Integrating Molecular Biology and Network Pharmacology to Analyze the Antidepressant Mechanism of Glycyrrhizaglabra.

Abstract

Introduction: Antidepressants have adverse effects and induce drug resistance when used excessively or frequently. Therefore, adjuvants are needed to reduce the use of antidepressants during treatment. Traditional Chinese medicine (TCM) is an important adjunctive approach to depression with safety, environmental protection, and low toxicity. Glycyrrhizaglabra (licorice, GG) is a plant commonly used in various herbal remedies.

Method: To explore the potential antidepressant-related targets of Glycyrrhizaglabra (GG) and its underlying mechanisms, we utilized a combination of animal behavioral experiments, molecular biology, and network pharmacology to analyze the antidepressant effects of GG. Initially, we conducted behavioral assays to verify the capacity of GG to mitigate depressive-like behaviors in mice. Subsequently, we selected 56 active compounds and 695 target compounds of licorice from TCMSP. The PPI network screened 80 core targets for enrichment analysis. Lastly, Western blot and ELISA techniques were utilized to authenticate and corroborate the predicting outcomes of PPI and enrichment analysis.

Result: GG extracts reversed lipopolysaccharide (LPS)-induced depression-like behavior in behavioral tests. The results of enrichment analysis showed that,GG significantly affected neurodegeneration pathways, neuroactive ligand-receptor interaction, cAMP signaling pathway, serotonergic synapse, dopaminergic synapse, and MAPK signaling pathway. Mechanistic studies showed that GG reduced IL-1β, IL-6, and TNF-α levels, 5-HTRA1 expression, and GSK3β phosphorylation in mouse hippocampus. It also increased BDNF and DRD1 expression and CREB and ERK1/2 phosphorylation.

Conclusion: Our experimental results demonstrate that GG targets multiple proteins associated with depression, influencing diverse pathways and consequently regulating depressive-like behaviors in mice.