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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...

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Autores principales: Gerö, Domokos, Szoleczky, Petra, Suzuki, Kunihiro, Módis, Katalin, Oláh, Gabor, Coletta, Ciro, Szabo, Csaba
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2013
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.
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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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