Corni Fructus water extract relieves depressive behaviors by reducing oxidative stress and neuroinflammation as well as modulating gut microbiota.

Abstract

BACKGROUND: Depression is a global public health concern with limited therapies. Traditional Chinese medicines are attractive for safety and multi-target actions. Corni Fructus water extract (CFWE) is a candidate, but its mechanisms and the main active ingredients remain unclear. METHODS: A chronic unpredictable mild stress (CUMS) mouse model was established and given CFWE intervention. Depressive-like behaviors were evaluated by sucrose preference test (SPT), tail suspension test (TST), and open field test (OFT). Hippocampal histopathology was examined using H&E staining. Inflammatory and oxidative stress-related factors in the hippocampus and serum were detected using ELISA kits. RT-qPCR and Western blot measured Nrf2/HO-1 and IκBα/NF-κB pathway components. Gut microbiota and short-chain fatty acids (SCFAs) were analyzed via 16S rRNA sequencing and GC-MS. LC-MS determined the major chemical constituents of CFWE. RESULTS: CFWE significantly alleviated CUMS-induced depressive-like phenotypes, including preserved body weight, reduced immobility time in TST, increased sucrose preference, and greater central distance in OFT (P < 0.05 or P < 0.01). It also increased neuronal survival in hippocampal CA1/CA3 (P < 0.01), lowered pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and MDA (P < 0.05) in serum and hippocampus, and elevated CAT and SOD activities dose-dependently (P < 0.05). Mechanistically, CFWE upregulated Nrf2, HO-1, and IκBα expression, while downregulating phosphorylated NF-κB p65 expression (P < 0.05). It also restored gut microbial diversity (P < 0.05), promoted beneficial taxa (Muribaculaceae and Lactobacillus), enhanced SCFAs production, and elevated peripheral peptide YY (PYY). LC-MS analysis revealed that the main active constituents in CFWE were terpenoid glycosides, flavonoid glycosides, and organic oxygen compounds. CONCLUSION: The antidepressant-like effects of CFWE might involve activation of the Nrf2/HO-1 antioxidant pathway, suppression of the IκBα/NF-κB inflammatory response, and modulation of gut microbiota composition and SCFA metabolism, while PYY might serve as a candidate mediator in gut-brain communication.

Key Findings

• Corni Fructus water extract (CFWE) alleviated depressive-like behaviors in a chronic unpredictable mild stress mouse model.
• CFWE reduced oxidative stress markers (MDA) and pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in serum and hippocampus while increasing antioxidant enzyme activities (CAT and SOD).
• CFWE activated the Nrf2/HO-1 antioxidant pathway and suppressed the IκBα/NF-κB inflammatory pathway.
• CFWE modulated gut microbiota by restoring diversity, promoting beneficial taxa (Muribaculaceae and Lactobacillus), enhancing short-chain fatty acid production, and increasing peripheral peptide YY levels.
• LC-MS identified terpenoid glycosides, flavonoid glycosides, and organic oxygen compounds as the main active constituents of CFWE.

Clinical Significance

Citation

Hui Heping, Liu Ziyang, Mao Haojiet al.. Corni Fructus water extract relieves depressive behaviors by reducing oxidative stress and neuroinflammation as well as modulating gut microbiota. Pharmacology, biochemistry, and behavior. 2026-Nov-01.