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. 2010 Oct;177(4):1725-31.
doi: 10.2353/ajpath.2010.100098. Epub 2010 Aug 13.

Resveratrol prevents light-induced retinal degeneration via suppressing activator protein-1 activation

Shunsuke Kubota  1 , Toshihide Kurihara, Mari Ebinuma, Miyuki Kubota, Kenya Yuki, Mariko Sasaki, Kousuke Noda, Yoko Ozawa, Yuichi Oike, Susumu Ishida, Kazuo Tsubota
Affiliations

Resveratrol prevents light-induced retinal degeneration via suppressing activator protein-1 activation

Shunsuke Kubota et al. Am J Pathol. 2010 Oct.

Abstract

Light damage to the retina accelerates retinal degeneration in human diseases and rodent models. Recently, the polyphenolic phytoalexin resveratrol has been shown to exert various bioactivities in addition to its classical antioxidant property. In the present study, we investigated the effect of resveratrol on light-induced retinal degeneration together with its underlying molecular mechanisms. BALB/c mice with light exposure (5000-lux white light for 3 hours) were orally pretreated with resveratrol at a dose of 50 mg/kg for 5 days. Retinal damage was evaluated by TdT-mediated dUTP nick-end labeling, outer nuclear layer morphometry, and electroretinography. Administration of resveratrol to mice with light exposure led to a significant suppression of light-induced pathological parameters, including TdT-mediated dUTP nick-end labeling-positive retinal cells, outer nuclear layer thinning, and electroretinography changes. To clarify the underlying molecular mechanisms, the nuclear translocation of activator protein-1 subunit c-fos was evaluated by enzyme-linked immunosorbent assay, and the retinal activity of sirtuin 1 was measured by deacetylase fluorometric assay. Retinal activator protein-1 activation, up-regulated following light exposure, was significantly reduced by application of resveratrol. In parallel, retinal sirtuin 1 activity, reduced in animals with light damage, was significantly augmented by resveratrol treatment. Our data suggest the potential use of resveratrol as a therapeutic agent to prevent retinal degeneration related to light damage.

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Figures

Figure 1
Figure 1
Suppression of light-induced apoptotic cell death with resveratrol. A: Representative images of TUNEL staining for retinal sections. B: Quantification of the number of TUNEL-positive cells. Light exposure to vehicle-treated mice induced apoptotic cell death in the ONL, which was significantly reduced by application with resveratrol. n = 9 to 11. *P < 0.05.
Figure 2
Figure 2
Suppression of light-induced ONL thinning with resveratrol. Data obtained at four days (A–E) and two weeks (F–J) after light exposure. A–D and F–I: Representative images of H&E staining for retinal sections. E and J: Quantification of ONL thickness (arrowheads in A–D and F–I). Compared to vehicle-treated mice receiving no light exposure (A and F), light exposure to vehicle-treated mice (C and H) led to significant (red versus green in E and J) reduction of ONL thickness, which was significantly (green versus navy in E and J) recovered by application with resveratrol (D and I). Scale bars = 50 μm. n = 6 to 8. *P < 0.05; **P < 0.01.
Figure 3
Figure 3
Suppression of light-induced retinal dysfunction with resveratrol. Data obtained at four days (A, C, and E) and two weeks (B, D, and F) after light exposure. A and B: Representative ERG wave responses. Quantification of the amplitude of a-wave (C and D) and b-wave (E and F). Light exposure to vehicle-treated mice led to significant reduction of the amplitude of a-wave (C and D) and b-wave (E and F), both of which were significantly recovered by application with resveratrol. n = 6 to 12. *P < 0.05; **P < 0.01.
Figure 4
Figure 4
Suppression of light-induced AP-1 activation with resveratrol. Levels of nuclear translocation of c-fos, the subunit of AP-1, were quantified. Light exposure to vehicle-treated mice significantly induced retinal AP-1 activation, which was significantly suppressed by application with resveratrol. n = 6 to 10. **P < 0.01.
Figure 5
Figure 5
Suppression of light-induced SIRT1 deactivation with resveratrol. Light exposure to vehicle-treated mice led to significant reduction of retinal SIRT1 activity, which was significantly reversed by application with resveratrol. n = 5 to 7. *P < 0.05; **P < 0.01.
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