Abstract
Oxidative stress is a hallmark of retinal degenerations such as age-related macular degeneration and diabetic retinopathy. Enhancement of heme oxygenase-1 (HO-1) activity in the retina would exert beneficial effects by protecting cells from oxidative stress, therefore promoting cell survival. Because a crosstalk exists between nitric oxide (NO) and HO-1 in promotion of cell survival under oxidative stress, we designed novel NO-releasing molecules also capable to induce HO-1. Starting from curcumin and caffeic acid phenethyl ester (CAPE), two known HO-1 inducers, the molecules were chemically modified by acylation with 4-bromo-butanoyl chloride and 2-chloro-propanoyl chloride, respectively, and then treated in the dark with AgNO(3) to obtain the nitrate derivatives VP10/12 and VP10/39. Human retinal pigment epithelial cells (ARPE-19) subjected to H(2)O(2)-mediated oxidative stress were treated with the described NO-releasing compounds. VP10/39 showed significant (p < 0.05) antioxidant and protecting activity against oxidative damage, in comparison to VP10/12, which in turn showed at 100 μM concentration a slight but significant cell toxicity. Only VP10/39 significantly (p < 0.05) induced HO-1 in ARPE-19, most likely through covalent bond formation at Cys151 of the Keap1-BTB domain, as revealed from molecular docking analysis. In conclusion, the present data indicate VP10/39 as a promising candidate to protect ARPE-19 cells against oxidative stress.