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Novel Thiol Containing Hybrid Antioxidant-Nitric Oxide Donor Small Molecules for Treatment of Glaucoma

Oxidative stress induced death and dysregulation of trabecular meshwork (TM) cells contribute to the increased intraocular pressure (IOP) in primary open angle (POAG) glaucoma patients. POAG is one of the major causes of irreversible vision loss worldwide. Nitric oxide (NO), a small gas molecule, ha...

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Autores principales: Amankwa, Charles E., Gondi, Sudershan R., Dibas, Adnan, Weston, Courtney, Funk, Arlene, Nguyen, Tam, Nguyen, Kytai T., Ellis, Dorette Z., Acharya, Suchismita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068288/
https://www.ncbi.nlm.nih.gov/pubmed/33917924
http://dx.doi.org/10.3390/antiox10040575
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author Amankwa, Charles E.
Gondi, Sudershan R.
Dibas, Adnan
Weston, Courtney
Funk, Arlene
Nguyen, Tam
Nguyen, Kytai T.
Ellis, Dorette Z.
Acharya, Suchismita
author_facet Amankwa, Charles E.
Gondi, Sudershan R.
Dibas, Adnan
Weston, Courtney
Funk, Arlene
Nguyen, Tam
Nguyen, Kytai T.
Ellis, Dorette Z.
Acharya, Suchismita
author_sort Amankwa, Charles E.
collection PubMed
description Oxidative stress induced death and dysregulation of trabecular meshwork (TM) cells contribute to the increased intraocular pressure (IOP) in primary open angle (POAG) glaucoma patients. POAG is one of the major causes of irreversible vision loss worldwide. Nitric oxide (NO), a small gas molecule, has demonstrated IOP lowering activity in glaucoma by increasing aqueous humor outflow and relaxing TM. Glaucomatous pathology is associated with decreased antioxidant enzyme levels in ocular tissues causing increased reactive oxygen species (ROS) production that reduce the bioavailability of NO. Here, we designed, synthesized, and conducted in vitro studies of novel second-generation sulfur containing hybrid NO donor-antioxidants SA-9 and its active metabolite SA-10 to scavenge broad-spectrum ROS as well as provide efficient protection from t-butyl hydrogen peroxide (TBHP) induced oxidative stress while maintaining NO bioavailability in TM cells. To allow a better drug delivery, a slow release nanosuspension SA-9 nanoparticles (SA-9 NPs) was prepared, characterized, and tested in dexamethasone induced ocular hypertensive (OHT) mice model for IOP lowering activity. A single topical eye drop of SA-9 NPs significantly lowered IOP (61%) at 3 h post-dose, with the effect lasting up to 72 h. This class of molecule has high potential to be useful for treatment of glaucoma.
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spelling pubmed-80682882021-04-25 Novel Thiol Containing Hybrid Antioxidant-Nitric Oxide Donor Small Molecules for Treatment of Glaucoma Amankwa, Charles E. Gondi, Sudershan R. Dibas, Adnan Weston, Courtney Funk, Arlene Nguyen, Tam Nguyen, Kytai T. Ellis, Dorette Z. Acharya, Suchismita Antioxidants (Basel) Article Oxidative stress induced death and dysregulation of trabecular meshwork (TM) cells contribute to the increased intraocular pressure (IOP) in primary open angle (POAG) glaucoma patients. POAG is one of the major causes of irreversible vision loss worldwide. Nitric oxide (NO), a small gas molecule, has demonstrated IOP lowering activity in glaucoma by increasing aqueous humor outflow and relaxing TM. Glaucomatous pathology is associated with decreased antioxidant enzyme levels in ocular tissues causing increased reactive oxygen species (ROS) production that reduce the bioavailability of NO. Here, we designed, synthesized, and conducted in vitro studies of novel second-generation sulfur containing hybrid NO donor-antioxidants SA-9 and its active metabolite SA-10 to scavenge broad-spectrum ROS as well as provide efficient protection from t-butyl hydrogen peroxide (TBHP) induced oxidative stress while maintaining NO bioavailability in TM cells. To allow a better drug delivery, a slow release nanosuspension SA-9 nanoparticles (SA-9 NPs) was prepared, characterized, and tested in dexamethasone induced ocular hypertensive (OHT) mice model for IOP lowering activity. A single topical eye drop of SA-9 NPs significantly lowered IOP (61%) at 3 h post-dose, with the effect lasting up to 72 h. This class of molecule has high potential to be useful for treatment of glaucoma. MDPI 2021-04-08 /pmc/articles/PMC8068288/ /pubmed/33917924 http://dx.doi.org/10.3390/antiox10040575 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Amankwa, Charles E.
Gondi, Sudershan R.
Dibas, Adnan
Weston, Courtney
Funk, Arlene
Nguyen, Tam
Nguyen, Kytai T.
Ellis, Dorette Z.
Acharya, Suchismita
Novel Thiol Containing Hybrid Antioxidant-Nitric Oxide Donor Small Molecules for Treatment of Glaucoma
title Novel Thiol Containing Hybrid Antioxidant-Nitric Oxide Donor Small Molecules for Treatment of Glaucoma
title_full Novel Thiol Containing Hybrid Antioxidant-Nitric Oxide Donor Small Molecules for Treatment of Glaucoma
title_fullStr Novel Thiol Containing Hybrid Antioxidant-Nitric Oxide Donor Small Molecules for Treatment of Glaucoma
title_full_unstemmed Novel Thiol Containing Hybrid Antioxidant-Nitric Oxide Donor Small Molecules for Treatment of Glaucoma
title_short Novel Thiol Containing Hybrid Antioxidant-Nitric Oxide Donor Small Molecules for Treatment of Glaucoma
title_sort novel thiol containing hybrid antioxidant-nitric oxide donor small molecules for treatment of glaucoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068288/
https://www.ncbi.nlm.nih.gov/pubmed/33917924
http://dx.doi.org/10.3390/antiox10040575
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