly divided and fed with diet supplemented with lutein, zeaxanthin, and DHA/EPA or an isocaloric control diet for 3 months. Fundoscopy was performed monthly. Mice were sacrificed, and eyes were harvested for histology and retinal A2E (a lipofuscin fluorophore accumulated in AMD retinas). Outer nuclear layer thickness was measured from retinal sections. Retinal transcripts of iNos, Tnf-α, Cox-2, Vegf, and Il-1β were analyzed by quantitative RT-PCR. Retinal fatty acid concentrations were measured by thin layer chromatography.
After 3 months of treatment, 75% of control Ccl2 -/-/Cx3cr1-/- mice had lesion progression, compared to only 19% of AREDS2-treated Ccl2 -/-/Cx3cr1-/- mice. Clinical findings were confirmed by histopathology including ultrastructure. Retinal A2E (pmole/eye) was lower in AREDS2-treated Ccl2 -/-/Cx3cr1-/- mice (63±3 vs. 39±3 in controls, p<0.001). Retinal expression of iNos, Tnf-α, Cox-2, and Vegf werelower in AREDS2- treated Ccl2 -/-/Cx3cr1-/- mice (p<0.05). The mean outer nuclear layer thickness (µm) of AREDS2- treated Ccl2 -/-/Cx3cr1-/- mice was 17.9±1.2 vs. 3.1±0.9 in controls (p<0.0001). Retinal concentrations of EPA and DHA were higher in AREDS2-treated mice (p<0.001). Wild-type mice did not develop retinal lesions in either treatment group.
Our data demonstrate that the AREDS2 formula is protective to Ccl2 -/-/Cx3cr1-/- mice and arrests retinal lesions. Lutein and zeaxanthin quench reactive oxidative species, and DHA is neuroprotective, anti-angiogenic, and anti-inflammatory. While the AREDS2 clinical trial is underway, our results support the AREDS epidemiologic findings. We demonstrate that Ccl2 -/-/Cx3cr1-/- mice with lesions that mimic AMD can be used for testing AMD therapeutics.
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