Journal of Traditional Chinese Medicine ›› 2026, Vol. 46 ›› Issue (4): 798-808.DOI: 10.19852/j.cnki.jtcm.2026.04.003
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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 Qiaoyun1, HAN Yuanshan2, LIU Yang4, TANG Lin3, WANG Tianyu1, WANG Yuhong4, ZHAO Hongqing4(
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School of Pharmacy ,Hunan University of Chinese Medicine Changsha 410208, China
2Drug Clinical Research Center ,the First Hospital, Hunan University of Chinese Medicine Changsha 410007, China
3Pharmaceutical Preparation Center ,the first affiliated Hospital, Hunan University of Chinese Medicine Changsha 410007, China
4Academy of Chinese Medical Sciences/Science & Technology Innovation Center ,Hunan University of Chinese Medicine Changsha 410208, China
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Received:2025-03-27Accepted:2025-10-16Online:2026-08-15Published:2026-08-08 -
Contact: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
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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)
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.
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Figure 1 HPLC fingerprints of the main components of BDD extracts A: sample chromatogram; B: mixed standards; C: negative control lacking Baihe (Bulbus Lilii Lancifolii); D: negative control lacking. Peaks: 1: regaloside C; 2: regaloside A; 3: verbascoside; 4: isoacteoside; 5: regaloside; HPLC: high-performance liquid chromatography; BDD: Baihe Dihuang decoction.
Figure 1 HPLC fingerprints of the main components of BDD extracts A: sample chromatogram; B: mixed standards; C: negative control lacking Baihe (Bulbus Lilii Lancifolii); D: negative control lacking. Peaks: 1: regaloside C; 2: regaloside A; 3: verbascoside; 4: isoacteoside; 5: regaloside; HPLC: high-performance liquid chromatography; BDD: Baihe Dihuang decoction.
Figure 2 Effect of BDD on anxiety-like behavior in CRS mice A: distance in the center area in the OFT, OFT: open field test;; B: entries in the open arm of the EPM, EPM: elevated plus maze; C: time spent in the open arm of the EPM; D: distance in the light area of the LDT, LDT: light-dark box test; E: residence time in the light area of the LDT; F: immobility time in the FST, FST: forced swim test. Ctrl: control group (distilled water); Model: model group (CRS + distilled water); DZP: diazepam group (CRS + 2 mg/kg diazepam); BDD-H: high dose of BDD group (CRS + 16 g/kg BDD); BDD-L: low dose of BDD group (CRS + 8 g/kg BDD); AM630: high dose of BDD combined with AM630 group (CRS + 16 g/kg BDD + 1 mg/kg AM630). BDD: Baihe Dihuang decoction; CRS: chronic restraint stress; ANOVA: analysis of variance. Statistical significance was assessed using one way ANOVA, followed by pairwise comparisons between groups using the t-test. Data were presented as mean ± standard deviation (n = 10). aP < 0.01, eP < 0.05, vs the control group; bP < 0.01, dP < 0.05, vs the model group; cP < 0.05, vs the BDD-H group.
Figure 2 Effect of BDD on anxiety-like behavior in CRS mice A: distance in the center area in the OFT, OFT: open field test;; B: entries in the open arm of the EPM, EPM: elevated plus maze; C: time spent in the open arm of the EPM; D: distance in the light area of the LDT, LDT: light-dark box test; E: residence time in the light area of the LDT; F: immobility time in the FST, FST: forced swim test. Ctrl: control group (distilled water); Model: model group (CRS + distilled water); DZP: diazepam group (CRS + 2 mg/kg diazepam); BDD-H: high dose of BDD group (CRS + 16 g/kg BDD); BDD-L: low dose of BDD group (CRS + 8 g/kg BDD); AM630: high dose of BDD combined with AM630 group (CRS + 16 g/kg BDD + 1 mg/kg AM630). BDD: Baihe Dihuang decoction; CRS: chronic restraint stress; ANOVA: analysis of variance. Statistical significance was assessed using one way ANOVA, followed by pairwise comparisons between groups using the t-test. Data were presented as mean ± standard deviation (n = 10). aP < 0.01, eP < 0.05, vs the control group; bP < 0.01, dP < 0.05, vs the model group; cP < 0.05, vs the BDD-H group.
