Abstract
PurposeTo determine if oral losartan treatment decreases the retinal ganglion cell (RGC) death caused by experimental intraocular pressure (IOP) elevation in mice.MethodsWe 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.ResultsLosartan 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.ConclusionsThe neuroprotective effect of losartan in mouse glaucoma is associated with adaptive changes in the sclera expressed at the optic nerve head.
Highlights
Glaucoma is the most common preventable cause of blindness worldwide [1], and its damaging effects are known to be mediated through alterations at the optic nerve head (ONH) produced by the action intraocular pressure (IOP) [2,3]
The neuroprotective effect of losartan in mouse glaucoma is associated with adaptive changes in the sclera expressed at the optic nerve head
The median Tonolab IOP at each of 5 levels of set IOP did not significantly differ among the eyes of animals that had been treated with losartan, enalapril, or no drug for both glaucoma treated or untreated groups (Fig 1)
Summary
Glaucoma is the most common preventable cause of blindness worldwide [1], and its damaging effects are known to be mediated through alterations at the optic nerve head (ONH) produced by the action intraocular pressure (IOP) [2,3]. In human glaucoma eyes the sclera is stiffer by in vivo indirect measurement [8] and by in vitro inflation testing [9], and undergoes alterations in PPS collagen fiber orientation [10]. The sclera is substantially altered in experimental glaucoma in mice [11] including axial elongation, increase in stiffness on inflation testing [12], loss of non-fibrillar matrix [13] thickening and reorientation of collagenous fiber layers, decreased scleral permeability [14], increased scleral fibroblast activity and division, and increase in integrin-linked and actin-cytoskeletal signaling by proteomic analysis [15]. It is likely that both the baseline state of the sclera and its dynamic alteration could affect the manner in which IOP is translated into a damaging stimulus in glaucoma
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
