The Antioxidant Drug Edaravone Binds to the Aryl Hydrocarbon Receptor (AHR) and Promotes the Downstream Signaling Pathway Activation

Author:

Veroni Caterina1,Olla Stefania2ORCID,Brignone Maria Stefania1,Siguri Chiara2ORCID,Formato Alessia3ORCID,Marra Manuela4ORCID,Manzoli Rosa5,Macario Maria Carla56,Ambrosini Elena1ORCID,Moro Enrico5ORCID,Agresti Cristina1ORCID

Affiliation:

1. Department of Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy

2. Institute for Genetic and Biomedical Research (IRGB), The National Research Council (CNR), Monserrato, 09042 Cagliari, Italy

3. Institute of Biochemistry and Cell Biology, IBBC-CNR, Campus Adriano Buzzati Traverso, Monterotondo Scalo, 00015 Rome, Italy

4. Core Facilities Technical-Scientific Service, Istituto Superiore di Sanità, 00161 Rome, Italy

5. Department of Molecular Medicine, University of Padova, 35121 Padova, Italy

6. Department of Biology, University of Padova, 35121 Padova, Italy

Abstract

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.

Funder

Fondazione Italiana Sclerosi Multipla- FISM

University of Padua

Istituto Superiore di Sanità

Publisher

MDPI AG

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3