Cell-based screening identifies paroxetine as an inhibitor of diabetic
endothelial dysfunction.
Authors Gerö D, Szoleczky P, Suzuki K, Módis K, Oláh G, Coletta C, Szabo C
Submitted By Csaba Szabo on 7/10/2013
Status Published
Journal Diabetes
Year 2013
Date Published 3/1/2013
Volume : Pages 62 : 953 - 964
PubMed Reference 23223176
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.

Investigators with authorship
Csaba SzaboUniversity of Texas Medical Branch