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?

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 alpha-tocopherol in liposomes and cells provided substantial protection, enhancing cell viability from similar to 26% in the absence of antioxidants to similar to 63% in the presence of 4 mu M zeaxanthin and 80 mu M alpha-tocopherol, and this protective effect was further increased to similar 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 alpha-tocopherol partly ameliorated the cytotoxic effects. Altogether, our results suggest that the optimal combination includes upper levels of zeaxanthin and oc-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.

Automated summary

The study aimed to determine the optimal combinations of vitamins C, E, and zeaxanthin to prevent phototoxicity mediated by vitamin A aldehyde. Results showed that combining zeaxanthin with alpha-tocopherol provided substantial protection, enhancing cell viability significantly.