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This is a Animal Study study (also classified as: Human Clinical Trial).

October 7, 2025Open Access

Novel intranasal delivery of sihosogansan demonstrates rapid antidepressant activity via GABAergic and BDNF/TrkB pathways: identification of potential bioactive quality markers

Key Points

Intranasal sihosogansan significantly enhanced antidepressant effects within 30 minutes in mice and zebrafish.
Key findings include three identified Q-markers of sihosogansan with consistent antidepressant effects across various assays.
Mechanistic investigations revealed significant activation of GABAergic and BDNF signaling pathways in the brain.
These results suggest a rapid treatment strategy that can lead to faster symptom relief in depressive conditions.

Abstract

Abstract Background Sihosogansan (SHSGS) is a traditional medicine used to treat depression. However, conventional oral administration requires high doses and prolonged treatment periods. This study aimed to investigate the rapid antidepressant effects of intranasal SHSGS and to identify its Q-markers. Methods In zebrafish, SHSGS effects were evaluated in an MK-801-induced anxiety model using electroencephalogram (EEG) recordings. In mice, the rapid effects of intranasal versus oral SHSGS were compared through the open field and tail suspension tests. Mechanistic investigations combined computational network analysis with molecular studies of hippocampal tissue and primary neurons. Q-markers were identified through the integrative analysis of gas chromatography–mass spectrometry data, molecular docking, and experimental validation in behavioral and cellular models. Results SHSGS normalized MK-801-induced EEG abnormalities within 30 min in zebrafish, particularly restoring delta/beta and theta/beta ratios. In mice, intranasal SHSGS showed rapid anxiolytic and antidepressant effects at 30 min post-administration, whereas oral administration had no significant effect. SHSGS enhanced gamma-aminobutyric acid (GABA)ergic signaling by increasing hippocampal GABA type B receptor subunit 1, glutamate decarboxylase 67, and GABA levels, while activating the brain-derived neurotrophic factor/tropomyosin receptor kinase B/extracellular signal-regulated protein kinase (BDNF/TrkB/ERK) pathways. Three monoterpenes β-pinene, terpinen-4-ol, and α-terpineol were identified as bioactive Q-markers of SHSGS based on their consistent antidepressant-like effects across behavioral, cellular, and molecular assays. Inhibitor experiments further revealed that α-terpineol’s action required GABA B1 receptor signaling, while β-pinene and terpinen-4-ol showed indirect dependency on GABA B1 receptor or TrkB pathways. Conclusion These findings demonstrate that intranasal SHSGS acts rapidly against depression through the GABAergic and BDNF/TrkB/ERK pathways, with identified Q-markers providing a foundation for optimization of quality.

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