Antidepressant Paroxetine Exerts Developmental Neurotoxicity in an iPSC-Derived 3D Human Brain Model

Frontiers in Cellular Neuroscience
Xiali ZhongDavid Pamies

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are frequently used to treat depression during pregnancy. Various concerns have been raised about the possible effects of these drugs on fetal development. Current developmental neurotoxicity (DNT) testing conducted in rodents is expensive, time-consuming, and does not necessarily represent human pathophysiology. A human, in vitro testing battery to cover key events of brain development, could potentially overcome these challenges. In this study, we assess the DNT of paroxetine-a widely used SSRI which has shown contradictory evidence regarding effects on human brain development using a versatile, organotypic human induced pluripotent stem cell (iPSC)-derived brain model (BrainSpheres). At therapeutic blood concentrations, which lie between 20 and 60 ng/ml, Paroxetine led to an 80% decrease in the expression of synaptic markers, a 60% decrease in neurite outgrowth and a 40-75% decrease in the overall oligodendrocyte cell population, compared to controls. These results were consistently shown in two different iPSC lines and indicate that relevant therapeutic concentrations of Paroxetine induce brain cell development abnormalities which could lead to adverse effects.

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Citations

Jun 5, 2020·Alternatives to Laboratory Animals : ATLA
Sep 8, 2020·Pharmacogenomics·Elena GenovaGiuliana Decorti
Jan 14, 2021·In Vitro Cellular & Developmental Biology. Animal·Wesley A AndersonMichael J Moore
Feb 9, 2021·Toxicological Sciences : an Official Journal of the Society of Toxicology·Thomas B KnudsenTodd J Zurlinden
Aug 8, 2021·International Journal of Molecular Sciences·Megan ChesnutDavid Pamies

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Methods Mentioned

BETA
protein assay
X-ray
genetic modifications

Software Mentioned

Sholl ImageJ
AxoSim
ImageJ
BrainSphere
BrainSpheres
BrainSphereshave

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