<scp>RS</scp>9, a novel Nrf2 activator, attenuates light‐induced death of cells of photoreceptor cells and Müller glia cells

<jats:title>Abstract</jats:title><jats:sec><jats:label /><jats:p>The retina is highly sensitive to oxidative stress because of its high consumption of oxygen associated with the phototransductional processes. Recent findings have suggested that oxidative stress is involved in the pathology of age‐related macular degeneration, a progressive degeneration of the central retina. A well‐known environmental risk factor is light exposure, as excessive and continuous light exposure can damage photoreceptors. Nuclear factor‐erythroid 2‐related factor 2 (Nrf2) is a transcriptional factor that controls antioxidative responses and phase 2 enzymes. Thus, we hypothesized that <jats:styled-content style="fixed-case">RS</jats:styled-content>9, a specific activator of Nrf2, decreases light‐induced retinal cell death <jats:italic>in vivo</jats:italic> and <jats:italic>in vitro</jats:italic>. Nrf2 was detected in the nucleus of the 661W cells exposed to <jats:styled-content style="fixed-case">RS</jats:styled-content>9 and also after light exposure, and the Nrf2‐antioxidant response element binding was increased in 661W cells after exposure to <jats:styled-content style="fixed-case">RS</jats:styled-content>9. Consequentially, the expression of the phase 2 enzyme's <jats:styled-content style="fixed-case">mRNA</jats:styled-content>s of <jats:italic>Ho‐1</jats:italic>,<jats:italic> Nqo‐1</jats:italic>, and <jats:italic>Gclm</jats:italic> genes was increased in 661W cells after exposure to <jats:styled-content style="fixed-case">RS</jats:styled-content>9. Furthermore, <jats:styled-content style="fixed-case">RS</jats:styled-content>9 decreased the light‐induced death of 661W cells (2500 lux, 24 h), and also reduced the functional damages and the histological degeneration of the nuclei in the outer nuclear layer or the retina in the <jats:italic>in vivo</jats:italic> studies (8000 lux, 3 h). Heme oxygenase‐1 was increased after light exposure, and Nrf2 was translocated into the nucleus after light exposure <jats:italic>in vivo</jats:italic>. Silencing of <jats:italic>Ho‐1</jats:italic> reduced the protective effects of <jats:styled-content style="fixed-case">RS</jats:styled-content>9 against light‐induced death of 661W cells. These findings indicate that <jats:styled-content style="fixed-case">RS</jats:styled-content>9 has therapeutic potential for retinal diseases that are aggravated by light exposure.</jats:p></jats:sec><jats:sec><jats:label /><jats:p> <jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/png" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/jnc14029-fig-0011-m.png"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text> </jats:p></jats:sec>