Antidepressant Paroxetine Exerts Developmental Neurotoxicity in an iPSC-Derived 3D Human Brain ModelPublications
February 21. 2020
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 (BrainSim™ Myelinated Organoids). 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.
While initial animal testing often costs over $1 million and fails over 90% of the time when applied to humans, BrainSim™ Myelinated Organoids serve as a much lower cost and more accurate alternative. In addition to helping pharmaceutical companies determine potential neurological side effects of chemical compounds and drugs, BrainSim™ also has the potential to reduce drug development time and costs for disorders such as multiple sclerosis and Alzheimer’s disease.
Dr. Hartung noted “There’s a growing concern that we have an epidemic of neurodevelopmental disorders, including autism, and that these might be caused by exposures to common drugs or other chemicals. However, since traditional animal testing is so expensive, we haven’t been able to properly investigate this question.”
AxoSim’s 3D BrainSim™ technology enables human-relevant oligodendrocyte myelination, representing a breakthrough for testing in neurotoxicity and neurodegenerative diseases. This proprietary platform was invented in 2016 by Dr. Thomas Hartung at Johns Hopkins and has been exclusively licensed by AxoSim.