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.
Objective: Measure social interaction and social avoidance as an indicator of depression-like behavior in a chronic social defeat stress (CSDS) depression model
This is a Social Interaction Test protocol using mouse as the model organism. The procedure involves 14 procedural steps, 7 equipment items, 4 materials. Extracted from a 2022 paper published in Journal of Neuroinflammation.
Model and subjects
mouse • Not specified • unknown • Not specified • Not specified
Study window
~30 minute study window | ~1 hours hands-on
Core workflow
Chronic Social Defeat Stress (CSDS) Model Implementation • Social Interaction Test • Inhibitor Injection Protocol
Primary readouts
Key equipment and reagents
Verified items
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Perform chronic social defeat stress protocol to establish depression model in mice
Note: This is the baseline stress induction procedure
“A chronic social defeat stress (CSDS) depression model was performed”
Conduct social interaction test to measure social avoidance as indicator of depression-like behavior
Note: One of multiple behavioral tests performed
“Behaviors tests were carried out to examine depressive, anxiety-like and cognitive behaviors including social interaction (SI) test”
Inject EX527 (Sirt1 inhibitor) and ML385 (Nrf2 inhibitor) intraperitoneally 30 minutes before EDA injection daily
Note: Injections performed daily as part of knockdown experiments
“EX527, a Sirt1 inhibitor and ML385, a Nrf2 inhibitor were injected intraperitoneally 30 min before EDA injection daily”
Administer EDA injection daily following inhibitor injection
Note: Timing follows 30 minutes after inhibitor injection
“EX527, a Sirt1 inhibitor and ML385, a Nrf2 inhibitor were injected intraperitoneally 30 min before EDA injection daily”
Perform adeno-associated virus vector containing miRNAi (Gpx4)–EGFP infusion for knockdown experiments
Note: Knockdown experiments performed to determine effects of Gpx4 on CSDS mice with EDA treatment
“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”
Collect hippocampal and medial prefrontal cortex (mPFC) tissues for analysis
Note: Tissues collected for multiple downstream analyses
“Hippocampal and medial prefrontal cortex (mPFC) tissues were collected”
Perform Nissl staining on collected tissues
Note: Part of tissue analysis protocol
“Hippocampal and medial prefrontal cortex (mPFC) tissues were collected for Nissl staining”
Perform immunofluorescence on collected tissues
Note: Part of tissue analysis protocol
“Hippocampal and medial prefrontal cortex (mPFC) tissues were collected for Nissl staining, immunofluorescence”
Perform targeted energy metabolomics analysis on collected tissues
Note: Part of tissue analysis protocol
“targeted energy metabolomics analysis”
Perform enzyme-linked immunosorbent assay (ELISA) on collected tissues
Note: Part of tissue analysis protocol
“enzyme-linked immunosorbent assay (ELISA)”
Measure MDA, SOD, GSH, GSH-PX, and T-AOC levels in collected tissues
Note: Oxidative stress biomarkers measured
“measurement of MDA, SOD, GSH, GSH-PX, T-AOC”
Perform transmission electron microscopy (TEM) on collected tissues
Note: Ultrastructural analysis of tissues
“transmission electron microscopy (TEM)”
Perform Western blotting (WB) to detect Sirt1/Nrf2/HO-1/Gpx4 signaling pathway
Note: Protein expression analysis
“Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) detected the Sirt1/Nrf2/HO-1/Gpx4 signaling pathway”
Perform quantitative real-time polymerase chain reaction (qRT-PCR) to detect Sirt1/Nrf2/HO-1/Gpx4 signaling pathway
Note: Gene expression analysis
“Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) detected the Sirt1/Nrf2/HO-1/Gpx4 signaling pathway”
This section explains what the experiment is doing, which readouts matter, what the data artifacts usually look like, and how the analysis should flow from raw capture to reported result.
Measure social interaction and social avoidance as an indicator of depression-like behavior in a chronic social defeat stress (CSDS) depression model
Objective
Measure social interaction and social avoidance as an indicator of depression-like behavior in a chronic social defeat stress (CSDS) depression model
Subjects
From papermouse • Not specified • unknown • Not specified • Not specified
Cohort notes
From paperCSDS depression model was performed on subjects
Chronic Social Defeat Stress (CSDS) Model Implementation (Not specified)
Social Interaction Test (Not specified)
Inhibitor Injection Protocol (30 minutes before EDA injection)
EDA Treatment Administration (Daily administration)
Social interaction behavior and social avoidance
From paperNot specified in text
Artifact type
Representative image panels with region or marker comparisons
Comparison focus
Compare staining intensity, structure, or cell counts across matched conditions
Depressive-like behavior
From paperNot specified in text
Artifact type
Representative image panels with region or marker comparisons
Comparison focus
Compare staining intensity, structure, or cell counts across matched conditions
Anxiety-like behavior
From paperNot specified in text
Artifact type
Representative image panels with region or marker comparisons
Comparison focus
Compare staining intensity, structure, or cell counts across matched conditions
Cognitive behavior
From paperNot specified in text
Artifact type
Representative image panels with region or marker comparisons
Comparison focus
Compare staining intensity, structure, or cell counts across matched conditions
Social interaction behavior and social avoidance
From paperRaw artifact
Field or section images captured from matched samples
Processed artifact
Selected representative panels with quantified intensity, counts, or area measurements
Final reported form
Per-group imaging summaries with representative figures and quantified endpoints
Depressive-like behavior
From paperRaw artifact
Field or section images captured from matched samples
Processed artifact
Selected representative panels with quantified intensity, counts, or area measurements
Final reported form
Per-group imaging summaries with representative figures and quantified endpoints
Anxiety-like behavior
From paperRaw artifact
Field or section images captured from matched samples
Processed artifact
Selected representative panels with quantified intensity, counts, or area measurements
Final reported form
Per-group imaging summaries with representative figures and quantified endpoints
Cognitive behavior
From paperRaw artifact
Field or section images captured from matched samples
Processed artifact
Selected representative panels with quantified intensity, counts, or area measurements
Final reported form
Per-group imaging summaries with representative figures and quantified endpoints
Acquisition
Capture matched images from the relevant tissue region using the same acquisition settings across samples.
Preprocessing / cleaning
Not specified in text
Scoring or quantification
Quantify the primary readouts for this experiment: Social interaction behavior and social avoidance; Depressive-like behavior; Anxiety-like behavior; Cognitive behavior.
Normalization
Normalize image-derived measurements against the matched acquisition or segmentation rules before comparing groups.
Statistical comparison
Statistical method not yet structured for this page.
Reporting output
Report representative outputs alongside summary comparisons for Social interaction behavior and social avoidance, Depressive-like behavior, Anxiety-like behavior, Cognitive behavior.
Source links and direct wording from the methods section for validation and deeper review.
Citation
Ruozhi Dang et al. (2022). Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway. Journal of Neuroinflammation
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