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Lily L Wong, Sudipta Seal, James F McGinnis; Persistent Pre-conditioning Effects of Nanoceria after Intravitreal Injection—a Microarray Analysis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5034.
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© ARVO (1962-2015); The Authors (2016-present)
Nanoceria are potent catalytic antioxidants. They are effective in slowing retinal degeneration in four rodent models. In vitro studies show that they scavenge reactive oxygen species and possess mimetic activities of two endogenous oxidative enzymes. In healthy rat retinas, nanoceria show no toxic effects apropos retinal function or morphology. In this study, we sought to reveal how the change of the redox environment after a single intravitreal injection of nanoceria altered ocular gene expression.
We delivered 0.344 ng of nanoceria in 2 µl of saline or saline alone to the vitreous of Sprague Dawley rats at 10 weeks of age. Retinas were collected at 24, 48, and 72 hours post injection. Gene expression levels were compared to uninjected animals. Nanoceria at this same dose inhibited rod degeneration in the light damage on-demand rat model when administered three days earlier or 2 hours after bright light exposure. We used the Illumina Rat Ref-12 Whole-Genome Gene Expression BeadChips to interrogate gene expression levels. We used Ingenuity Pathway Analysis (IPA, Qiagen) to find relevant networks and regulators of gene clusters that satisfied the 2.0 fold-change cutoff criterion.
Approximately 4500 ocular genes were identified as significantly expressed at 10% false discovery rate. Over 700 genes were up-regulated after saline injection. Expression levels of these genes returned to uninjected level at 48 and 72 hours. Remarkably, these same genes were up-regulated for all three time points in the nanoceria injected eyes. The IPA analysis identified protein synthesis as the top pathway being up-regulated together with a number of regulators and biological processes that were predicted to be involved according to the gene expression pattern.
We conclude that nanoceria likely act analogous to dietary antioxidants (polyphenols) such as resveratrol, quercetin, etc., by inducing endogenous adaptive cellular stress responses collectively known as “hormesis” to prepare cells for potential insults. We also show that the well documented pre-conditioning effect of intravitreal injection of saline for neuroprotection triggered the same responses but short-lived. Since nanoceria in the rodent retina did not trigger undesirable cellular responses but beneficial ones, they should be deemed safe for treatment of neurodegenerative diseases in humans.
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