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Harry A Quigley, Wilmer Glaucoma Center of Excellence Laboratory; Losartan is neuroprotective in experimental mouse glaucoma. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2591.
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© ARVO (1962-2015); The Authors (2016-present)
To assess the neuroprotective effect of losartan
CD1 mice were treated with the angiotensin 1 receptor inhibitor losartan (40-60 mg/kg/day in drinking water) compared to spironolactone at 20 mg/kg/day and to mice without added drug. Forty mice per group underwent unilateral anterior chamber bead injection with elevated intraocular pressure (IOP) up to 6 weeks measured with Tonolab. Ganglion cell axon loss was quantified in optic nerve cross sections. Peripapillary scleral (PPS) thickness was measured in fresh and fixed tissue. Inflation testing and diffusion of fluorescein—dextran (FRAP) in PPS of glaucoma and control eyes, losartan vs. control, was performed in vitro.
With high IOP, median axon loss in the losartan-glaucoma group was 2.5% (p=0.13), significantly lower (p=0.001, multivariable regression) than water-glaucoma and spironolactone-glaucoma groups (medians 26.4%, 28.3% (p<0.0001)). Exposure to elevated IOP (positive integral IOP statistic) was not significantly different among drug and placebo groups. Mean BP was significantly lower in losartan-treated than water alone mice (tail cuff, p=0.001, t test). In losartan-treated mice without elevated IOP, unfixed PPS was thinner than controls (p=0.0017, t test). Water-treated glaucoma eyes had thinner fresh PPS than fellow eyes (p=0.03), but losartan-treated glaucoma eyes were slightly thicker than fellow eyes (p=0.07). In losartan-treated eyes (no glaucoma), fixed PPS thickness was 11% thicker than untreated eyes of control mice (p = 0.005). While fixed PPS in placebo-treated glaucoma eyes was significantly thicker than fellow eyes, losartan-treated glaucoma eyes exposure had unchanged fixed PPS thickness vs. fellow eyes (p=0.6). Inflation tests showed a 40% decrease in strain in losartan-glaucoma eyes compared to controls, while water-glaucoma eyes had only 20% strain decrease (p<0.001). Losartan and spironolactone had no effect on IOP or retinal layer thickness. By FRAP, losartan-glaucoma eyes failed to show decreased PPS diffusion as in control-glaucoma. Western blot and immunohistology of PPS will be shown.
Losartan, an inhibitor of transforming growth factor β activity, was protective for glaucoma damage in mice, associated with substantial PPS changes and despite decreased perfusion pressure. Potential benefits of losartan were changes in dynamic remodeling of scleral matrix components.
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