Effects of Novel Nitric Oxide-Releasing Molecules against Oxidative Stress on Retinal Pigmented Epithelial Cells

Abstract EN

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 AgNO3 to obtain the nitrate derivatives VP10/12 and VP10/39.

Human retinal pigment epithelial cells (ARPE-19) subjected to H2O2-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.