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

Abstract

Background The 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. Methods A 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. Results The 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. Conclusion These 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.

Edaravone Modulates Neuronal GPX4/ACSL4/5-LOX to Promote Recovery After Spinal Cord Injury

“…Edaravone rescues both xCT and GPX4 level after SCI. The upregulation of GPX4 is consistent with the recent mechanism revealed of edaravone on depression, and GPX4 knockdown abolished the effect of edaravone treatment ( Dang et al, 2022 ).…”

“…Recently the study reported the anti-ferroptosis role of edaravone via the anti-ferroptosis proteins, the Nrf/GPX4 pathway on depression ( Dang et al, 2022 ). Here on the other side, we found edaravone reduced the pro-ferroptosis ACSL4 and 5-LOX in SCI.…”

Targeting Molecular Mediators of Ferroptosis and Oxidative Stress for Neurological Disorders

“…Moreover, there is increasing evidence that oxidative stress has close contact with anxiety and depression [98,99]. As a free radical scavenger [100], Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, EDA) can improve depression and anxiety-like behavior, as well as inhibit oxidative stress and neuroinflammation in a mouse model of depression, and knocking down of GPX4 expression in CSDs mouse model can inhibit the therapeutic effect of EDA on depression and anxiety [101]. The study has shown that GPX4 can affect the role of EDA in mouse models of anxiety and depression, which suggests that GPX4mediated ferroptosis may be a potential mechanism affecting anxiety and depression.…”

Zhi-Zi-Chi Decoction Reverses Depressive Behaviors in CUMS Rats by Reducing Oxidative Stress Injury Via Regulating GSH/GSSG Pathway

“…Because brain tissue is the direct target organ of stress stimulation, it can directly and completely reflect the changes of metabolites related to depression caused by a variety of stressors. Therefore, we chose the brain as the research object of analysis ( Dang et al, 2022 ). The whole brain tissue was removed rapidly and quick-frozen by liquid nitrogen before stored at −80°C.…”