| Autor: |
Veroni C; Department of Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy., Olla S; Institute for Genetic and Biomedical Research (IRGB), The National Research Council (CNR), Monserrato, 09042 Cagliari, Italy., Brignone MS; Department of Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy., Siguri C; Institute for Genetic and Biomedical Research (IRGB), The National Research Council (CNR), Monserrato, 09042 Cagliari, Italy., Formato A; Institute of Biochemistry and Cell Biology, IBBC-CNR, Campus Adriano Buzzati Traverso, Monterotondo Scalo, 00015 Rome, Italy., Marra M; Core Facilities Technical-Scientific Service, Istituto Superiore di Sanità, 00161 Rome, Italy., Manzoli R; Department of Molecular Medicine, University of Padova, 35121 Padova, Italy., Macario MC; Department of Molecular Medicine, University of Padova, 35121 Padova, Italy.; Department of Biology, University of Padova, 35121 Padova, Italy., Ambrosini E; Department of Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy., Moro E; Department of Molecular Medicine, University of Padova, 35121 Padova, Italy., Agresti C; Department of Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy. |
| Abstrakt: |
A considerable effort has been spent in the past decades to develop targeted therapies for the treatment of demyelinating diseases, such as multiple sclerosis (MS). Among drugs with free radical scavenging activity and oligodendrocyte protecting effects, Edaravone (Radicava) has recently received increasing attention because of being able to enhance remyelination in experimental in vitro and in vivo disease models. While its beneficial effects are greatly supported by experimental evidence, there is a current paucity of information regarding its mechanism of action and main molecular targets. By using high-throughput RNA-seq and biochemical experiments in murine oligodendrocyte progenitors and SH-SY5Y neuroblastoma cells combined with molecular docking and molecular dynamics simulation, we here provide evidence that Edaravone triggers the activation of aryl hydrocarbon receptor (AHR) signaling by eliciting AHR nuclear translocation and the transcriptional-mediated induction of key cytoprotective gene expression. We also show that an Edaravone-dependent AHR signaling transduction occurs in the zebrafish experimental model, associated with a downstream upregulation of the NRF2 signaling pathway. We finally demonstrate that its rapid cytoprotective and antioxidant actions boost increased expression of the promyelinating Olig2 protein as well as of an Olig2:GFP transgene in vivo. We therefore shed light on a still undescribed potential mechanism of action for this drug, providing further support to its therapeutic potential in the context of debilitating demyelinating conditions. |
