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L. M. Hernandez-Denlinger, J. L. Edelman; A Surrogate Model of Intravitreal Glucocorticoid-Induced Cataract and Ocular Hypertension. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1658. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Intravitreal glucocorticoid (GC) pharmacotherapy is a primary treatment option for multiple retinal indications such as vein occlusions, uveitis, and diabetic macular edema. A potentially use-limiting drawback to chronic GC treatment is its potential to cause posterior lens subcapsular cataract and ocular hypertension (steroid glaucoma). Since there are no animal models that reproducibly mimic these side-effects, we developed a surrogate model in rabbits that measures the effects of intravitreal GC administration on changes in gene expression in crystalline lens and aqueous drainage tissue (e.g. trabecular meshwork).
Female Dutch Belt rabbits were treated intravitreally with 2 mg Kenalog-40 (triamcinolone acetonide (ivtTA)), 1 mg fluocinolone acetonide (ivtFA), or appropriate vehicle. At 1 and 3 weeks after GC injection, total RNA was extracted from the excised lens and aqueous drainage tissue. The mRNA was reverse transcribed to cDNA, and the expression of twenty-one GC-sensitive genes was quantified with real-time PCR using rabbit-specific Taqman probes and primers.
In lens, ivtFA resulted in changes in the expression of 12/21 genes, including the suppression of COLA1 by 93% and upregulation of PDGFRB by 8.1-fold at week 1, and the upregulation of FGF-2 by 11.0-fold at week 3. In comparison, ivtTA altered the expression of fewer lens-associated genes (5/21). In aqueous drainage tissue, ivtTA and ivtFA altered the expression of 9/21 genes (80% overlap), the most notable changes in gene expression were the suppression of COLA1 by 65-81% and the upregulation of myocilin by 3.8-4.8 fold.
Intravitreal fluocinolone acetonide and triamcinolone acetonide generate overlapping but unique patterns of gene expression in lens and aqueous drainage tissue. This newly developed animal model may be useful in the discovery of glucocorticoids with reduced side-effect profiles.
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