The Possible Antidepressant Effect of Celastrol in Reserpine-Induced Depression Rats Model Targeting Foxp3+ Regulatory T (Treg) Cells and NLRP3 Inflammasome-Dependent Pyroptosis

Background: Major depressive disorder (MDD) constitutes a critical public health challenge. Recent research has revealed the immune system's role in its pathogenesis, suggesting that NLRP3 inflammasome-mediated pyroptosis and Treg cells may play a crucial role. Celastrol has attracted interest for its potential in MDD treatment Methods: Rats were divided into 5 equal groups: control, reserpine-induced untreated depression, depression treated with fluoxetine, depression treated with celastrol, and depression treated with fluoxetine+celastrol. Behavioral evaluations were conducted first, subsequently, the hippocampus was dissected for assessment of biochemical, histopathological, and immunohistochemical parameters. Results: Celastrol (CLS) ameliorated depressive-like behaviors, significantly increasing biochemical parameters and Foxp3+ expression. It also significantly improved the histopathological changes and reduced NLRP3 expression. Moreover, the combination treatment group demonstrated superior results across all evaluated parameters compared to the other groups. Conclusion: CLS shows promising preclinical potential for MDD treatment, and its combination with fluoxetine was more effective than either treatment alone.