Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway

Ruozhi Dang,Mingyang Wang,Xinhui Li,Lanxiang Liu,Julio Licinio,Qingyuan Wu,Haiyang Wang,Ping Ji,Peng Xie,Jianting Zhao,Lianmei Zhong

doi:10.1186/s12974-022-02400-6

Abstract

BackgroundThe inflammation and oxidative stress (OS) have been considered crucial components of the pathogenesis of depression. Edaravone (EDA), a free radical scavenger, processes strong biological activities including antioxidant, anti-inflammatory and neuroprotective properties. However, its role and potential molecular mechanisms in depression remain unclear. The present study aimed to investigate the antidepressant activity of EDA and its underlying mechanisms.MethodsA chronic social defeat stress (CSDS) depression model was performed to explore whether EDA could produce antidepressant effects. Behaviors tests were carried out to examine depressive, anxiety-like and cognitive behaviors including social interaction (SI) test, sucrose preference test (SPT), open field test (OFT), elevated plus maze (EPM), novel object recognition (NOR), tail suspension test (TST) and forced swim test (FST). Hippocampal and medial prefrontal cortex (mPFC) tissues were collected for Nissl staining, immunofluorescence, targeted energy metabolomics analysis, enzyme-linked immunosorbent assay (ELISA), measurement of MDA, SOD, GSH, GSH-PX, T-AOC and transmission electron microscopy (TEM). Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) detected the Sirt1/Nrf2/HO-1/Gpx4 signaling pathway. EX527, a Sirt1 inhibitor and ML385, a Nrf2 inhibitor were injected intraperitoneally 30 min before EDA injection daily. Knockdown experiments were performed to determine the effects of Gpx4 on CSDS mice with EDA treatment by an adeno-associated virus (AAV) vector containing miRNAi (Gpx4)–EGFP infusion.ResultsThe administrated of EDA dramatically ameliorated CSDS-induced depressive and anxiety-like behaviors. In addition, EDA notably attenuated neuronal loss, microglial activation, astrocyte dysfunction, oxidative stress damage, energy metabolism and pro-inflammatory cytokines activation in the hippocampus (Hip) and mPFC of CSDS-induced mice. Further examination indicated that the application of EDA after the CSDS model significantly increased the protein expressions of Sirt1, Nrf2, HO-1 and Gpx4 in the Hip. EX527 abolished the antidepressant effect of EDA as well as the protein levels of Nrf2, HO-1 and Gpx4. Similarly, ML385 reversed the antidepressant and anxiolytic effects of EDA via decreased expressions of HO-1 and Gpx4. In addition, Gpx4 knockdown in CSDS mice abolished EDA-generated efficacy on depressive and anxiety-like behaviors.ConclusionThese findings suggest that EDA possesses potent antidepressant and anxiolytic properties through Sirt1/Nrf2/HO-1/Gpx4 axis and Gpx4-mediated ferroptosis may play a key role in this effect.

Highlights

The inflammation and oxidative stress (OS) have been considered crucial components of the pathogenesis of depression
glutathione peroxidase 4 (Gpx4) knockdown in chronic social defeat stress (CSDS) mice abolished EDA-generated efficacy on depressive and anxiety-like behaviors. These findings suggest that EDA possesses potent antidepressant and anxiolytic properties through Silent information regulator homolog 1 (Sirt1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme oxygenase-1 (HO-1)/Gpx4 axis and Gpx4-mediated ferroptosis may play a key role in this effect
EDA ameliorates depression and anxiety‐related behaviors after CSDS exposure To investigate the effect of EDA on depression, we exposed mice to a well-established animal model of depression, CSDS, and subsequently performed multiple behavioral tests including social interaction (SI), sucrose preference test (SPT), open field test (OFT), novel object recognition (NOR), elevated plus maze (EPM), TST, and forced swim test (FST) (Fig. 1A)

Summary

Introduction

The inflammation and oxidative stress (OS) have been considered crucial components of the pathogenesis of depression. Preclinical and clinical evidence on OS and antioxidant effects of antidepressants addressed that they can scavenge ROS and RNS by scavenging free radicals and inhibiting OS pathways [11]. This process will protect neurons from the effect of OS and alleviate depression. Recent studies have shown that Sirt plays a crucial role in depression and regulates downstream transcription factor including nuclear factor erythroid 2-related factor 2 (Nrf2) and NF-κB to prevent OS and inflammation damage [20,21,22]. Heme oxygenase-1 (HO-1), a critical downstream target stress inducible protein of Nrf, exerts antioxidant stress and anti-inflammatory effects [25]

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Conclusion