Nature-inspired Nrf2 activators in retinal pigment epithelial cells: a source for therapeutics in Age-related Macular Degeneration

Purpose: Age-related Macular Degeneration (AMD) is a severe neurodegenerative disease and a major cause of blindness in the elderly worldwide. Oxidative stress is a common feature of AMD pathogenesis, and a positive modulation of Nrf2 activity has been demonstrated to be protective. Natural products are generally a rich source of therapeutics; we recently combined polyphenols from curcumin and diallyl sulfide in new chemical entities to produce hybrids with anti-oxidant activity. To confirm Nrf2 pathway as a valuable therapeutic target, we studied the modulation of this cascade by our new hybrids.
Methods: The human retinal pigment epithelium cell line ARPE-19 was exposed to increasing concentrations of the new nature-inspired hybrids. Cell viability was evaluated by MTT assay. Nrf2 nuclear translocation and target gene expression were measured by Western blotting.
Results: New nature-inspired hybrids induce Nrf2 nuclear translocation and modulation of its target genes involved in phase II response in ARPE-19 cells. These molecules show a potency on Nrf2 activation profile comparable to that induced by the reference compounds curcumin and dimethylfumarate, the latter being currently used in clinic for multiple sclerosis.
Conclusion: The new nature-inspired hybrids show to be promising to counteract some features related to AMD pathogenesis, thus suggesting the potential use of Nrf2 activators as therapeutics.