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Cell-Based Screening Identifies Paroxetine as an Inhibitor of Diabetic Endothelial Dysfunction
We have conducted a phenotypic screening in endothelial cells exposed to elevated extracellular glucose (an in vitro model of hyperglycemia) to identify compounds that prevent hyperglycemia-induced reactive oxygen species (ROS) formation without adversely affecting cell viability. From a focused lib...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581231/ https://www.ncbi.nlm.nih.gov/pubmed/23223176 http://dx.doi.org/10.2337/db12-0789 |
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author | Gerö, Domokos Szoleczky, Petra Suzuki, Kunihiro Módis, Katalin Oláh, Gabor Coletta, Ciro Szabo, Csaba |
author_facet | Gerö, Domokos Szoleczky, Petra Suzuki, Kunihiro Módis, Katalin Oláh, Gabor Coletta, Ciro Szabo, Csaba |
author_sort | Gerö, Domokos |
collection | PubMed |
description | We have conducted a phenotypic screening in endothelial cells exposed to elevated extracellular glucose (an in vitro model of hyperglycemia) to identify compounds that prevent hyperglycemia-induced reactive oxygen species (ROS) formation without adversely affecting cell viability. From a focused library of >6,000 clinically used drug-like and pharmacologically active compounds, several classes of active compounds emerged, with a confirmed hit rate of <0.5%. Follow-up studies focused on paroxetine, a clinically used antidepressant compound that has not been previously implicated in the context of hyperglycemia or diabetes. Paroxetine reduced hyperglycemia-induced mitochondrial ROS formation, mitochondrial protein oxidation, and mitochondrial and nuclear DNA damage, without interfering with mitochondrial electron transport or cellular bioenergetics. The ability of paroxetine to improve hyperglycemic endothelial cell injury was unique among serotonin reuptake blockers and can be attributed to its antioxidant effect, which primarily resides within its sesamol moiety. Paroxetine maintained the ability of vascular rings to respond to the endothelium-dependent relaxant acetylcholine, both during in vitro hyperglycemia and ex vivo, in a rat model of streptozotocin-induced diabetes. Thus, the current work identifies a novel pharmacological action of paroxetine as a protector of endothelial cells against hyperglycemic injury and raises the potential of repurposing of this drug for the experimental therapy of diabetic cardiovascular complications. |
format | Online Article Text |
id | pubmed-3581231 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-35812312014-03-01 Cell-Based Screening Identifies Paroxetine as an Inhibitor of Diabetic Endothelial Dysfunction Gerö, Domokos Szoleczky, Petra Suzuki, Kunihiro Módis, Katalin Oláh, Gabor Coletta, Ciro Szabo, Csaba Diabetes Complications We have conducted a phenotypic screening in endothelial cells exposed to elevated extracellular glucose (an in vitro model of hyperglycemia) to identify compounds that prevent hyperglycemia-induced reactive oxygen species (ROS) formation without adversely affecting cell viability. From a focused library of >6,000 clinically used drug-like and pharmacologically active compounds, several classes of active compounds emerged, with a confirmed hit rate of <0.5%. Follow-up studies focused on paroxetine, a clinically used antidepressant compound that has not been previously implicated in the context of hyperglycemia or diabetes. Paroxetine reduced hyperglycemia-induced mitochondrial ROS formation, mitochondrial protein oxidation, and mitochondrial and nuclear DNA damage, without interfering with mitochondrial electron transport or cellular bioenergetics. The ability of paroxetine to improve hyperglycemic endothelial cell injury was unique among serotonin reuptake blockers and can be attributed to its antioxidant effect, which primarily resides within its sesamol moiety. Paroxetine maintained the ability of vascular rings to respond to the endothelium-dependent relaxant acetylcholine, both during in vitro hyperglycemia and ex vivo, in a rat model of streptozotocin-induced diabetes. Thus, the current work identifies a novel pharmacological action of paroxetine as a protector of endothelial cells against hyperglycemic injury and raises the potential of repurposing of this drug for the experimental therapy of diabetic cardiovascular complications. American Diabetes Association 2013-03 2013-02-14 /pmc/articles/PMC3581231/ /pubmed/23223176 http://dx.doi.org/10.2337/db12-0789 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Complications Gerö, Domokos Szoleczky, Petra Suzuki, Kunihiro Módis, Katalin Oláh, Gabor Coletta, Ciro Szabo, Csaba Cell-Based Screening Identifies Paroxetine as an Inhibitor of Diabetic Endothelial Dysfunction |
title | Cell-Based Screening Identifies Paroxetine as an Inhibitor of Diabetic Endothelial Dysfunction |
title_full | Cell-Based Screening Identifies Paroxetine as an Inhibitor of Diabetic Endothelial Dysfunction |
title_fullStr | Cell-Based Screening Identifies Paroxetine as an Inhibitor of Diabetic Endothelial Dysfunction |
title_full_unstemmed | Cell-Based Screening Identifies Paroxetine as an Inhibitor of Diabetic Endothelial Dysfunction |
title_short | Cell-Based Screening Identifies Paroxetine as an Inhibitor of Diabetic Endothelial Dysfunction |
title_sort | cell-based screening identifies paroxetine as an inhibitor of diabetic endothelial dysfunction |
topic | Complications |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581231/ https://www.ncbi.nlm.nih.gov/pubmed/23223176 http://dx.doi.org/10.2337/db12-0789 |
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