Evaluation of the rotenone-induced activation of the Nrf2 pathway in a neuronal model derived from human induced pluripotent stem cells. (June 2017)

• Record Type: Journal Article
• Authors: Zagoura, Dimitra; Canovas-Jorda, David; Pistollato, Francesca; Bremer-Hoffmann, Susanne; Bal-Price, Anna
• Is Part Of: Neurochemistry international. Volume 106(2017)
• Page Start: 62
• Page End: 73
• Publication Date: 2017-06
• Subjects: Human induced pluripotent stem cells -- Neuronal/glial cultures -- Nrf2 pathway -- Rotenone; AOPs Adverse Outcome Pathways -- ARE Antioxidant-Responsive-Element -- GABA Gamma-Aminobutyric Acid -- GABRA1 Gamma-Aminobutyric Acid Type A Receptor Alpha1 Subunit -- GABRA3 Gamma-Aminobutyric Acid Type A Receptor Alpha3 Subunit -- GAP43 Growth Associated Protein 43 -- GAPDH Glyceraldehyde 3-phosphate dehydrogenase -- GFAP Glial FibrillaryAcidic Protein -- GSR Glutathione Reductase -- GRIA1 Glutamate Ionotropic Receptor AMPA Type Subunit 1 -- HCI High Content Imaging -- hESCs Human Embryonic Stem Cells -- hiPSCs Human Induced Pluripotent Stem Cells -- HMOX1 Heme Oxygenase-1 -- IATA Integrated Approaches to Testing and Assessment -- Keap1 Kelch-like ECH-Associated Protein 1 -- MAP2 Microtubule-Associated Protein 2 -- MEA Multi Electrode Array -- MFR Mean Firing Rate -- NF200 Neurofilament 200 -- NQO1 NAD(P)H Quinone Oxidoreductase 1 -- NR4A2 Nuclear Receptor Subfamily 4 Group A Member 2 -- Nrf2 Nuclear Factor (erythroid-derived 2)-like 2 -- NSCs Neural Stem Cells -- Pax6 Paired Box 6 -- PSCs Pluripotent Stem Cells -- SRXN1 Sulfiredoxin1 -- TH Tyrosine Hydroxylase -- VGlut1 Vesicular Glutamate Transporter 1; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2016.09.004
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: Human induced pluripotent stem cells (hiPSCs) are considered as a powerful tool for drug and chemical screening and development of new in vitro testing strategies in the field of toxicology, including neurotoxicity evaluation. These cells are able to expand and efficiently differentiate into different types of neuronal and glial cells as well as peripheral neurons. These human cells-based neuronal models serve as test systems for mechanistic studies on different pathways involved in neurotoxicity. One of the well-known mechanisms that are activated by chemically-induced oxidative stress is the Nrf2 signaling pathway. Therefore, in the current study, we evaluated whether Nrf2 signaling machinery is expressed in human induced pluripotent stem cells (hiPSCs)-derived mixed neuronal/glial culture and if so whether it becomes activated by rotenone-induced oxidative stress mediated by complex I inhibition of mitochondrial respiration. Rotenone was found to induce the activation of Nrf2 signaling particularly at the highest tested concentration (100 nM), as shown by Nrf2 nuclear translocation and the up-regulation of the Nrf2-downstream antioxidant enzymes, NQO1 and SRXN1. Interestingly, exposure to rotenone also increased the number of astroglial cells in which Nrf2 activation may play an important role in neuroprotection. Moreover, rotenone caused cell death of dopaminergic neurons since a decreased percentage of tyrosine hydroxylase (TH + ) cells was observed. The obtained results suggest that hiPSC-derived mixed neuronal/glial culture could be a valuable in vitro human model for the establishment of neuronal specific assays in order to link Nrf2 pathway activation (biomarker of oxidative stress) with additional neuronal specific readouts that could be applied to in vitro neurotoxicity evaluation. Highlights: Oxidative stress is a common key event in developmental and adult neurotoxicity. hiPSC-derived mixed culture is a reliable model for neurotoxicity testing. Rotenone causes oxidative stress and leads to the activation of the Nrf2 pathway. Rotenone activates Nrf2 and increases astrocytes in hiPSC-derived neurons and glia. Rotenone decreases the number of dopaminergic neurons derived from hiPSCs.