title: Cell-based screening identifies paroxetine as an inhibitor of diabetic endothelial dysfunction.
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 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.
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Domokos
authors.initials: D
authors.lastname: Gerö
authors.forename: Petra
authors.initials: P
authors.lastname: Szoleczky
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Katalin
authors.initials: K
authors.lastname: Módis
authors.forename: Gabor
authors.initials: G
authors.lastname: Oláh
authors.forename: Ciro
authors.initials: C
authors.lastname: Coletta
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects / Q000494:pharmacology; D000975:Antioxidants / Q000009:adverse effects / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology; D002317:Cardiovascular Agents / Q000009:adverse effects / Q000494:pharmacology*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000737:chemistry; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D017374:Paroxetine / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D018687:Antidepressive Agents, Second-Generation; D000975:Antioxidants; D002317:Cardiovascular Agents; D004272:DNA, Mitochondrial; D017374:Paroxetine; D017382:Reactive Oxygen Species; D017367:Selective Serotonin Reuptake Inhibitors