A comprehensive pharmacology study reveals the molecular mechanisms underlying the antidepressant effects of Gastrodiae Rhizoma.

BACKGROUND

Gastrodiae Rhizoma (GR) and its extract have been widely used in the treatment of depression, but the underlying mechanism of its antidepressant effects is unclear due to its numerous components.

PURPOSE

Revealing the cellular and molecular mechanisms underlying the antidepressant effects of GR through a comprehensive pharmacology-based in vivo and in vitro investigation.

METHODS

A mouse model of depression was established using chronic mild stress (CMS) procedure, and the antidepressant effects of GR were evaluated using systematic behavior. Metabolites in GR decoction and in mouse brain were identified by UPLC-QTOF-MS technology. Core components and targets of GR against MDD were screened based on network pharmacology analysis and molecular docking. The mechanism through which GR mitigated MDD was explored using transcriptome analysis, immunohistochemistry and western blotting in vitro and in vivo.

RESULTS

A total of 273 components were identified in the GR decoction, out of which 15 were detected in the brain of depressed mice treated with the GR decoction. We further identified nine key active ingredients, six essential targets, and fifth signaling pathways associated with the therapeutic effects of GR against MDD. We confirmed that the active ingredients of GR can target the neural stem/precursor cells (NSPCs) in the hippocampus of depressed mice to promote neurogenesis, as evidenced by a significant increase in the numbers of DCX cells, BrdU cells, BrdU-DCX cells, and BrdU-NeuN cells within the hippocampus of GR-treated mice compared to salinetreated mice under CMS exposure. Moreover, we have identified that the key active constituents of GR, namely gastrodin and parishin C, exert a targeted effect on EGFR to activate PI3K-Akt signaling in NSPCs, thereby facilitating proliferation and differentiation of NSPCs.

CONCLUSION

The antidepressant effect of GR involves the facilitation of PI3K/Akt-mediated neurogenesis through gastrodin and parishin C targeting EGFR in NSPCs.