Novel <scp>N</scp>rf2 activators from microbial transformation products inhibit blood–retinal barrier permeability in rabbits

Nakagami, Yasuhiro; Masuda, Kayoko; Hatano, Emiko; Inoue, Tatsuya; Matsuyama, Takuya; Iizuka, Mayumi; Ono, Yasunori; Ohnuki, Takashi; Murakami, Yoko; Iwasaki, Masanori; Yoshida, Kazuhiro; Kasuya, Yuko; Komoriya, Satoshi

doi:10.1111/bph.12999

Cited by 27 publications

(30 citation statements)

References 39 publications

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“…Using in vivo studies we demonstrated that oral administration of RS9 inhibits neovascularization in oxygen-induced retinopathy in rats, and an intravitreal injection of RS9 suppressed blood-retinal barrier permeability in glycated albumin-injected rabbits [53]. The chemical structure of RS9 is unique because it contains epoxidation in the A-ring and hydroxylation in the E-ring.…”

Section: Nrf2 Activators Ameliorate Oxidative Stress-related Retinmentioning

confidence: 99%

Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases

Nakagami

2016

Oxidative Medicine and Cellular Longevity

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Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many species. The retina is constantly exposed to reactive oxygen species, and oxidative stress is a major contributor to age-related macular diseases. Moreover, the resulting inflammation and neuronal degeneration are also related to other retinal diseases. The well-known Nrf2 activators, bardoxolone methyl and its derivatives, have been the subject of a number of clinical trials, including those aimed at treating chronic kidney disease, pulmonary arterial hypertension, and mitochondrial myopathies. Recent studies suggest that Nrf2 activation protects the retina from retinal diseases. In particular, this is supported by the finding that Nrf2 knockout mice display age-related retinal degeneration. Moreover, the concept has been validated by the efficacy of Nrf2 activators in a number of retinal pathological models. We have also recently succeeded in generating a novel Nrf2 activator, RS9, using a biotransformation technique. This review discusses current links between retinal diseases and Nrf2 and the possibility of treating retinal diseases by activating the Nrf2 signaling pathway.

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Section: Nrf2 Activators Ameliorate Oxidative Stress-related Retinmentioning

confidence: 99%

Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases

Nakagami

2016

Oxidative Medicine and Cellular Longevity

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“…RS9 is a specific activator of Nrf2 (Nakagami et al . ,b). RS9 alters the permeability of the blood–retinal barrier and has cytoprotective effects in the retina of mice and rabbits (Nakagami et al .…”

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confidence: 99%

“…RS9 alters the permeability of the blood–retinal barrier and has cytoprotective effects in the retina of mice and rabbits (Nakagami et al . ,b). However, a more accurate determination of the mechanism(s) underlying the protective effects of RS9 must be made.…”

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confidence: 99%

RS9, a novel Nrf2 activator, attenuates light‐induced death of cells of photoreceptor cells and Müller glia cells

Inoue

Shimazawa

Noda

et al. 2017

Journal of Neurochemistry

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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.

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“…RS9 and its microspheres were prepared as previously reported. 7 In brief, RS9 and poly-lactic acid in dichloromethane was poured into an aqueous solution for preparation of microspheres. With continuous stirring of the mixture, dichloromethane was evaporated, leaving solid RS9-containing microspheres.…”

Section: Methodsmentioning

confidence: 99%

“…We recently succeeded in obtaining a novel Nrf2 activator, RS9, and demonstrated that RS9 inhibits blood-retinal barrier permeability in rabbits. 7 The present study used optical coherence tomography (OCT) to examine the effectiveness of RS9 in inhibiting retinal degeneration in rhodopsin Pro347Leu rabbits.…”

Section: Introductionmentioning

confidence: 99%