| Summary: | Age-related macular degeneration (AMD) is a significant visual impairment in older people, and there is no treatment for dry AMD. <i>Spirulina maxima</i> (<i>S. maxima</i>), a cyanobacterium, has inhibitory effects against oxidative stress. However, the protective effects of <i>S. maxima</i> and its underlying mechanisms on blue light (BL)-caused macular degeneration are unknown. We aimed to investigate the protective effects of <i>S. maxima</i> on blue light-caused retinal damage and demonstrate its underlying mechanisms in human retinal pigment epithelial (ARPE-19) cells and Balb/c retinas. Additionally, the active component of <i>S. maxima</i> was examined in the RPE cells. <i>In vitro</i>, <i>S. maxima</i> decreased BL-induced RPE cell death by inhibiting reactive oxygen species (ROS) production. <i>S. maxima</i> inhibited BL-induced inflammation via regulating the NF-κB pathway, inflammatory-related gene expression, and the apoptosis pathway in RPE cells. <i>In vivo</i>, administration of <i>S. maxima</i> inhibited BL-induced retinal degeneration by restoring the thicknesses of whole retina, ONL (outer nuclear layer), INL (inner nuclear layer), and PL (photoreceptor layer) by BL exposure. Phycocyanin exerted protective effects in the pre-and post-treatment system. Therefore, <i>S. maxima</i> could be a potential nutraceutical approach to intercept the patho-physiological processes leading to dry AMD and advancement to wet AMD. Moreover, phycocyanin was a major active compound of <i>S. maxima</i>. These findings need to be investigated in human studies, particularly through a clinical trial.
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