The liver-hippocampus metabolic dialogue: a novel target and mechanism for the antidepressant action of Zhi-Zi-Hou-Po decoction.

BACKGROUND

The Chinese formula Zhi-Zi-Hou-Po decoction (ZZHPD) has been clinically applied for relieving depressive symptoms. Nonetheless, the underlying mechanisms, particularly the role of the liver-hippocampus metabolic correlation, await further clarification.

AIM OF THE STUDIES: This investigation sought to quantify the antidepressant efficacy of ZZHPD and elucidate its therapeutic basis by examining metabolic regulation along the liver-hippocampus metabolic network in a rat model of depression.

MATERIALS AND

METHODS

A depression model was established in rats using chronic restraint stress combined with lipopolysaccharide administration. The animals were treated with ZZHPD or fluoxetine as a positive control. Depressive phenotypes were quantified via three behavioral paradigms: sucrose preference test (SPT), open field exploration (OFT), and forced swim test (FST). Serum biochemical parameters (D-xylose absorption, dopamine, ALT, AST) and liver histopathology were evaluated. Untargeted metabolomics analysis using UPLC-Q-TOF-MS was performed on liver, serum, and hippocampus tissues.

RESULTS

ZZHPD treatment significantly ameliorated depression-like behaviors, improved liver injury markers, normalized intestinal absorption function, and restored dopamine levels. Metabolomic analysis revealed that ZZHPD coordinately regulated metabolic pathways across multiple tissues, primarily involving glycerophospholipid metabolism in all three tissues, purine metabolism and pantothenate/CoA biosynthesis in the liver, while hippocampal tissue specifically exhibited altered alanine, aspartate and glutamate biotransformation.

CONCLUSIONS

ZZHPD exerts significant antidepressant effects through multi-tissue metabolic regulation along the liver-hippocampus metabolic network, furnishing a metabolic rationale for the traditional Chinese medicine tenet of "treating depression from the liver".