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

Zhong, Xingwu; Harris, Georgina; Smirnova, Lena; Zufferey, Valentin; Sá, Rita de Cássia da Silveira e; Russo, Fabiele Baldino; Braga, Patricia; Chesnut, Megan; Zurich, Marie-Gabrielle; Högberg, Helena T.; Hartung, Thomas; Pamies, David

doi:10.3389/fncel.2020.00025

Cited by 62 publications

(48 citation statements)

References 83 publications

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“…Although there are some limitations with the cell model including but not limited to kinetics, metabolism, being non-human, nonetheless it is valuable in showing how alternate streams may aid toward mechanistic understanding of classes of compounds. The advent of human brainspheres (Pamies et al 2017 ) now enables similar studies in human cell models (Pamies et al 2018 ; Zhong et al 2020 ) work on FR is ongoing. This model also captures several end points that are not currently evaluated in traditional DNT guideline studies including, but not limited to the role of neurotransmitters and critical receptors that have previously been implicated in neurodevelopment (e.g.…”

Section: Discussionmentioning

confidence: 99%

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Organophosphorus flame retardants are developmental neurotoxicants in a rat primary brainsphere in vitro model

et al. 2020

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Due to regulatory bans and voluntary substitutions, halogenated polybrominated diphenyl ether (PBDE) flame retardants (FR) are increasingly substituted by mainly organophosphorus FR (OPFR). Leveraging a 3D rat primary neural organotypic in vitro model (rat brainsphere), we compare developmental neurotoxic effects of BDE-47—the most abundant PBDE congener—with four OPFR (isopropylated phenyl phosphate—IPP, triphenyl phosphate—TPHP, isodecyl diphenyl phosphate—IDDP, and tricresyl phosphate (also known as trimethyl phenyl phosphate)—TMPP). Employing mass spectroscopy-based metabolomics and transcriptomics, we observe at similar human-relevant non-cytotoxic concentrations (0.1–5 µM) stronger developmental neurotoxic effects by OPFR. This includes toxicity to neurons in the low µM range; all FR decrease the neurotransmitters glutamate and GABA (except BDE-47 and TPHP). Furthermore, n-acetyl aspartate (NAA), considered a neurologic diagnostic molecule, was decreased by all OPFR. At similar concentrations, the FR currently in use decreased plasma membrane dopamine active transporter expression, while BDE-47 did not. Several findings suggest astrogliosis induced by the OPFR, but not BDE-47. At the 5 µM concentrations, the OPFR more than BDE-47 interfered with myelination. An increase of cytokine gene and receptor expressions suggests that exposure to OPFR may induce an inflammatory response. Pathway/category overrepresentation shows disruption in 1) transmission of action potentials, cell–cell signaling, synaptic transmission, receptor signaling, (2) immune response, inflammation, defense response, (3) cell cycle and (4) lipids metabolism and transportation. Taken together, this appears to be a case of regretful substitution with substances not less developmentally neurotoxic in a primary rat 3D model.

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Section: Discussionmentioning

confidence: 99%

“…The exposure to industrial chemicals, including FR, and drugs during early development has been associated with the occurrence of neurodevelopmental disorders in children such as autism, mental retardation, dyslexia, epilepsy or mental deficit (Grandjean and Landrigan 2006 , 2014 ; Rice and Barone 2000 ; Zhong et al 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Organophosphorus flame retardants are developmental neurotoxicants in a rat primary brainsphere in vitro model

et al. 2020

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“…Dopaminergic neurons were especially sensitive to rotenone treatment and showed selective toxicity at "non-cytotoxic" concentrations, sparing astrocytes and other neuron subtypes. Moreover, the model identified the antidepressant paroxetine as a developmental neurotoxicant where synaptogenesis, neurite outgrowth and the number of oligodendrocyte were significantly decreased at therapeutic blood concentrations (Zhong et al 2020). This demonstrates that this model's usefulness for studying neurotoxicity (Schmidt et al 2017) and developmental neurotoxicity (Smirnova et al 2014).…”

