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Clemence Bonnet, Min Zhao, Marie Seminel, Remi Dailleux, Emmanuelle Gelize, Jean Louis Bourges, Francine F Behar-Cohen; Anti-angiogenic effect of Spironolactone on a model of corneal neovascularization. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5406. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Corneal neovascularization (NV) is a vision-threatening condition secondary to inflammatory and hypoxic disorders of the ocular surface. While topical steroids are the first-line treatment for corneal NV, the results are highly variable, with frequent and severe side effects. Glucocorticoids act through binding to both glucorticoid (GR) and mineralocorticoid receptors (MR). MR has been identified as a player in vascular inflammation, fibrosis and angiogenesis, its activation by glucocorticoids could paradoxically contributes to corneal NV. We thus aimed to evaluate the role of MR and the effect of MR antagonism on corneal NV.
Corneal NV was induced in one eye of Lewis rats by a 360° circumstance corneal de-epithelialization and limbal cell scratching. A complete tarsorrhaphy was performed and maintained for 3 days. Rats were treated with systemic spironolactone (25mg/kg/day) or vehicle from day 0 to day 14. A group of rats received a topical micellar formulation releasing spironolactone (0.1%) from day 3 to day 14 compared to placebo micelles. Corneal NV was also induced in transgenic mice with MR invalidation specifically in vascular endothelial cells (Vecadh-MR-KO). Fluorescein and indocyanin green angiographies were performed at day 14 to evaluate the surface of corneal NV. Eyes were removed at day 16 for immunostaining of ED1 and IBA1. Rat cornea and limbus were also dissected at day 7 for quantitative PCR.
Systemic spironolactone significantly reduced the surface of corneal NV compared to vehicle. Immunofluorescence showed that spironolactone diminished ED1 and IBA1 positive macrophages/microglial cells and inhibited their infiltration into the deep stroma. Corneal edema was also reduced with spironolactone. Quantitative PCR showed an up-regulation of GR in spironolactone treated corneas, tilting the GR/MR balance in favor of GR pathway. No difference was observed between the topical micellar treatments. Vecadh-MR-KO mice protected from corneal NV compared to control littermates.
Spironolactone has an anti-angiogenic and anti-inflammatory effect on corneal NV. Vascular endothelial MR play a role in corneal NV development. As MR antagonism up-regulates GR, a combination of spironolactone with glucocorticoid could be tested on corneal NV. Micellar formulation of spironolactone should be further investigated in animals with eyes of large size.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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