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RS9, a novel Nrf2 activator, attenuates light-induced death of cells of photoreceptor cells and Müller glia cells.
J Neurochem. 2017 06; 141(5):750-765.JN

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+Show Affiliations

Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.Daiichi Sankyo Co., Ltd., Tokyo, Japan.Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28345128

Citation

Inoue, Yuki, et al. "RS9, a Novel Nrf2 Activator, Attenuates Light-induced Death of Cells of Photoreceptor Cells and Müller Glia Cells." Journal of Neurochemistry, vol. 141, no. 5, 2017, pp. 750-765.
Inoue Y, Shimazawa M, Noda Y, et al. RS9, a novel Nrf2 activator, attenuates light-induced death of cells of photoreceptor cells and Müller glia cells. J Neurochem. 2017;141(5):750-765.
Inoue, Y., Shimazawa, M., Noda, Y., Nagano, R., Otsuka, T., Kuse, Y., Nakano, Y., Tsuruma, K., Nakagami, Y., & Hara, H. (2017). RS9, a novel Nrf2 activator, attenuates light-induced death of cells of photoreceptor cells and Müller glia cells. Journal of Neurochemistry, 141(5), 750-765. https://doi.org/10.1111/jnc.14029
Inoue Y, et al. RS9, a Novel Nrf2 Activator, Attenuates Light-induced Death of Cells of Photoreceptor Cells and Müller Glia Cells. J Neurochem. 2017;141(5):750-765. PubMed PMID: 28345128.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RS9, a novel Nrf2 activator, attenuates light-induced death of cells of photoreceptor cells and Müller glia cells. AU - Inoue,Yuki, AU - Shimazawa,Masamitsu, AU - Noda,Yasuhiro, AU - Nagano,Ryota, AU - Otsuka,Tomohiro, AU - Kuse,Yoshiki, AU - Nakano,Yukimichi, AU - Tsuruma,Kazuhiro, AU - Nakagami,Yasuhiro, AU - Hara,Hideaki, Y1 - 2017/04/18/ PY - 2017/02/06/received PY - 2017/03/12/revised PY - 2017/03/13/accepted PY - 2017/3/28/pubmed PY - 2017/8/18/medline PY - 2017/3/28/entrez KW - AMD KW - HO-1 KW - Nrf2 KW - light-induced retinal degeneration KW - photoreceptor KW - retina SP - 750 EP - 765 JF - Journal of neurochemistry JO - J. Neurochem. VL - 141 IS - 5 N2 - 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. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/28345128/RS9_a_novel_Nrf2_activator_attenuates_light_induced_death_of_cells_of_photoreceptor_cells_and_Müller_glia_cells_ L2 - https://doi.org/10.1111/jnc.14029 DB - PRIME DP - Unbound Medicine ER -