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Journal of Traditional Chinese Medicine >

2026 , Vol. 46 >Issue 4: 798 - 808

DOI: https://doi.org/10.19852/j.cnki.jtcm.2026.04.003

Original Articles

Baihe Dihuang decoction (百合地黄汤) activates cannabinoid type 2 receptor to regulate microglial polarization and alleviate anxiety-like behavior in chronic restraint stress mice

  • LUO Qiaoyun ,
  • HAN Yuanshan ,
  • LIU Yang ,
  • TANG Lin ,
  • WANG Tianyu ,
  • WANG Yuhong ,
  • ZHAO Hongqing
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  • 1 School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
    2 Drug Clinical Research Center, the First Hospital, Hunan University of Chinese Medicine, Changsha 410007, China
    3 Pharmaceutical Preparation Center, the first affiliated Hospital, Hunan University of Chinese Medicine, Changsha 410007, China
    4 Academy of Chinese Medical Sciences/Science & Technology Innovation Center, Hunan University of Chinese Medicine, Changsha 410208, China
ZHAO Hongqing, Academy of Chinese Medical Sciences/Science & Technology Innovation Center, Hunan University of Chinese Medicine, Changsha 410208, China. zhaohongq@hnucm.edu.cn,Telephone: +86-731-88459550

Received date: 2025-03-27

  Accepted date: 2025-10-16

  Online published: 2026-08-08

Supported by

National Natural Science Foundation of China: Mechanism Study of Baihe Dihuang Decoction in Ameliorating Neural Pathway Injury of Basolateral Amygdala-Ventral Hippocampus in Anxious Depression via Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase 2(82104836);Natural Science Foundation of Hunan Province: Study on the Mechanism of Anxiolytic Mechanism of Baihe Dihuang Decoction by Activating Cannabinoid Type 2 Receptor to Regulate the Polarization Phenotype of Microglia(2023JJ60482);Mechanism Study of Baihe Dihuang Decoction in Improving Synaptic Homeostasis of Basolateral Amygdala-ventral Hippocampus in Anxious Depression by Regulating Microglial Function via Cannabinoid Type 2 Receptor(2026JJ50265);Scientific Research Project of Hunan Provincial Department of Education: Scientific Research Project of Hunan Provincial Department of Education: Mechanism of Excitatory/Inhibitory Imbalance of Spiny Neurons in Basolateral Amygdala to Nucleus Accumbens Neural Circuit Inducing Anxiety and Intervention Research of Baihe Shugan Anshen Tablets(23B0391);Open Fund of National Key Laboratory Cultivation Base of Chinese Medicinal Powder & Innovative Medicinal Jointly Established by Province and Ministry: Mechanism of Anxiolytic Neural Circuitry of Baihe Jielü Anshen Granules was Studied Based on Basolateral Amygdala to Nucleus Accumbens Neuronal Excitation/Inhibition Imbalance(25PTKF1002);Science and Technology Talent Promotion Project of Hunan Province: Young and Talented Science and Technology Talent Development Program(2023TJ-N22)

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Abstract

OBJECTIVE: To investigate the anxiolytic effects of Baihe Dihuang decoction (百合地黄汤, BDD) and its underlying molecular mechanisms, focusing on cannabinoid type 2 receptor (CB2R)-mediated regulation of microglial polarization and the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB) signaling pathway.

METHODS: A total of 60 male C57BL/6J mice were randomly divided into six groups (n= 10 per group): control group, model group, diazepam (2 mg/kg) group, high-dose BDD (16 g/kg) group, low-dose BDD (8 g/kg) group, and high-dose BDD (16 g/kg) combined with CB2R antagonist AM630 (1 mg/kg) group. Except for the control group, all other groups were subjected to chronic restraint stress (CRS) to establish an anxiety model. Anxiety-like behaviors were assessed using the open field test, light-dark box test, and elevated plus maze. Serum levels of interleukin (IL)-1β, IL-6, IL-10, and IL-4 and amygdala concentrations of 2-arachidonoylglycerol (2-AG) and anandamide (AEA) were quantified by enzyme-linked immunosorbent assay. Hematoxylin and eosin, Nissl, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining were used to evaluate neuronal damage in the amygdala. Immunofluorescence staining was employed to assess microglial polarization and CB2R expression. The expression levels of CB2R and downstream signaling molecules TLR4/MyD88/NF-κB in the amygdala were determined by quantitative polymerase chain reaction and Western blot.

RESULTS: BDD significantly alleviated CRS-induced anxiety-like behaviors and reduced neuronal damage in the amygdala. It downregulated pro-inflammatory cytokines IL-1β, IL-6 and upregulated anti-inflammatory cytokines IL-10, IL-4 in serum while increasing 2-AG and AEA levels in the amygdala. Furthermore, BDD promoted microglial polarization toward the M2 phenotype and enhanced CB2R expression, while suppressing the TLR4/MyD88/NF-κB signaling pathway. The administration of the CB2R antagonist AM630 reversed these effects, confirming the essential role of CB2R activation in the anxiolytic and neuroprotective effects of BDD.

CONCLUSION: BDD treatment activated CB2R, which in turn modulated microglial polarization in the amygdala viathe TLR4/MyD88/NF-κB signaling pathway, thereby alleviating anxiety-like behaviors and exerting neuro-protective effects.

Key words： receptor, cannabinoid, CB2; neuroinflammatory diseases; anxiety disorders; anti-anxiety agents; microglial polarization; Baihe Dihuang decoction

Cite this article

LUO Qiaoyun , HAN Yuanshan , LIU Yang , TANG Lin , WANG Tianyu , WANG Yuhong , ZHAO Hongqing . Baihe Dihuang decoction (百合地黄汤) activates cannabinoid type 2 receptor to regulate microglial polarization and alleviate anxiety-like behavior in chronic restraint stress mice[J]. Journal of Traditional Chinese Medicine, 2026 , 46(4) : 798 -808 . DOI: 10.19852/j.cnki.jtcm.2026.04.003

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