Oral administration of a dual ET A /ET B receptor antagonist promotes neuroprotection in a rodent model of glaucoma.
| Autor: | Kodati B; University of North Texas Health Science Center, Pharmacology and Neuroscience, North Texas Eye Research Institute, Fort Worth, TX., McGrady NR; Vanderbilt University Medical Center, Nashville, TN., Jefferies HB; University of Texas Health Science Center, McGovern Medical School, Houston, TX., Stankowska DL; University of North Texas Health Science Center, Pharmacology and Neuroscience, North Texas Eye Research Institute, Fort Worth, TX., Krishnamoorthy RR; University of North Texas Health Science Center, Pharmacology and Neuroscience, North Texas Eye Research Institute, Fort Worth, TX. |
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| Jazyk: | angličtina |
| Zdroj: | Molecular vision [Mol Vis] 2022 Aug 07; Vol. 28, pp. 165-177. Date of Electronic Publication: 2022 Aug 07 (Print Publication: 2022). |
| Abstrakt: | 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 (ET Methods: Male and female Brown Norway rats were subjected to the Morrison model of ocular hypertension by injection of hypertonic saline through the episcleral veins. Following IOP elevation, macitentan (5 mg/kg body wt) was administered orally 3 days per week, and rats with IOP elevation were maintained for 4 weeks. RGC function was determined by pattern electroretinography (PERG) at 2 and 4 weeks post-IOP elevation. Rats were euthanized by approved humane methods, and retinal flat mounts were generated and immunostained for the RGC-selective marker Brn3a. PPD-stained optic nerve sections were imaged by confocal microscopy. RGC and axon counts were conducted in a masked manner and compared between the treatment groups. Results: Significant protection against loss of RGCs and optic nerve axons was found following oral administration of macitentan in rats with elevated IOP. In addition, a protective trend for RGC function, as measured by pattern ERG analysis, was evident following macitentan treatment. Conclusions: Macitentan treatment had a neuroprotective effect on RGCs and their axons, independent of its IOP-lowering effect, suggesting that macitentan may 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. (Copyright © 2022 Molecular Vision.) |
| Databáze: | MEDLINE |
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