The Role of Estrogen Receptors in the Therapeutic Effect of Oxyresveratrol, Phytoestrogen, During, and After Oxidative Stress

Objective: Oxidative stress plays a significant role in the development and progression of various neurodegenerative disorders, including aging, atherosclerosis, cancer, ischemia reperfusion, inflammation, rheumatoid arthritis, liver diseases. Additionally, it is implicated in retinal diseases (RD) such as glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), and age-related macular degeneration (AMD). In our study, we studied the therapeutic effect of oxyresveratrol, against H₂O₂-induced oxidative damage. Additionally, we investigated the role of estrogen receptors in the observed effects. Methods: Oxidative stress was induced by H₂O₂ in ARPE-19 cells. Oxyresveratrol was applied at seven different concentrations during and after oxidative stress. Besides, estrogen receptor inhibitors were applied 1 h before the treatment to investigate the role of estrogen receptors. Changes in cell viability were assessed using XTT. To investigate the effectiveness of oxyresveratrol at the molecular level, cell death detection, Caspase-3, and TOS measurement kits were employed. Results and Discussion: Our findings indicated that oxyresveratrol at concentrations of 10 and 100 µM reduced cell damage in ARPE-19 cells during and after-induced oxidative stress. Additionally, the therapeutic effect of oxyresveratrol in ARPE-19 cells during oxidative stress formation appeared to be dependent on estrogen receptors α and β, while the therapeutic effect after oxidative stress seemed to be GPER1-dependent. Furthermore, oxyresveratrol suppressed apoptosis in ARPE-19 cells under oxidative stress, reducing cell death, and both during and after oxidative stress, oxyresveratrol application decreased TOS levels. Although the antioxidant, anti-inflammatory, and neuroprotective effects of oxyresveratrol are well known, this is the first study to investigate its therapeutic effects on H₂O₂ induced oxidative stress in ARPE-19 cells and the involvement of estrogen receptors in these effects. Conclusions: We believe that oxyresveratrol may be an alternative therapy in the prevention and treatment of retinal diseases.