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Losartan Treatment Protects Retinal Ganglion Cells and Alters Scleral Remodeling in Experimental Glaucoma.
PLoS One. 2015; 10(10):e0141137.Plos

Abstract

PURPOSE

To determine if oral losartan treatment decreases the retinal ganglion cell (RGC) death caused by experimental intraocular pressure (IOP) elevation in mice.

METHODS

We produced IOP increase in CD1 mice and performed unilateral optic nerve crush. Mice received oral losartan, spironolactone, enalapril, or no drug to test effects of inhibiting angiotensin receptors. IOP was monitored by Tonolab, and blood pressure was monitored by tail cuff device. RGC loss was measured in masked axon counts and RGC bodies by β-tubulin labeling. Scleral changes that could modulate RGC injury were measured including axial length, scleral thickness, and retinal layer thicknesses, pressure-strain behavior in inflation testing, and study of angiotensin receptors and pathways by reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry.

RESULTS

Losartan treatment prevented significant RGC loss (median loss = 2.5%, p = 0.13), while median loss with water, spironolactone, and enalapril treatments were 26%, 28% and 43%; p < 0.0001). The lower RGC loss with losartan was significantly less than the loss with spironolactone or enalapril (regression model p = 0.001; drug treatment group term p = 0.01). Both losartan and enalapril significantly lowered blood pressure (p< 0.001), but losartan was protective, while enalapril led to worse than water-treated RGC loss. RGC loss after crush injury was unaffected by losartan treatment (difference from control p = 0.9). Survival of RGC in cell culture was not prolonged by sartan treatment. Axonal transport blockade after 3 day IOP elevations was less in losartan-treated than in control glaucoma eyes (p = 0.007). Losartan inhibited effects of glaucoma, including reduction in extracellular signal-related kinase activity and modification of glaucoma-related changes in scleral thickness and creep under controlled IOP.

CONCLUSIONS

The neuroprotective effect of losartan in mouse glaucoma is associated with adaptive changes in the sclera expressed at the optic nerve head.

Authors+Show Affiliations

The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.Department of Mechanical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26505191

Citation

Quigley, Harry A., et al. "Losartan Treatment Protects Retinal Ganglion Cells and Alters Scleral Remodeling in Experimental Glaucoma." PloS One, vol. 10, no. 10, 2015, pp. e0141137.
Quigley HA, Pitha IF, Welsbie DS, et al. Losartan Treatment Protects Retinal Ganglion Cells and Alters Scleral Remodeling in Experimental Glaucoma. PLoS One. 2015;10(10):e0141137.
Quigley, H. A., Pitha, I. F., Welsbie, D. S., Nguyen, C., Steinhart, M. R., Nguyen, T. D., Pease, M. E., Oglesby, E. N., Berlinicke, C. A., Mitchell, K. L., Kim, J., Jefferys, J. J., & Kimball, E. C. (2015). Losartan Treatment Protects Retinal Ganglion Cells and Alters Scleral Remodeling in Experimental Glaucoma. PloS One, 10(10), e0141137. https://doi.org/10.1371/journal.pone.0141137
Quigley HA, et al. Losartan Treatment Protects Retinal Ganglion Cells and Alters Scleral Remodeling in Experimental Glaucoma. PLoS One. 2015;10(10):e0141137. PubMed PMID: 26505191.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Losartan Treatment Protects Retinal Ganglion Cells and Alters Scleral Remodeling in Experimental Glaucoma. AU - Quigley,Harry A, AU - Pitha,Ian F, AU - Welsbie,Derek S, AU - Nguyen,Cathy, AU - Steinhart,Matthew R, AU - Nguyen,Thao D, AU - Pease,Mary Ellen, AU - Oglesby,Ericka N, AU - Berlinicke,Cynthia A, AU - Mitchell,Katherine L, AU - Kim,Jessica, AU - Jefferys,Joan J, AU - Kimball,Elizabeth C, Y1 - 2015/10/27/ PY - 2015/08/20/received PY - 2015/10/05/accepted PY - 2015/10/28/entrez PY - 2015/10/28/pubmed PY - 2016/6/11/medline SP - e0141137 EP - e0141137 JF - PloS one JO - PLoS One VL - 10 IS - 10 N2 - PURPOSE: To determine if oral losartan treatment decreases the retinal ganglion cell (RGC) death caused by experimental intraocular pressure (IOP) elevation in mice. METHODS: We produced IOP increase in CD1 mice and performed unilateral optic nerve crush. Mice received oral losartan, spironolactone, enalapril, or no drug to test effects of inhibiting angiotensin receptors. IOP was monitored by Tonolab, and blood pressure was monitored by tail cuff device. RGC loss was measured in masked axon counts and RGC bodies by β-tubulin labeling. Scleral changes that could modulate RGC injury were measured including axial length, scleral thickness, and retinal layer thicknesses, pressure-strain behavior in inflation testing, and study of angiotensin receptors and pathways by reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry. RESULTS: Losartan treatment prevented significant RGC loss (median loss = 2.5%, p = 0.13), while median loss with water, spironolactone, and enalapril treatments were 26%, 28% and 43%; p < 0.0001). The lower RGC loss with losartan was significantly less than the loss with spironolactone or enalapril (regression model p = 0.001; drug treatment group term p = 0.01). Both losartan and enalapril significantly lowered blood pressure (p< 0.001), but losartan was protective, while enalapril led to worse than water-treated RGC loss. RGC loss after crush injury was unaffected by losartan treatment (difference from control p = 0.9). Survival of RGC in cell culture was not prolonged by sartan treatment. Axonal transport blockade after 3 day IOP elevations was less in losartan-treated than in control glaucoma eyes (p = 0.007). Losartan inhibited effects of glaucoma, including reduction in extracellular signal-related kinase activity and modification of glaucoma-related changes in scleral thickness and creep under controlled IOP. CONCLUSIONS: The neuroprotective effect of losartan in mouse glaucoma is associated with adaptive changes in the sclera expressed at the optic nerve head. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/26505191/Losartan_Treatment_Protects_Retinal_Ganglion_Cells_and_Alters_Scleral_Remodeling_in_Experimental_Glaucoma_ L2 - https://dx.plos.org/10.1371/journal.pone.0141137 DB - PRIME DP - Unbound Medicine ER -