TY - JOUR
T1 - Oral administration of a dual ETA /ETB receptor antagonist promotes neuroprotection in a rodent model of glaucoma
AU - Kodati, Bindu
AU - McGrady, Nolan R.
AU - Jefferies, Hayden B.
AU - Stankowska, Dorota L.
AU - Krishnamoorthy, Raghu R.
N1 - Funding Information:
The authors thank Dr. Thomas Yorio for several useful discussions and feedback on this project. The authors thank Dr. Vittorio Porciatti for providing training to learn pattern ERG in his laboratory. RRK and DLS performed Morrison surgeries. BK, NRM, DLS, and HBJ measured IOP. BK, NRM and DLS performed immunohistochemistry, imaging and pattern ERG. RRK and HBJ performed RGC counts. NRM, BK wrote the manuscript. RRK conceived the experimental plan and designed the study. This work was supported by an extramural grant to RRK from the National Eye Institute [R01EY028179] and from an intramural grant from the UNT Health Science Center. The co-first author, Mr. Nolan McGrady, was supported by a NIH training grant [T32AG020494] awarded to the Neurobiology of Aging training program. Macitentan was a kind gift from Actelion Pharmaceuticals.
Funding Information:
discussions and feedback on this project. The authors thank Dr. Vittorio Porciatti for providing training to learn pattern ERG in his laboratory. RRK and DLS performed Morrison surgeries. BK, NRM, DLS, and HBJ measured IOP. BK, NRM and DLS performed immunohistochemistry, imaging and pattern ERG. RRK and HBJ performed RGC counts. NRM, BK wrote the manuscript. RRK conceived the experimental plan and designed the study. This work was supported by an extramural grant to RRK from the National Eye Institute [R01EY028179] and from an intramural grant from the UNT Health Science Center. The co-first author, Mr. Nolan McGrady, was supported by a NIH training grant [T32AG020494] awarded to the Neurobiology of Aging training program. Macitentan was a kind gift from Actelion Pharmaceuticals.
Publisher Copyright:
© 2022 Molecular Vision.
PY - 2022
Y1 - 2022
N2 - 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 contribute to the pathophysiology of glaucoma. The purpose of this study was to determine whether administration of the endothelin receptor antagonist macitentan was neuroprotective to RGCs and optic nerve axons when administered after the onset of intraocular pressure (IOP) elevation in ocular hypertensive rats. 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 IOPlowering 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.
AB - 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 contribute to the pathophysiology of glaucoma. The purpose of this study was to determine whether administration of the endothelin receptor antagonist macitentan was neuroprotective to RGCs and optic nerve axons when administered after the onset of intraocular pressure (IOP) elevation in ocular hypertensive rats. 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 IOPlowering 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.
UR - http://www.scopus.com/inward/record.url?scp=85140008053&partnerID=8YFLogxK
M3 - Article
C2 - 36274816
AN - SCOPUS:85140008053
SN - 1090-0535
VL - 28
SP - 165
EP - 177
JO - Molecular Vision
JF - Molecular Vision
ER -