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Elad Moisseiev, Zeljka Smit-McBride, Sara Modjtahedi, David Telander, Leonard M Hjelmeland, Lawrence S Morse; In Vivo Gene Expression Profiling of the RPE/Choroid Following Intravitreal Steroid Injections Shows Alteration of Circadian Rhythm and Neurotransmitter Signaling. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):226.
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© ARVO (1962-2015); The Authors (2016-present)
We have previously reported that intravitreal injection of triamcinolone and dexamethasone alters retinal gene expression in a mouse model, causing a change in the balance between neuroprotective and neurodegenerative pathways. The purpose of this study was to identify the gene expression effects of these steroids on the retinal pigment epithelial RPE/choroid in mice.
Intravitreal injections were performed transconjunctivally in anesthetized C57BL/6J mice with Hamilton 33g needles delivering 1 ul of solution. In group 1 (n=8) animals received balanced intravitreal salt solution (BSS), in group 2 (n=8) Dexamethasone (2μg), group 3 (n=8) TAA (20μg). The intravitreal concentrations used were comparable to those commonly used in humans. At each time point (1 week and 1 month) 4 mice/group were sacrificed, RPE/choroid tissue collected in RNAlater, RNA isolated, labeled as probe and hybridized to Affymetrix Mouse Genome 430 2.0 microarrays. Differential gene expression of over 34,000 well-characterized mouse genes, in the RPE/choroid was established using GeneSpringGX12.5. One way ANOVA was applied to identify significantly differentially expressed genes at a significance level of p≤0.01. The lists of candidate genes identified by GeneSpring analysis was subjected to pathway analysis using Ingenuity Pathway Analysis (IPA) software.
Both steroids caused differential activation of genes involved in ‘Circadian Rhythm Signaling’ pathway at both time points tested. Both steroids also induced significant changes in the GABA and glutamate signaling pathways, which have been linked to circadian rhythm control. Triamcinolone uniquely induced significant changes in gene expression in ‘Calcium Signaling’ pathway at 1 week, and dexamethasone uniquely affected the ‘Serotonin Receptor Signaling’ pathway.
Understanding how intraocular steroids affect the gene expression of the RPE/choroid is clinically relevant. This in vivo study has elucidated several genes and pathways that are potentially altering the circadian rhythms and several other neurotransmitter pathways in RPE/choroid during intravitreal steroid injections. These changes may be part of the anti-inflammatory effect of steroids, but may also have consequences in the alteration of RPE/choroid function and neurodegeneration of the retina.
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