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.

Potential of Müller Glia for Retina Neuroprotection

“…In response to oxidative stress, Müller cells have been shown to upregulate mRNA expression of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), an important antioxidant molecule that regulates transcription of more than 100 antioxidant/cytoprotective genes. 74,75 NRF2 is also a potent inductor of glutathione release, which as indicated above, is a major antioxidant produced by Müller glia in vivo and in vitro. In cultured Müller glia, NRF2 inhibition significantly decreases antioxidant gene expression and exacerbates induced oxidative stress, whilst its activation suppresses oxidant-induced reactive oxygen species.…”

Nrf2 Activator RS9 Suppresses Pathological Ocular Angiogenesis and Hyperpermeability

“…Japan) at a ratio of 1:9 of RS9 to PLA-0020. 31 The concentration of RS9 was 0.3 mM. Sustained-release formulation RS9 PLA0020 was intravitreally administrated four times, just after laser irradiation and 1, 3, and 5 weeks after laser irradiation.…”

“…28 We thought that RS9 would be useful for some diseases related to vascular injuries as a Nrf2 activator. In fact, RS9 also attenuates ischemia reperfusion-or intracerebral hemorrhage-induced brain injury, 29,30 light-induced photoreceptor cell death, 31 and NaIO3-induced retinal pigment epithelium (RPE) cell damage. 32 We hypothesized that the Nrf2 activation would inhibit ocular neovascularization and be effective for hyperpermeability through regulating antioxidant genes.…”

Potential Protective and Therapeutic Roles of the Nrf2 Pathway in Ocular Diseases: An Update

“…2-(3,4,5-trihydroxyphenyl) chromenylium-3,5,7-triol) RPEs Reverses the decreased activities of SOD, CAT, and GSH-PX and the elevated MDA level via increasing nuclear Nrf2 protein expression [229] 4-Hydroxy-7-oxo-5-heptanoate (HOHA) lactone RPEs Induces upregulation of Nrf2, GCLM, HO-1, and NQO1 [230] Melatonin The retina of diabetic rats Significantly upregulates glutamate-cysteine ligase by retaining Nrf2 in the nucleus and stimulating Akt phosphorylation [231] Galangin RECs and RPEs Alleviates DR by reversing TNFα-induced blood-retinal barrier dysfunction by abrogating oxidative stress injury via activating Nrf2 [232] Nonsteroidal anti-inflammatory drugs (NSAIDs) Laser-induced CNV model in rat; RPEs Inhibits neovascularization of choroid through the HO-1-dependent pathway [233]RS9Retinal microvascular endothelial cells (RMECs) Decreases retinal neovascularization through suppressing VEGF expression and increasing Nrf2, HO-1, and NQO1[234] 661W cells and Müller glia cells Enhances the expression of Nrf2 and increases the expression of HO-1, GCLC, GCLM, and NQO1[235] Acetaldehyde dehydrogenase 2 (ALDH2) Diabetic rats' retinas Increases the expression of Nrf2[236] …”