title: RS9, a novel Nrf2 activator, attenuates light-induced death of cells of photoreceptor cells and Müller glia cells.
abstract: 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 RS9, a specific activator of Nrf2, decreases light-induced retinal cell death in vivo and in vitro. Nrf2 was detected in the nucleus of the 661W cells exposed to RS9 and also after light exposure, and the Nrf2-antioxidant response element binding was increased in 661W cells after exposure to RS9. Consequentially, the expression of the phase 2 enzyme's mRNAs of Ho-1, Nqo-1, and Gclm genes was increased in 661W cells after exposure to RS9. Furthermore, RS9 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 in vivo studies (8000 lux, 3 h). Heme oxygenase-1 was increased after light exposure, and Nrf2 was translocated into the nucleus after light exposure in vivo. Silencing of Ho-1 reduced the protective effects of RS9 against light-induced death of 661W cells. These findings indicate that RS9 has therapeutic potential for retinal diseases that are aggravated by light exposure.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Noda
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Nagano
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Otsuka
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kuse
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Yukimichi
authors.initials: Y
authors.lastname: Nakano
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakagami
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Hideaki
authors.identifier: 0000-0003-2046-9001
authors.initials: H
authors.lastname: Hara
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects* / Q000528:radiation effects; D002461:Cell Line, Transformed; D002466:Cell Nucleolus / Q000187:drug effects / Q000528:radiation effects; D003600:Cytosol / Q000187:drug effects / Q000528:radiation effects; D063928:Ependymoglial Cells / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D008027:Light / Q000009:adverse effects*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D050983:NF-E2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D010786:Photoreceptor Cells / Q000187:drug effects* / Q000528:radiation effects; D014176:Protein Biosynthesis / Q000187:drug effects / Q000528:radiation effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D012160:Retina / Q000166:cytology; D012162:Retinal Degeneration / Q000209:etiology / Q000517:prevention & control; D013997:Time Factors; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008565:Membrane Proteins; D050983:NF-E2 Transcription Factor; D034741:RNA, Small Interfering; C000602880:RS9 triterpenoid; D014315:Triterpenes; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: 
  AMD
  ; HO-1; Nrf2; light-induced retinal degeneration; photoreceptor; retina