Aloe-emodin alleviates CUMS-induced depressive-like behavior in male C57BL6 mice via neuroinflammation

Abstract

The global incidence of depression continues to rise, with its pathogenesis closely linked to neuroinflammation. Within the central nervous system, microglia—as core effector cells of the immune system—serve as key regulators of neuroinflammation while being intrinsically associated with the pathological progression of depression. Given the significant limitations of existing treatments, developing more effective antidepressants has become an urgent scientific challenge. Research indicates that natural products represent a crucial source for antidepressant drug development. Among these, the natural active compound aloe-emodin, with its well-established anti-inflammatory activity, demonstrates highly promising potential for antidepressant applications. To investigate the antidepressant mechanism of aloe-emodin, this study employed network pharmacology prediction methods, validated through in vitro and in vivo experiments. Results indicate that aloe-emodin significantly ameliorates depressive-like behaviour in CUMS-induced depressed mice, enhances sucrose preference, reduces immobility time, and mitigates neuronal damage. Mechanistic studies revealed that this compound blocks glial cell polarisation towards the pro-inflammatory M1 phenotype by activating the PI3K/AKT signalling pathway, inhibiting NF-κB pathway activation, and downregulating the CD68/Iba1 ratio in microglia. ELISA assays further confirmed that aloe emodin significantly reduced inflammatory cytokine expression levels in mouse serum and hippocampal tissue, ultimately exerting neuroinflammatory-alleviating effects. In summary, by modulating the PI3K/AKT/NF-κB signalling pathways and suppressing glial cell-mediated neuroinflammation, aloe emodin effectively alleviates depression-like behaviour, providing a foundation for functional food development.