Is There an Optimal Combination of AREDS2 Antioxidants Zeaxanthin, Vitamin E and Vitamin C on Light-Induced Toxicity of Vitamin A Aldehyde to the Retina?

Abstract

Vitamins C and E and zeaxanthin are components of a supplement tested in a large clinical trial—Age-Related Eye Disease Study 2 (AREDS2)—and it has been demonstrated that they can inhibit the progression of age-related macular degeneration. The aim of this study was to determine the optimal combinations of these antioxidants to prevent the phototoxicity mediated by vitamin A aldehyde (ATR), which can accumulate in photoreceptor outer segments (POS) upon exposure to light. We used cultured retinal pigment epithelial cells ARPE-19 and liposomes containing unsaturated lipids and ATR as a model of POS. Cells and/or liposomes were enriched with lipophilic antioxidants, whereas ascorbate was added just before the exposure to light. Supplementing the cells and/or liposomes with single lipophilic antioxidants had only a minor effect on phototoxicity, but the protection substantially increased in the presence of both ways of supplementation. Combinations of zeaxanthin with α-tocopherol in liposomes and cells provided substantial protection, enhancing cell viability from ~26% in the absence of antioxidants to ~63% in the presence of 4 µM zeaxanthin and 80 µM α-tocopherol, and this protective effect was further increased to ~69% in the presence of 0.5 mM ascorbate. The protective effect of ascorbate disappeared at a concentration of 1 mM, whereas 2 mM of ascorbate exacerbated the phototoxicity. Zeaxanthin or α-tocopherol partly ameliorated the cytotoxic effects. Altogether, our results suggest that the optimal combination includes upper levels of zeaxanthin and α-tocopherol achievable by diet and/or supplementations, whereas ascorbate needs to be at a four-fold smaller concentration than that in the vitreous. The physiological relevance of the results is discussed.

Scavenging of Cation Radicals of the Visual Cycle Retinoids by Lutein, Zeaxanthin, Taurine, and Melanin

“…It has been shown that about 15–25% of retinal carotenoids are present in POS [ 34 , 35 ]. Sommerburg et al determined the content of lutein and zeaxanthin in POS isolated from the entire human retina so their molar concentrations can be estimated as 1.01 µM for lutein and 0.47 µM for zeaxanthin [ 34 , 37 ]. It is reasonable to expect that in the macula, where the concentrations of these carotenoids in the RPE are several-fold greater than in the periphery and their concentrations in the inner retina of the central macula reach millimolar values, the concentrations of lutein and zeaxanthin in POS will be also greater than in the periphery.…”

“…Based on data of Friedrichson et al, it has been determined that molar concentrations of vitamin E in the neural retina of the macular area and periphery are 46 and 77 µM, respectively [ 29 , 37 ]. Comparison of calculated effectiveness of retinol cation radicals scavenging clearly shows that, in comparison with lutein and zeaxanthin, α-tocopherol can provide only a minor contribution to the scavenging of the retinol cation radical in the macula but is similar or exceeds the contribution of these carotenoids in the periphery despite that the rate constant for scavenging of retinol cation radicals is 158 times greater for lutein than for α-tocopherol ( Table 3 ).…”

“…In addition to vitamins E and C, the area where the trafficking of the visual cycle retinoids takes place contains other antioxidants. The POS and RPE of the human retina accumulate two carotenoids: lutein and zeaxanthin [ 34 , 35 , 36 , 37 ], which are thought to play important antioxidant functions in the retina [ 38 , 39 ]. The retinas of vertebrates contain high concentrations of taurine (2-amino-ethanesulfonic acid), which is essential for the viability of retinal neurons, including photoreceptors [ 40 , 41 , 42 ].…”

The Biochemistry and Effectiveness of Antioxidants in Food, Fruits, and Marine Algae

“…Vitamin A or all-trans-retinal, which accumulates in the retina because of the absorption of light by visual pigments, is found in carrots, egg yolk, liver, and sweet potatoes [ 238 , 239 ]. Being a liposoluble vitamin, a balance in its intake is to be considered [ 239 ].…”

Lipofuscin, Its Origin, Properties, and Contribution to Retinal Fluorescence as a Potential Biomarker of Oxidative Damage to the Retina

“…6 In addition, the lysosomal degradation in the RPE can be hindered by oxidative damage to the phagocytosed material due to the photosensitizing properties of retinaldehydes. Following the photoexcitation of visual pigment, which is the first step leading to visual perception, the Schiff base linkage between the protein and the isomerized chromophore is hydrolyzed, resulting in a release of all-trans-retinaldehyde from the protein, opsin [88,[94][95][96][97][98]. The lysosomal degradation of the visual pigments can lead to the release of their intact chromophore, 11-cis-retinaldehyde.…”