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Xue Cai, Lijuan Chen, Sudipta Seal, James F. McGinnis; Sustained Therapeutic Effects of Nanoceria In A Mouse Model For AMD. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3638.
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The Vldlr-/- mouse is a model for a form of Age-related Macular Degeneration (AMD) called Retinal Angiomatous Proliferation (RAP). It develops retinal vascular lesions, choroidal neovascularization and retinal degeneration. Previously we showed that nanoceria can inhibit developing neovascularization in Vldlr-/- mice by intravitreal injection at P7 and can regress the existing abnormal blood vessels for one week when administered at P28. This study examines the long-term effect and the mechanisms by which nanoceria act.
Vldlr-/- mice were intravitreally injected with 1µl of 1mM nanoceria at P28. Wild type (wt), untreated Vldlr-/-, and saline injected litter mates were used as controls. At P49, oxidative stress associated gene expression was surveyed by mouse "oxidative stress and antioxidant defense" PCR arrays. The fundus and vessel leakage were observed with a micron III fundoscope. At P49 and P70, retinal neovascular "blebs" (RNV) and choroidal neovascular "tufts" (CNV) were counted using a vascular filling assay. The expression of VEGF, rhodopsin, m-opsin and s-opsin was analyzed by qRT-PCR. The protein levels of ASK1, P38, JNK and NF-ΚB were analyzed by western blots.
Nanoceria significantly up-regulated numerous genes associated with antioxidant production and down-regulated genes related to ROS production, DNA damage and apoptosis. The effect of nanoceria in regressing the existing RNV and CNV lasted for up to 6 weeks (P70) (the last time point we tested). The elevated VEGF in the Vldlr-/- mice was reduced to wt level by nanoceria injection. The expression of rhodopsin and cone opsin in the Vldlr-/- mice was down regulated compared to the wt and was increased in nanoceria treated eyes compared to untreated and saline injected controls. These effects were achieved by modulation of ASK1/P38/JNK/NF-ΚB signal transduction pathway.
Nanoceria are long-lasting catalytic antioxidants which modulate oxidative stress associated-gene expression; down-regulate VEGF expression, up-regulate photoreceptor-specific gene expression and thereby promote photoreceptor survival by a mechanism which suppresses the ASK1/P38/JNK/NF-ΚB signal transduction pathway.
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