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Svetlana V. Kiosseva, Sudipta Seal, James F. McGinnis; Inherited Neovascular Retinal Lesions are Regressed by Nanoceria-Induced Changes in Expression of Multiple Cytokine and Growth Factor Genes. Invest. Ophthalmol. Vis. Sci. 2011;52(14):421.
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The Very Low-Density Lipoprotein Receptor knockout mouse (Vldlr-/) has been identified as a model for Age-related Macular Degeneration (AMD) and in particular for Retinal Angiomatous Proliferation (RAP). Oxidative stress indicators are greatly increased in Vldlr-/- retina at day 28 compared to the normal retina. Recent evidence from our lab has shown that cerium oxide nanoparticles (nanoceria), injected at p28, cause almost complete regression of illicit blood vessels in the Vldlr-/- retina within one week. In this study, we hypothesized that nanoceria exert their effects by upregulating the expression of cytokine signaling and anti-angiogenic genes and down regulating pro-angiogenic genes.
Vldlr-/- mice received a single intravitreal injection of either saline or 1 µl of 1 mM nanoceria at postnatal day 28 and retinas were dissected at postnatal day 35. Age-matched wild type C57 mice served as controls. Total RNA was isolated and converted into first strand cDNA. Real-time PCR was performed to analyze a panel of genes using a mouse cytokine PCR array (realtimeprimers.com). Data were analyzed and shown as fold changes compared to controls.
Our data demonstrate a significant and differential modulation in the transcriptional responses of cytokine signaling pathway genes after Nanoceria treatment. Of the 88 genes analyzed 34 were upregulated and 18 downregulated. Consistent with the ability of nanoceria to inhibit neovascular lesions, many of the genes that are upregulated are either growth factor genes (neuroprotective) or anti-angiogenesis or anti-inflammatory genes whereas many of those that are down-regulated are pro-angiogenesis.
The Nanoceria do not correct the gene defect in the Vldlr-/- retina but by destroying ROS, the positive downstream effects are those expected from the combinatorial use of multiple anti-oxidant agents. These data suggest that nanoceria will have similar effects in humans and represent a novel therapeutic strategy to treat AMD, RAP and other neurodegenerative diseases associated with oxidative stress.
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