Abstract
BackgroundDetachment of photoreceptors from the underlying retinal pigment epithelium is seen in various retinal disorders such as retinal detachment and age-related macular degeneration and leads to loss of photoreceptors and vision. Pharmacologic inhibition of photoreceptor cell death may prevent this outcome. This study tests whether systemic administration of tauroursodeoxycholic acid (TUDCA) can protect photoreceptors from cell death after experimental retinal detachment in rodents.Methodology/Principal FindingsRetinal detachment was created in rats by subretinal injection of hyaluronic acid. The animals were treated daily with vehicle or TUDCA (500 mg/kg). TUNEL staining was used to evaluate cell death. Photoreceptor loss was evaluated by measuring the relative thickness of the outer nuclear layer (ONL). Macrophage recruitment, oxidative stress, cytokine levels, and caspase levels were also quantified. Three days after detachment, TUDCA decreased the number of TUNEL-positive cells compared to vehicle (651±68/mm2 vs. 1314±68/mm2, P = 0.001) and prevented the reduction of ONL thickness ratio (0.84±0.03 vs. 0.65±0.03, P = 0.002). Similar results were obtained after 5 days of retinal detachment. Macrophage recruitment and expression levels of TNF-a and MCP-1 after retinal detachment were not affected by TUDCA treatment, whereas increases in activity of caspases 3 and 9 as well as carbonyl-protein adducts were almost completely inhibited by TUDCA treatment.Conclusions/SignificanceSystemic administration of TUDCA preserved photoreceptors after retinal detachment, and was associated with decreased oxidative stress and caspase activity. TUDCA may be used as a novel therapeutic agent for preventing vision loss in diseases that are characterized by photoreceptor detachment.
Highlights
Photoreceptor loss occurs acutely after retinal detachment
After three days of detachment, the outer nuclear layer (ONL) thickness ratio of the vehicle-treated group decreased to 0.6560.03, while tauroursodeoxycholic acid (TUDCA) significantly prevented the reduction of ONL thickness ratio (0.8460.03, P = 0.0016, Fig 1C)
We demonstrate that systemic administration of the hydrophilic bile acid TUDCA has photoreceptor neuroprotective effects in an experimental retinal detachment model and in agreement with studies by others, where TUDCA has been shown to mediate its cytoprotective effects partially through inhibition of caspase mediated apoptosis. [29,30,31] The neuroprotective effect of TUDCA treatment in our model of experimental retinal detachment was correlated with inhibition of caspases 2, 3 and 9 and a decrease in Terminal dUTP Nick-End Labeling (TUNEL)- positive cells
Summary
Photoreceptor loss occurs acutely after retinal detachment. surgery is performed for rhegmatogenous retinal detachment the visual acuity of patients is not always restored after successful reattachment surgery. [1,2,3] In other retinal disorders including age-related macular degeneration and diabetic retinopathy, retinal photoreceptor detachment persists chronically and vision loss progresses for many patients. [4,5] Studies in humans and in experimental animal models have demonstrated that after detachment of the retina, the photoreceptors begin to degenerate and die over time. [6,7,8] therapeutic agents targeting photoreceptor death may improve treatment for retinal disorders associated with retinal detachment.TUDCA is a minor component of human bile and a primary constituent of bear bile. [9,10] Bear bile has been used in Chinese medicine for ophthalmic and hepatic indications for over 3000 years. [9,10] Recently, researchers have tested TUDCA and related bile acids for biological activity using modern scientific methods. [1,2,3] In other retinal disorders including age-related macular degeneration and diabetic retinopathy, retinal photoreceptor detachment persists chronically and vision loss progresses for many patients. This study tests whether the systemic administration of tauroursodeoxycholic acid (TUDCA) can protect photoreceptors from cell death after experimental retinal detachment. We show that this agent has neuroprotective effects, associated with inhibition of apoptosis and decrease in oxidative stress, thereby exhibiting potential as a novel neuroprotective therapeutic drug in eye diseases characterized by photoreceptor cell loss due to retinal detachment. This study tests whether systemic administration of tauroursodeoxycholic acid (TUDCA) can protect photoreceptors from cell death after experimental retinal detachment in rodents
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