Losartan Treatment Protects Retinal Ganglion Cells and Alters Scleral Remodeling in Experimental Glaucoma

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.

Therapeutic targets of renin-angiotensin system in ocular disorders

“…Additionally, it also reduces aqueous humor formation by reducing blood flow in the ciliary body 96 . AT 1 RBs may be slightly increased uveoscleral outflow 94 and effectively suppresses retinal ganglion cell death 132, 133…”

The connective tissue phenotype of glaucomatous cupping in the monkey eye - Clinical and research implications

“…While these concepts remain central to the discussion of ONH biomechanics in general, and the pathophysiology of glaucomatous damage to the ONH tissues specifically, a large group of investigators have expanded our understanding of glaucoma through the application of biomechanics and mechanobiology to the cornea (He and Liu, 2009, 2011; Liu and He, 2009; Liu and Roberts, 2005), trabecular meshwork (Braakman et al, 2014; Li et al, 2012; Overby et al, 2009; Stamer et al, 2014; Thomasy et al, 2012; Zhou et al, 2012), sclera (Coudrillier et al, 2013; Coudrillier et al, 2015a, b; Coudrillier et al, 2015c; Dastiridou et al, 2013; Fazio et al, 2014a; Fazio et al, 2014b; Girard et al, 2011b; Grytz et al, 2014; Nguyen and Ethier, 2015; Pijanka et al, 2012; Quigley et al, 2015) and ONH (Clark, 2012; Downs, 2015; Eilaghi et al, 2010; Girard et al, 2016; Girard et al, 2011a; Girard et al, 2013; Grytz et al, 2012a; Lei et al, 2011; Sigal et al, 2012; Sigal and Ethier, 2009; Sigal et al, 2005b, 2009a, b; Sigal and Grimm, 2012; Sigal et al, 2014; Stewart et al, 2014; Wang et al, 2016; Zhang et al, 2015) in health and disease. In sections 2.2 through 2.10, the details of these concepts are reviewed.…”

Neuroprotection for glaucoma: Requirements for clinical translation

“…Intracellular signaling of axonal damage can be interrupted with dual leucine zipper kinase (DLK) inhibitors (Huntwork-Rodriguez et al, 2013; Welsbie et al, 2013) or reduction in reactive oxygen species (Almasieh et al, 2011; Kanamori et al, 2010). Modulation of scleral rigidity via TGFβ signaling pathways can prevent mechanical effects on optic nerve head neurons or glia (Quigley et al, 2015). Gene therapy (Dahlmann-Noor et al, 2010; Johnson et al, 2010; Martin et al, 2003) can provide a mechanism to induce or repress any of the previously listed targets, while broader-acting interventions such as exercise can have wide-ranging effects (Roddy and Ellemberg, 2012).…”

“…Histone deacetylase inhibitors, for example, are currently used for cancer treatment and are considered neuroprotective in CNS disease (Pelzel et al, 2010; Schmitt et al, 2015). Similarly, potential drugs which are already marketed for other uses include CoQ10 (which can serve as an electron carrier in the mitochondrial electron transport chain (Lee et al, 2014)), losartan (which is a selective angiotensin 1 receptor that can modulate scleral rigidity via the TGFβ pathway (Quigley et al, 2015)), and others. The vast number of biochemical pathways and potential treatments hint at the complexity of glaucoma as a disease and the potential need for multiple drugs in a treatment regimen, or alternatively, the tailoring of treatment to the dominant mechanism operative in each individual.…”