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Losartan Treatment Protects Retinal Ganglion Cells and Alters Scleral Remodeling in Experimental Glaucoma
Harry A Quigley1, Ian F Pitha1, Derek S Welsbie1
1The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
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.
Insights
Oral losartan treatment significantly reduced retinal ganglion cell death in a mouse model of glaucoma. This neuroprotective effect in glaucoma is linked to adaptive scleral changes at the optic nerve head.
Area of Science:
- Ophthalmology
- Neuroscience
- Pharmacology
Background:
- Glaucoma is a leading cause of irreversible blindness.
- Elevated intraocular pressure (IOP) is a primary risk factor for glaucoma.
- Retinal ganglion cell (RGC) death is a hallmark of glaucomatous damage.
Purpose of the Study:
- To investigate the neuroprotective potential of oral losartan in a mouse model of experimental glaucoma.
- To determine if losartan mitigates RGC death induced by elevated IOP.
- To explore the association between losartan treatment and scleral remodeling in glaucoma.
Main Methods:
- Experimental glaucoma was induced in mice by increasing IOP and performing optic nerve crush.
- Mice were treated with oral losartan, spironolactone, enalapril, or a control solution.
- RGC loss was quantified using axon counts and β-tubulin labeling.
- Scleral biomechanics, thickness, and molecular pathways were analyzed.
Main Results:
- Losartan treatment significantly prevented RGC loss (2.5% median loss) compared to controls (26% median loss).
- Losartan's protective effect was superior to spironolactone and enalapril.
- Losartan mitigated IOP-induced axonal transport deficits and modulated scleral changes.
Conclusions:
- Oral losartan exhibits significant neuroprotective effects against RGC death in experimental glaucoma.
- The protective mechanism of losartan involves adaptive changes in the sclera at the optic nerve head.
- Losartan represents a potential therapeutic strategy for managing glaucoma.
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