Exposure to enriched environment protects the central retinal pigment epithelium and retina on a dry-AMD experimental model in mice

DIEGUEZ HH; ROMEO EH; ALAIMO A; GONZALEZ FLEITAS MC; SANDE PH; ROSENSTEIN RE; DORFMAN D

Nashville

Congreso; XIXth International Symposium On Retinal Degeneration; 2021

RETINAL DEGENERATION MEETINGS

Purpose: Dry age-related macular degeneration (dAMD), the world blindness leading cause in the elderly, is characterized by the progressive degeneration of photoreceptors (PR) and retinal pigment epithelium (RPE) exclusively circumscribed to the macula. Currently, there are not readily available therapies to prevent or delay the disease onset and progression, respectively. We have developed a dAMD experimental model in mice through unilateral superior cervical ganglionectomy (SCGx), which reproduces the disease central hallmarks exclusively circumscribed to the central temporal retina, an area that has been previously described to share some characteristics of the human macula in the mice retina. Environmental enrichment (EE) is a complex paradigm in which sensory, motor, social and cognitive activities are enhanced compared with standard laboratory conditions. Several reports have demonstrated the beneficial effects of EE on different experimental retinal neurodegenerative models. In this context, our aim was to analyze the effect of EE on the outer retina/RPE alterations induced by experimental dAMD. Approach: Adult male C57BL/6j mice were submitted to unilateral SCGx, whereas the contralateral side was submitted to a sham procedure, and 48 h later housed either in enriched environment (EE) or standard environment (SE) for 10 weeks, when visual function (electroretinography and visual behavior tests) as well as retinal histology and ultrastucture were analyzed. RPE oxidative stress markers and mitochondrial mass were assessed at 6 weeks post-SCGx. Results: Exposure to EE prevented the visual dysfunction, the reduction of both RPE melanin content and RPE65-immunoreactivity, and the RPE/PR ultrastructural alterations observed at 10 weeks post-SCGx in eyes from animals housed in SE. Exposure to EE prevented oxidative stress and the decrease in mitochondrial mass at 6 weeks-post-SCGx. Moreover, EE increased BDNF-immunoreactivity and protein levels at the outer retina and RPE exclusively in SCGx-treated eyes. When EE started 4 weeks post-SCGx, it reversed the visual dysfunction as well as the decrease of both RPE melanin content and RPE65-immunoreactivity at 10 weeks post-SCGx. Conclusion: The exposure to EE prevented and reversed the alterations induced by experimental dAMD, possibly through oxidative stress modulation and a BDNF-dependent mechanism. Therefore, EE could become a novel and promising therapeutic strategy for dAMD.