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other·ophthalmology, glaucoma, preclinical research, biomedical research·PMC10921982

The endothelin receptor antagonist macitentan ameliorates endothelin-mediated vasoconstriction and promotes the survival of retinal ganglion cells in rats

Frontiers in ophthalmology · 14 authors, 11 centres

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TL;DR

This preclinical study in rats used intravitreal endothelin-1 to model acute glaucoma-like injury and tested the drug macitentan.

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The dual endothelin receptor antagonist, macitentan, was administered orally at 5 mg/kg body weight. The central results showed that macitentan attenuated ET-1-induced vasoconstriction and significantly reduced RGC loss, which was 40% in ET-1-only rats. Macitentan treatment resulted in RGC counts similar to control retinas. However, the treatment did not preserve RGC axonal integrity or functionality. The study also observed that ET-1 increased GFAP expression in retina and optic nerve head regions at 24 hours, indicative of glial activation. A limitation is the acute nature of the ET-1 model, which may not fully replicate chronic glaucoma pathology, and the findings are specific to the animal model used. The implications suggest macitentan has neuroprotective potential but may require combination with other therapies to address both somatic and axonal degeneration.

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other

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ophthalmology

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ORIGINAL PAPER

PMC10921982

The endothelin receptor antagonist macitentan ameliorates endothelin-mediated vasoconstriction and promotes the survival of retinal ganglion cells in rats

Frontiers in ophthalmology

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ABSTRACT

Glaucoma is a chronic and progressive eye disease, commonly associated with elevated intraocular pressure (IOP) and characterized by optic nerve degeneration, cupping of the optic disc, and loss of retinal ganglion cells (RGCs). The pathological changes in glaucoma are triggered by multiple mechanisms and both mechanical effects and vascular factors are thought to contribute to the etiology of glaucoma. Various studies have shown that endothelin-1 (ET-1), a vasoactive peptide, acting through its G protein coupled receptors, ET A and ET B , plays a pathophysiologic role in glaucoma. However, the mechanisms by which ET-1 contribute to neurodegeneration remain to be completely understood. Our laboratory and others demonstrated that macitentan (MAC), a pan endothelin receptor antagonist, has neuroprotective effects in rodent models of IOP elevation. The current study aimed to determine if oral administration of a dual endothelin antagonist, macitentan, could promote neuroprotection in an acute model of intravitreal administration of ET-1. We demonstrate that vasoconstriction following the intravitreal administration of ET-1 was attenuated by dietary administration of the ET A /ET B dual receptor antagonist, macitentan (5 mg/kg body weight) in retired breeder Brown Norway rats. ET-1 intravitreal injection produced a 40% loss of RGCs, which was significantly lower in macitentan-treated rats. We also evaluated the expression levels of glial fibrillary acidic protein (GFAP) at 24 h and 7 days post intravitreal administration of ET-1 in Brown Norway rats as well as following ET-1 treatment in cultured human optic nerve head astrocytes. We observed that at the 24 h time point the expression levels of GFAP was upregulated (indicative of glial activation) following intravitreal ET-1 administration in both retina and optic nerve head regions. However, following macitentan administration for 7 days after intravitreal ET-1 administration, we observed an upregulation of GFAP expression, compared to untreated rats injected intravitreally with ET-1 alone. Macitentan treatment in ET-1 administered rats showed protection of RGC somas but was not able to preserve axonal integrity and functionality. The endothelin receptor antagonist, macitentan, has neuroprotective effects in the retinas of Brown Norway rats acting through different mechanisms, including enhancement of RGC survival and reduction of ET-1 mediated vasoconstriction.

CITATION EXPORT

Bindu Kodati, Wei Zhang, Shaoqing He et al.. The endothelin receptor antagonist macitentan ameliorates endothelin-mediated vasoconstriction and promotes the survival of retinal ganglion cells in rats. Frontiers in ophthalmology. (2023). https://doi.org/10.3389/fopht.2023.1185755

AUTHORS

14 · 11 CENTRES

Bindu Kodati, Wei Zhang, Shaoqing He, Jennifer H. Pham, Kallen J. Beall, Zoe E. Swanger, Vignesh R. Krishnamoorthy, Payton E. Harris, Trent Hall, Ashley V. Tran, Renuka M. Chaphalkar, Sai H. Chavala, Dorota L. Stankowska, Raghu R. Krishnamoorthy

1Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, United States
2North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, United States
3Department of Pathology, Children’s Health at Dallas, Dallas, TX, United States
4Department of General Surgery, Honor Health, Phoenix, AZ, United States
5Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TX, United States
6Department of Cell and Molecular Pharmacology, Loyola University, Maywood, IL, United States
7Department of Graduate Medical Education, Medical City, Fort Worth, TX, United States
8Williams College, Williamstown, MA, United States
9School of Natural Sciences and Mathematics, The University of Texas at Dallas, Richardson, TX, United States
10Department of Ophthalmology, School of Medicine, University of California, San Francisco, CA, United States
11Department of Surgery, Burnett School of Medicine at Texas Christian University (TCU), Fort Worth, TX, United States