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.2013 Sep 11;8(9):e75735.
doi: 10.1371/journal.pone.0075735. eCollection 2013.

Protective effects of resveratrol in experimental retinal detachment

Affiliations

Protective effects of resveratrol in experimental retinal detachment

Wei Huang et al. PLoS One..

Abstract

Background: Oxidative stress is one of the major factors that trigger photoreceptor apoptosis. To investigate whether resveratrol, a potent antioxidant and small molecule activator of the FoxO pathway, would be neuroprotective against photoreceptor cell death in a rodent model of retinal detachment.

Methods: Retinal detachment was created in adult Brown Norway rats by subretinal injection of sodium hyaluronate. The animals were treated daily with vehicle or resveratrol (20 mg/kg) intraperitoneal injection. Photoreceptor death was assessed by counting the number of apoptotic cells with TdT-dUTP terminal nick-end labeling (TUNEL) and measurement of the outer nuclear layer (ONL) thickness 3 days after RD. Changes in expression of FoxO1a, FoxO3a, and FoxO4 were analyzed by western blot. The activity of caspase 3, caspase 8, caspase 9, spectrin and their cleavage forms were studied.

Results: Three days after retinal detachment, caspase 3, caspase 8 and caspase 9 were significantly activated in the detached retina. Spectrin cleavage products at 120 and 145 kDa were also detected. Both caspase and calpain activation are involved in apoptotic photoreceptor cell death in detached retinas. Treatment with resveratrol increases FoxO1a, FoxO3a, and FoxO4 protein expression in detached retinas only. Resveratrol treatment decreases activation of intrinsic and extrinsic caspase apoptotic pathways triggered by RD. The number of TUNEL-positive cells decreases from 1301±51 cells/mm(2) in control groups to 430±35 cells/mm(2) in treatment groups (p<0.05). Resveratrol treatment also demonstrates 59% less ONL thickness loss compared to controls.

Conclusions: Resveratrol treatment up-regulates the FoxO family and blocks Caspase3, 8, and 9 activation. Resveratrol has the potential to be used as a novel therapeutic agent for preventing vision loss in diseases characterized by photoreceptor detachment.

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Conflict of interest statement

Competing Interests:The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Spectrin cleavage in detached retina.
(A) Western blots showing three days after RD, increased expression of 145 and 120-kDa bands in detached retina. Resveratrol treatment only decreases the production of 120-kDa bands. (B) Summary data show a statistically significant increase in the 120-kDa spectrin cleavage product in detached part of retina treated vehicle (RD vehicle) when comparing with attached part of retina (AR) of same eye. Resveratrol treatment significantly decreases 120-kDa spectrin cleavage product (mean ± SEM) in detached retina (RD Resveratrol). (C) Summary data show a statistically significant increase in the 145-kDa spectrin cleavage product in RD vehicle and RD Resveratrol. Resveratrol treatment dose not significantly decrease 145-kDa spectrin cleavage product (mean ± SEM). ★: P< 0.05 statistically significant compare to AR. ✖: P< 0.05 statistically significant compare to RD vehicle.
Figure 2
Figure 2. Effect of Resveratrol on levels of Caspase 3, 8 and 9 in RD.
(A) Western blots showing three days after RD, increased expression of caspase 3, cleaved caspase 3, caspase 8 and caspase 9 in detached retina. Resveratrol treatment decreases cleaved caspase 3, caspase 8 and caspase 9 production. (B) Summary data show a statistically significant deduction of cleaved caspase 3, caspase 8 and caspase 9 in detached part of retina treated Resveratrol (RD Resveratrol) when comparing with detached retina treated with Vehicle (RD Vehicle) (mean ± SEM). ★: P< 0.05 statistically significant compare to RD vehicle.
Figure 3
Figure 3. Systemic Resveratrol administration decreases photoreceptor cell loss in RD.
(A) DAPI (blue) and TUNEL (green) staining of detached retina sections. (B) Quantitative analysis of TUNEL positive cells 3 days after RD with or without daily treatment (20mg/kg/day, I.P.). Resveratrol treatment significantly decreases TUNEL positive cells (p<0.05, n=6).
Figure 4
Figure 4. The protective effect of Resveratrol on ONL.
Quantitative data exhibiting the protective effect of Resveratrol on ONL thickness preservation 3 days after RD. Resveratrol treatment group has 59% less of ONL thickness loss (p<0.05, n=6).
Figure 5
Figure 5. Resveratrol treatment increases FoxO1a, FoxO3a and FoxO4 expression in RD retina.
There is baseline expression of FoxO1a, FoxO3a and FoxO4 in attached retina without Resveratrol treatment, Resveratrol treatment doesn’t change FoxO family protein expression (Con Resveratrol). RD alone also does not increase FoxO family protein expression. Summary data show a statistically significant increase of all three FoxO transcription factors protein level in Resveratrol treatment RD retina (RD Resveratrol).
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