Triterpenoid saponins from Platycodon grandiflorus exhibit antidepressant-like effects and are associated with BDNF-mediated neuroplasticity signaling in a chronic stress model

초록

Ethnopharmacological relevance: The roots of Platycodon grandiflorus (Jacq.) A. DC. (Campanulaceae), known as Platycodi Radix (PR), have long been used as a traditional medicine for respiratory ailments and for relieving chest oppression, a symptom associated with qi stagnation and emotional imbalance resembling depressive states. However, the molecular mechanisms underlying this ethnopharmacological effect and neuroplastic signaling remain to be elucidated. Aim of the study: This study aimed to investigate the antidepressant-like activities of PR and its triterpenoid saponins, platycodin D (PD) and platycodin D2 (PD2), and their underlying molecular mechanisms. Materials and methods: In a chronic restraint stress (CRS) mouse model, antidepressant efficacy was evaluated using behavioral assessments, including open field tests and forced swimming tests. Hippocampal microarray and pathway enrichment analyses, as well as the compound combination-oriented natural product database unified terminology (COCONT) database, were used to explore signaling pathways and active components, respectively. The molecular mechanisms underlying brain-derived neurotrophic factor (BDNF) expression and secretion were investigated in N2a cells and hippocampal tissues. The activation of BDNF-related signaling pathways was examined using neurite outgrowth assays, quantitative PCR, immunoblotting, and immunofluorescence analysis. Results: PR extract (PRE), PD, and PD2 significantly improved depressive-like behavioral deficits induced by CRS and restored the expression of hippocampal neuroplasticity markers, including BDNF, neurofilament light, and PSD95. These effects were accompanied by enhanced activities in ERK/cAMP-response element binding protein (CREB) and Akt/mechanistic target of rapamycin (mTOR) signaling pathways. These compounds promoted neurite outgrowth and triggered alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs)dependent Ca2+-mediated BDNF secretion without increasing intracellular BDNF levels. Together, these findings suggest that PD and PD2 may act as neuroactive constituents of PR for the antidepressant-like effects that are associated with activation of BDNF-related neuroplasticity signaling. Conclusion: PR and its triterpenoid saponins, PD and PD2, could alleviate stress-induced depressive symptoms and modulate BDNF-centered neuroplasticity signaling, supporting their potential relevance as phytotherapeutic candidates for depressive disorders.

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