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Toxic effects of A2E in human ARPE-19 cells were prevented by resveratrol: a potential nutritional bioactive for age-related macular degeneration treatment

Abstract

Age-related macular degeneration (AMD) is a late-onset retinal disease and the leading cause of central vision loss in the elderly. Degeneration of retinal pigment epithelial cells (RPE) is a crucial contributing factor responsible for the onset and progression of AMD. The toxic fluorophore N-retinyl-N-retinylidene ethanolamine (A2E), a major lipofuscin component, accumulates in RPE cells with age. Phytochemicals with antioxidant properties may have a potential role in both the prevention and treatment of this age-related ocular disease. Particularly, there is an increased interest in the therapeutic effects of resveratrol (RSV), a naturally occurring polyphenol (3,4′,5-trihydroxystilbene). However, the underlying mechanism of the RSV antioxidative effect in ocular diseases has not been well explored. We hypothesized that this bioactive compound may have beneficial effects for AMD. To this end, to investigate the potential profits of RSV against A2E-provoked oxidative damage, we used human RPE cell line (ARPE-19). RSV (25 µM) attenuates the cytotoxicity and the typical morphological characteristics of apoptosis observed in 25 µM A2E-laden cells. RSV pretreatment strengthened cell monolayer integrity through the preservation of the transepithelial electrical resistance and reduced the fluorescein isothiocyanate (FITC)-dextran diffusion rate as well as cytoskeleton architecture. In addition, RSV exhorts protective effects against A2E-induced modifications in the intracellular redox balance. Finally, RSV also prevented A2E-induced mitochondrial network fragmentation. These findings reinforce the idea that RSV represents an attractive bioactive for therapeutic intervention against ocular diseases associated with oxidative stress such as AMD.

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Acknowledgements

The present report was supported by grants from the ANPCyT PICT Joven 2016-1151, PICT (Start Up 2015-3866 and 2017-1683), UBACyT 20020150100079BA, PIP 2017 11220170100420CO and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Authors thank Dr. Damián Dorfman and BSc. Hernán Dieguez (CEFYBO-CONICET, Argentina) for their support in the experimental ophthalmic field. We also appreciated the advice of Prof. Dr. Valeria Levi and BSc. Mariano Smoler (IQUIBICEN-CONICET, Argentina) who shared with us their knowledge about cytoskeleton analysis techniques with us.

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Correspondence to Agustina Alaimo or Oscar Edgardo Pérez.

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Fig.

S1. NMR Identification of trans- RSV. (A) Chemical structure of trans-resveratrol. (B) RVS was identified by NMR as (E)-isomer. 1H and 13C spectra in methanol-d4 displayed the characteristic peaks for unequivocal structure of trans-resveratrol. (TIF 1556 kb)

Fig. S2

. Effect of ethanol concentrations on ARPE-19 cells viability. Ethanol was used to dissolve RSV. The exposure of this polar organic solvent did not exert harmful effect by its own on the cell cultures into the concentration range considered. (TIF 260 kb)

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Alaimo, A., Di Santo, M.C., Domínguez Rubio, A.P. et al. Toxic effects of A2E in human ARPE-19 cells were prevented by resveratrol: a potential nutritional bioactive for age-related macular degeneration treatment. Arch Toxicol 94, 553–572 (2020). https://doi.org/10.1007/s00204-019-02637-w

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  • DOI: https://doi.org/10.1007/s00204-019-02637-w

Keywords

  • Resveratrol
  • N-retinylidene-N-retinylethanolamine (A2E)
  • Age-related macular degeneration
  • Retinal pigment epithelial cells
  • Oxidative stress
  • Transepithelial electrical resistance (TEER)