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M. I. Dorrell, E. Aguilar, R. A. Jacobson, R. Gariano, J. Heckenlively, E. Banin, M. Friedlander; Antioxidant Treatment Rescues Oxidative Stress-Induced Photoreceptor Degeneration That Results From Intraretinal and Subretinal Neovascularization in vldlr-/- Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4547.
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© ARVO (1962-2015); The Authors (2016-present)
Mice deficient for the very low density lipoprotein receptor (VLDLR) are characterized by abnormal intraretinal and subretinal neovascularization (NV). We examined the effects of the abnormal NV in vldlr-/- mice on photoreceptor stability and visual function, and examined the potential protective effects of antioxidant treatment.
Retinas from vldlr-/- mice were fully characterized using H & E, immunohistochemistry, electron microscopy, and fluorescein angiography. Evidence of oxidative stress was assessed using antibodies against acrolein, a product of lipid peroxidation. Photoreceptor degeneration was assessed by comparing the total levels of opsin-1 or rhodopsin mRNA between vldlr-/- or age matched wild-type (WT) control retinas using real-time quantitative RT-PCR normalized to β-actin. The effects on visual function were analyzed by electroretinograms (ERGs). Daily treatments with either an antioxidant cocktail (200 mg/kg ascorbic acid, 20 mg/kg α-lipoic acid, and 10 mg/kg reduced L-glutathione), or vehicle control were administered by feeding for 6 weeks, and the effects on opsin-1 and rhodopsin expression, as well as ERG visual function were assessed.
Subretinal NV associated with VLDLR deficiency is accompanied by a dramatic loss of cones, but only a small reduction in rods. By 1 month of age, opsin-1 mRNA expression was reduced by half, and by 7 months of age opsin mRNA levels in vldlr-/- mouse retinas were only 20% of WT retinal levels. At earlier times, oxidative stress was apparent within the neural retinas of vldlr-/- mice as determined by a dramatic increase in acrolein staining associated with subretinal vessels. The ERGs of 6 month old vldlr-/- mice were abnormal, primarily characterized by delayed signaling, reduction in the oscillatory potentials, and reduced cone responses. In the group treated with antioxidants, the ERGs of vldlr-/- mice were substantially normalized compared to control-treated animals.
Oxidative stress is associated with subretinal NV in vldlr-/- mice, presumably leading to a loss of cones and abnormal visual function. Protection using antioxidants reduces these effects and protects normal visual function. These studies may be applicable to human diseases where excessive retinal NV is associated with photoreceptor degeneration.
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