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

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

  • Chin Med. 2025 Oct 6;20(1):162. doi: 10.1186/s13020-025-01219-6.
Khoa Nguyen Tran # 1,  Yeasmin Akter Munni # 1,  Ly Thi Huong Nguyen 2,  Tae Woo Oh 3 4,  Ho Jin Choi 5 6,  Il Soo Moon 5,  In-Jun Yang 7
Affiliations

Affiliations

  • 1 Department of Physiology, Dongguk University College of Korean Medicine, Gyeongju, 38066, Republic of Korea.
  • 2 Department of Neuropsychiatry, College of Korean Medicine, Dongguk University, Goyang, 10326, Republic of Korea.
  • 3 Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu, 41062, Republic of Korea.
  • 4 Department of Korean Convergence Medical Science, University of Science & Technology (UST), 1672 Yuseongdae-Ro, Yuseong-Gu, Daejeon, 34054, Republic of Korea.
  • 5 Department of Anatomy, College of Medicine, Dongguk University, Gyeongju, 38066, Republic of Korea.
  • 6 Medical Institute of Dongguk University, Gyeongju, 38066, Republic of Korea.
  • 7 Department of Physiology, Dongguk University College of Korean Medicine, Gyeongju, 38066, Republic of Korea. injuny@dongguk.ac.kr.
  • # Contributed equally.
PMID: 41047379 DOI: 10.1186/s13020-025-01219-6
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 GABAB1 receptor signaling, while β-pinene and terpinen-4-ol showed indirect dependency on GABAB1 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.

Keywords

Chaihu-shugan-san; Intranasal administration; Neuritogenesis; Q-marker; Rapid-acting antidepressant; Sihosogansan.

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