Abstract
BackgroundOxidative 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.MethodsRetinal detachment was created in adult Brown Norway rats by subretinal injection of sodium hyaluronate. The animals were treated daily with vehicle or resveratrol (20mg/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.ResultsThree 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/mm2 in control groups to 430±35 cells/mm2 in treatment groups (p<0.05). Resveratrol treatment also demonstrates 59% less ONL thickness loss compared to controls.ConclusionsResveratrol 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.
Highlights
Photoreceptors are the primary transducers of visual stimuli and receive the majority of their nutritional and metabolic support from the underlying retinal pigment epithelium (RPE)
Calpain activation is involved in apoptotic photoreceptor cell death in detached retinas In order to study whether calpain activation is involved in a rat retinal detachment model, immunoblot analysis was performed using an antibody that recognizes both the caspase specific 120-kDa and the calpain specific 145-kDa fragments of cleaved spectrin
Resveratrol treatment only decreases the production of the 120-kDa band of spectrin and not the 145-KDa band
Summary
Photoreceptors are the primary transducers of visual stimuli and receive the majority of their nutritional and metabolic support from the underlying retinal pigment epithelium (RPE). Surgery can be done to reattach the retina, only two fifths of patients with a rhegmatogenous retinal detachment involving the macula recover 20/40 or better vision. Those that lose vision appear to do so because of photoreceptor death [1]. 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. Spectrin cleavage products at 120 and 145 kDa were detected Both caspase and calpain activation are involved in apoptotic photoreceptor cell death in detached retinas. Resveratrol treatment decreases activation of intrinsic and extrinsic caspase apoptotic pathways triggered by RD. 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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