Cell-based screening identifies paroxetine as an inhibitor of diabetic endothelial dysfunction

Domokos Gerö, Petra Szoleczky, Kunihiro Suzuki, Katalin Modis, Gabor Oláh, Ciro Coletta, Csaba Szabo

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

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 hyperglycemiainduced 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.

Original languageEnglish (US)
Pages (from-to)953-964
Number of pages12
JournalDiabetes
Volume62
Issue number3
DOIs
StatePublished - Mar 2013

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Paroxetine
Hyperglycemia
Endothelial Cells
Reactive Oxygen Species
Investigational Therapies
Experimental Diabetes Mellitus
Mitochondrial Proteins
Wounds and Injuries
Diabetes Complications
Electron Transport
Mitochondrial DNA
Energy Metabolism
Antidepressive Agents
DNA Damage
Libraries
Acetylcholine
Endothelium
Blood Vessels
Serotonin
Cell Survival

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Cell-based screening identifies paroxetine as an inhibitor of diabetic endothelial dysfunction. / Gerö, Domokos; Szoleczky, Petra; Suzuki, Kunihiro; Modis, Katalin; Oláh, Gabor; Coletta, Ciro; Szabo, Csaba.

In: Diabetes, Vol. 62, No. 3, 03.2013, p. 953-964.

Research output: Contribution to journalArticle

Gerö, Domokos ; Szoleczky, Petra ; Suzuki, Kunihiro ; Modis, Katalin ; Oláh, Gabor ; Coletta, Ciro ; Szabo, Csaba. / Cell-based screening identifies paroxetine as an inhibitor of diabetic endothelial dysfunction. In: Diabetes. 2013 ; Vol. 62, No. 3. pp. 953-964.
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