Resveratrol Protects Photoreceptors in Mouse Models of Retinal Degeneration.

Abstract

Photoreceptor/retinal degeneration is the major cause of blindness. Induced and inherited mouse models of retinal degeneration are valuable tools for investigating disease mechanisms and developing therapeutic interventions. This study investigated the potential of the antioxidant resveratrol to relieve photoreceptor degeneration using mouse models. Clinical studies have shown a potential association between thyroid hormone (TH) signaling and age-related retinal degeneration. Excessive TH signaling induces oxidative stress/damage and photoreceptor death in mice. C57BL/6 (rod-dominant) and Nrl^-/- (cone-dominant) mice at postnatal day 30 (P30) received triiodothyronine (T3) via drinking water (20 µg/mL) with or without concomitant treatment with resveratrol via drinking water (120 µg/mL) for 30 days, followed by evaluation of photoreceptor degeneration, oxidative damage, and retinal stress responses. In experiments using Leber congenital amaurosis model mice, mother Rpe65^-/- and Rpe65^-/-/Nrl^-/- mice received resveratrol via drinking water (120 µg/mL) for 20 days and 10-13 days, respectively, beginning on the day when the pups were at P5, and pups were then evaluated for cone degeneration. Treatment with resveratrol significantly diminished the photoreceptor degeneration induced by T3 and preserved photoreceptors in Rpe65-deficient mice, manifested as preserved retinal morphology/outer nuclear layer thickness, increased cone density, reduced photoreceptor oxidative stress/damage and apoptosis, reduced upregulation of genes involved in cell death/inflammatory responses, and reduced macroglial cell activation. These findings demonstrate the role of oxidative stress in photoreceptor degeneration, associated with TH signaling and Rpe65 deficiency, and support the therapeutic potential of resveratrol/antioxidants in the management of retinal degeneration.