Eleutheroside B alleviates LPS-induced depressive-like behaviors by suppressing the TLR4/MyD88/NF-κB signaling pathway in the dentate gyrus

Background: Inflammation is closely linked to depression, and natural compounds show promise for treating inflammatory depression, though their mechanisms remain unclear. Eleutheroside B (EB), a key bioactive component of the classic Araliaceae plant Eleutherococcus senticosus with various central protective effects, but its antidepressant properties remain to be explored.

Objective: The aim of this research is to investigate the antidepressant effect of EB and elucidate its underlying molecular mechanisms.

Methods: Lipopolysaccharide (LPS)-induced inflammatory depression model was used to induce inflammatory responses and depressive symptoms in mice. Behaviorally, novel object recognition (NOR), tail suspension test (TST) and sucrose preference test (SPT) were used to determine depression-like behaviors. Stereotactic brain injections were also performed. Molecularly, western blotting (WB) and immunofluorescence (IF) were used to detect the changes at the molecular level. Moreover, network pharmacology, molecular docking and molecular dynamics provided strong support for this study.

Results: LPS-induced depression mice showed significant neuroinflammation in the hippocampal dentate gyrus (DG) and CA3, which was manifested as microglia activation (Iba1) and increased pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Continuous EB administration (100 mg/kg) significantly improved depressive-like behavior and reduced neuroinflammation in LPS mice. Network pharmacology identified TLR4 signaling as a potential EB target, which was validated by molecular docking (binding energy = -5.8 kcal/mol) and molecular dynamics simulations. Molecular experiments showed that EB significantly down-regulated the activation of TLR4/MyD88/NF-κB in the DG but had no effect on the CA3. EB administered directly in the DG has antidepressant effects. These behavioral outcomes were all significantly different in the DG but not CA3.

Conclusions: Our findings establish that EB alleviates neuroinflammation and ameliorates depressive-like phenotypes in mice by suppressing TLR4 signaling specifically in the DG, providing novel insights into the molecular mechanism underlying the antidepressant activity of EB.

Dentate gyrus; Depression; Eleutheroside B; Neuroinflammation; TLR4.