Oral administration of a dual ETA/ETB receptor antagonist promotes neuroprotection in a rodent model of glaucoma

Purpose: Glaucoma is a neurodegenerative disease associated with elevated intraocular pressure and characterized by optic nerve axonal degeneration, cupping of the optic disc and loss of retinal ganglion cells (RGCs). The endothelin (ET) system of vasoactive peptides (ET-1, ET-2, ET-3) and their G-protein coupled receptors (ETA and ETB receptors) have been shown to be contributors to the pathophysiology of glaucoma. The purpose of this study was to determine if administration of the endothelin receptor antagonist, macitentan, after the onset of IOP elevation, was neuroprotective to retinal ganglion cells in ocular hypertensive rats. Methods: Brown Norway rats were subjected to the Morrison model of ocular hypertension by injection of hypertonic saline through episcleral veins. Macitentan (5 and 10 mg/kg body wt/day) was administered orally following the elevation of IOP and rats with IOP elevation were maintained for 4 weeks. RGC function was determined by pattern electroretinography at 2 and 4 weeks post IOP elevation. Rats were euthanized by approved humane methods and retinal flat-mounts generated were immunostained with RGC-selective markers RBPMS and Brn3a. RGC counts were conducted in a masked manner. Results: A significant protection of retinal ganglion cells against cell loss was found following oral administration of macitentan (5 and 10 mg/kg body wt/day) in rats with elevated intraocular pressure. In addition, treatment with macitentan was able to preserve RGC function as measured by pattern ERG analysis. Conclusions: Macitentan was able to promote neuroprotection independent of IOP-lowering suggesting that this could complement existing treatments to prevent neurodegeneration during ocular hypertension. The findings presented have implications for the use of macitentan as an oral formulation to promote neuroprotection in glaucoma patients.