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

Overview

Journal Front Cell Neurosci

Specialty Cell Biology

Date 2020 Mar 11

PMID 32153365

Citations 32

Authors

Xiali Zhong

Georgina Harris

Lena Smirnova

Valentin Zufferey

Rita de Cassia da Silveira E Sa

Fabiele Baldino Russo

Patricia Cristina Baleeiro Beltrao Braga

Megan Chesnut

Marie-Gabrielle Zurich

Helena T Hogberg

Thomas Hartung

David Pamies

Affiliations

Soon will be listed here.

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, 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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