Antidepressant effects of combined eucommia-gastrodia extract via modulation of the HIF-1α–EPO/cAMP–CREB–BDNF pathway: An integrated network pharmacology and in vivo study
Year: 2026
Type: article
Abstract: This study aims to elucidate the pharmacological basis and antidepressant mechanisms of a combined extract from Eucommia ulmoides Oliv. And Gastrodia elata Bl. (Eucommia-Gastrodia extract), employing an integrated strategy that combines UHPLC-QTOF-MS analysis, network pharmacology, molecular docking, and in vivo validation. This research integrated computational approaches network pharmacology, molecular docking and in vivo experimental investigations. Initially, the active constituents of the EGE were identified through ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). Potential targets related to depression were predicted using the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and SwissADME. Protein-protein interaction (PPI) networks were constructed via the STRING database, followed by the development of a comprehensive "drug-active ingredient-target-disease" network. Functional annotation through Gene Ontology (GO) and pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) were conducted on the intersecting targets using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Molecular docking studies were erformed employing AutoDock software to validate the interactions. Finally, the antidepressant-like behavioral effects were evaluated in treated and non-treated corticosterone-induced mouse models using sucrose preference tests, forced swimming tests, open field tests, and tail suspension tests. The morphological impacts and molecular basis of disease on the hippocampal neurons were assessed using Hematoxylin and Eosin staining (HE) staining, Nissl staining, immunohistochemistry, and Western blot analysis to substantiate the identified through network pharmacology. Network pharmacology analysis revealed a complex interplay between identified active ingredients of Eucommia-Gastrodia extract and depression targets. From an initial pool of 131 active components, 34 identified as interacting with 233 shared depression related molecular targets. These targets were involved in 390 biological processes (BP), 60 cellular compounds (CC), 134 molecular functions (MF), and 148 KEGG-enriched signaling pathways. Molecular docking studies highlighted 20 principal compounds that bind to key targets such as AKT1, SRC, HIF-1, CREB, BDNF, and EPO. The Eucommia-Gastrodia extract alleviated depression like behaviors in a cortisol-induced mouse model, as indicated by increased sucrose preference and mobility time, etc. Additionally, the extract restored the levels of neurotransmitters 5-hydroxytryptamine (5-HT) and dopamine (DA), alleviated hippocampal neuronal damage, and increased the positive expression of EPO and BDNF in the hippocampus. Furthermore, treatment with the extract significantly upregulated the protein expression of HIF-1, EPO, EPOR, CREB, p-CREB, BDNF and p-TrkB, which were otherwise downregulated in cortisol-induced depressive mice. The results indicate that the Eucommia-Gastrodia extract containing bioactive compounds such as oxysophocarpine, aucubin, pinoresinol, leonurine, syringaresinol, formononetin, icaritin, casticin, and 6-gingerol mitigates cortisol-induced neurodegeneration and depressive-like behaviors. This effect is mediated through modulation of the of HIF-1α-EPO/cAMP-CREB-BDNF signaling pathways. • This study for the first time identified 131 chemical components of the Eucommia-Gastrodia extract and screened 34 active components. This provides a material basis for future research on the antidepressant effects of the Eucommia-Gastrodia extract. • This study is the first to demonstrate that Eucommia-Gastrodia extract can ameliorate chronic cortisol-induced depressive behaviors. • This study is the first to reveal that Eucommia-Gastrodia extract exerts its antidepressant effect by simultaneously regulating two crucial signaling pathways: HIF-1α-EPO and cAMP-CREB-BDNF. • This study innovatively identifies HIF-1α and its downstream EPO pathway as key mechanisms of antidepressant action. Together with the classical cAMP-CREB-BDNF neurotrophic pathway, this pathway forms a hierarchical network that synergizes the neuroprotective and antidepressant effects. • This study ingeniously combined the "hypoxia stress response" and "neurotrophic support" mechanisms, providing a new strategy for the targeted treatment of depression using EPO or BDNF.
Source: Brain Research Bulletin
Authors: Lanqiong Xue, Zhuoyue Pan, Yao Liu, Qiuling Gan, Dong Liu, Dingding Liu
Language: English
Subfield: Complementary and alternative medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,280
Awards: G7342379427, G7380238, G7533541411, G7621377053
OpenAlex ID: W7143809709