Mechanisms of <i>Ginseng</i> – <i>Polygonatum</i> Medicine in Alleviating Depression with Cognitive Impairment: Regulation of the <i>PI3K/AKT/GSK3β</i> Pathway and Inhibition of Cell Apoptosis

Background Depression, often accompanied by cognitive impairment, remains a major clinical challenge due to the limited efficacy and side effects of conventional anti-depressants. The herbal pair of Ginseng and Polygonatum has demonstrated synergistic effects in tonifying qi, nourishing yin, and improving neurological function. Emerging evidence suggests this combination may offer multi-targeted benefits in alleviating depressive symptoms and cognitive deficits with fewer adverse effects. Purpose: This study employs network pharmacology, molecular docking, and animal experiments to investigate the mechanisms underlying the anti-depressant efficacy of the Ginseng – Polygonatum herbal pair. Materials and Methods The network pharmacology was adopted to analyze Ginseng and Polygonatum to identify core genes and perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyzes. A chronic unpredictable mild stress (CUMS) rat model of depression was established, and after administering Ginseng – Polygonatum extract via gavage, behavioral tests were performed to assess depressive-like symptoms in the CUMS rats. Hematoxylin–eosin (H&amp;E) staining was used to detect neuronal damage in the hippocampal tissue, and the expression levels of interleukin-1 beta (IL-1β), cysteine-aspartic protease 1 (Caspase-1), phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), glycogen synthase kinase 3 beta (GSK3β), B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax) in the rats’ hippocampus were measured. Results The key components of the Ginseng and Polygonatum herbal pair against depression include kaempferol, aposiopolamine, frutinone A, panaxadiol, and n -coumaroyltyramine. The critical targets identified are PIK3CA, AKT1, IL-1β, Bcl-2, Caspase-1, and ICAM1. Molecular docking results indicate that these core components exhibit strong binding affinity to the key targets. Additionally, animal experiments demonstrate that the Ginseng and Polygonatum herbal pair can improve cognitive impairment in CUMS rats by regulating the PI3K/AKT/GSK3β signaling pathway and inhibiting cell apoptosis. Conclusion Ginseng and Polygonatum herbal pair can regulate multiple targets through various active components, influencing several signaling pathways. It modulates biological processes and related pathways, such as inflammatory responses and metabolic functions, to improve depressive symptoms and cognitive impairment in CUMS rats. This effect is likely mediated by the regulation of the PI3K/AKT/GSK3β signaling pathway and the alleviation of cell apoptosis.