Section: Brain Spheroid Neurotoxicity Assaymentioning

confidence: 85%

“…Moreover, the model identified the antidepressant paroxetine as a developmental neurotoxicant where synaptogenesis, neurite outgrowth and the number of oligodendrocyte were significantly decreased at therapeutic blood concentrations (Zhong et al . 2020 ). This demonstrates that this model’s usefulness for studying neurotoxicity (Schmidt et al .…”

Section: Translational Aspects Of Mps: Modelling Neuropathiesmentioning

confidence: 99%

Advances in 3D neuronal microphysiological systems: towards a functional nervous system on a chip

Anderson

Bosak

Högberg

et al. 2021

In Vitro Cell.Dev.Biol.-Animal

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Microphysiological systems (MPS) designed to study the complexities of the peripheral and central nervous systems have made marked improvements over the years and have allowed researchers to assess in two and three dimensions the functional interconnectivity of neuronal tissues. The recent generation of brain organoids has further propelled the field into the nascent recapitulation of structural, functional, and effective connectivities which are found within the native human nervous system. Herein, we will review advances in culture methodologies, focused especially on those of human tissues, which seek to bridge the gap from 2D cultures to hierarchical and defined 3D MPS with the end goal of developing a robust nervous system-on-a-chip platform. These advances have far-reaching implications within basic science, pharmaceutical development, and translational medicine disciplines.

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“…5 Furthermore, the antidepressant drugs have significant adverse effects including constipation, dry mouth, sleeping trouble, cardiotoxicity, neurotoxicity, orthostatic hypotension and sexual dysfunction. [8][9][10][11] It has been also reported that about half of depressed patients have to reduce the dosage of the antidepressant drugs or even stop taking the antidepressant drugs because of the side effects of the drugs. 12 Therefore, seeking a both safe and effective pharmacotherapy with low side effects is still in high demand.…”

mentioning

confidence: 99%

Curcumin in antidepressant treatments: An overview of potential mechanisms, pre‐clinical/clinical trials and ongoing challenges

Zhang

2020

Basic Clin Pharma Tox

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Depression is one of the most common but serious psychiatric disorders affecting millions of people globally, which has become increasingly prevalent during the past few decades. To alleviate this challenging health and social burden, various therapeutic strategies have been developed to achieve efficient treatments for depression. In particular, plenty of chemical ingredients of natural origin have been investigated as new direct antidepressants or served as adjuvants to improve the current treatment outcomes of existing antidepressant drugs. Among them, curcumin, a natural compound derived from the herb Curcuma longa, exhibits a wide range of pharmacological properties and has been considered a potent antidepressant drug with diverse mechanisms including monoaminergic imbalances (associated with serotonin, dopamine, noradrenaline and glutamate), effect on neurotransmitters, neuroprogression, the hypothalamic‐pituitary‐adrenal (HPA) axis disturbances, dysregulated inflammation and immune pathways, oxidative and nitrosative stress, and mitochondrial disturbances. In this review, multiple potential mechanisms of curcumin for treating depression demonstrated in either animal or human studies are summarized. To better understand the significant role of curcumin, specific emphasis will be placed on the aetiopathogenesis of depression. Finally, current pre‐clinical/clinical trials and ongoing challenges of curcumin used for antidepressant treatments will be discussed and their future outlooks will be briefly presented.

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

Cited by 62 publications

References 83 publications

Organophosphorus flame retardants are developmental neurotoxicants in a rat primary brainsphere in vitro model

Organophosphorus flame retardants are developmental neurotoxicants in a rat primary brainsphere in vitro model

Advances in 3D neuronal microphysiological systems: towards a functional nervous system on a chip

Curcumin in antidepressant treatments: An overview of potential mechanisms, pre‐clinical/clinical trials and ongoing challenges

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