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

A considerable effort has been spent in the past decades to develop targeted therapies 20 for the treatment of demyelinating diseases, such as multiple sclerosis (MS). Among drugs with 21 free radical scavenging activity and oligodendrocyte protecting effects, Edaravone (Radicava) 22 has recently received increasing attention being able to enhance remyelination in experimental 23 in vitro and in vivo disease models. While its beneficial effects are highly supported by 24 experimental evidence, there is currently paucity of information regarding its mechanism of 25 action and main molecular targets. By using high-throughput RNA-seq and biochemical 26 experiments in murine oligodendrocyte progenitors and SH-SY5Y neuroblastoma cells 27 combined with molecular docking and molecular dynamics simulation, we here provide 28 evidence that Edaravone triggers the activation of the aryl hydrocarbon receptor (AHR) 29 signaling by eliciting AHR nuclear translocation and the transcriptional-mediated induction of 30 key cytoprotective gene expression. We also show that an Edaravone-dependent AHR signaling 31 transduction occurs in the zebrafish experimental model, associated with a downstream 32 upregulation of the NRF2 signaling pathway. We finally demonstrate that its rapid 33 cytoprotective and antioxidant actions boost in vivo increased expression of the promyelinating 34 Olig2 transgene. We therefore shed light on a still undescribed potential mechanism of action 35 for this drug, providing further support to its therapeutic potential in the context of debilitating 36 demyelinating conditions.