Table 1 Effect of BDD on inflammatory cytokines and endocannabinoid levels in CRS mice (pg/mL,$\bar{x}±s$)
| Group | n | IL-6 | IL-1β | IL-10 | IL-4 | AEA | 2-AG |
|---|---|---|---|---|---|---|---|
| Ctrl | 6 | 185±32 | 122±18 | 150±19 | 68±8 | 385±35 | 279±39 |
| Model | 6 | 251±29a | 167±18a | 110±10a | 53±3a | 320±22a | 172±16a |
| DZP | 6 | 228±23 | 132±19b | 130±19d | 66±6b | 350±40 | 225±21b |
| BDD-H | 6 | 204±26b | 126±14b | 126±10 | 61±4d | 358±30d | 227±19b |
| BDD-L | 6 | 227±25 | 139±12b | 110±14 | 58±6 | 360±16d | 214±20d |
| AM630 | 6 | 222±11 | 138±10 | 109±10e | 57±3c | 335±26 | 198±39 |
Table 1 Effect of BDD on inflammatory cytokines and endocannabinoid levels in CRS mice (pg/mL,$\bar{x}±s$)
| Group | n | IL-6 | IL-1β | IL-10 | IL-4 | AEA | 2-AG |
|---|---|---|---|---|---|---|---|
| Ctrl | 6 | 185±32 | 122±18 | 150±19 | 68±8 | 385±35 | 279±39 |
| Model | 6 | 251±29a | 167±18a | 110±10a | 53±3a | 320±22a | 172±16a |
| DZP | 6 | 228±23 | 132±19b | 130±19d | 66±6b | 350±40 | 225±21b |
| BDD-H | 6 | 204±26b | 126±14b | 126±10 | 61±4d | 358±30d | 227±19b |
| BDD-L | 6 | 227±25 | 139±12b | 110±14 | 58±6 | 360±16d | 214±20d |
| AM630 | 6 | 222±11 | 138±10 | 109±10e | 57±3c | 335±26 | 198±39 |
Figure 3 Effect of BDD on neuronal damage, apoptosis and microglial polarization in the amygdala A: representative images of HE staining showing neuronal morphology in the amygdala, scale bars: 100 μm; B: representative images of Nissl staining showing neuronal morphology in the amygdala, scale bars: 100 μm; C: representative images of TUNEL staining showing neuronal apoptosis in the amygdala (green: TUNEL, blue: DAPI), scale bars: 100 μm; D: number of TUNEL-positive cells in the amygdala; E: representative images of immunofluorescence staining for Iba-1 (green), iNOS (red) and DAPI (blue) in the amygdala, scale bars: 100 μm; F: representative images of immunofluorescence staining for Iba-1 (green), ARG-1 (red) and DAPI (blue) in the amygdala, scale bars: 100 μm; G: ratio of iNOS+/Iba-1+ positive cells in the amygdala; H: ratio of ARG-1+/Iba-1+ positive cells in the amygdala; A1, B1, C1, E1, F1: control group; A2, B2, C2, E2, F2: model group; A3, B3, C3, E3, F3: DZP group; A4, B4, C4, E4, F4: BDD-H group; A5, B5, C5, E5, F5: BDD-L group; A6, B6, C6, E6, F6: AM630 group. Ctrl: control group (distilled water); Model: model group (CRS + distilled water); DZP: diazepam group (CRS + 2 mg/kg diazepam); BDD-H: high dose of BDD group (CRS + 16 g/kg BDD); BDD-L: low dose of BDD group (CRS + 8 g/kg BDD); AM630: high dose of BDD combined with AM630 group (CRS + 16 g/kg BDD + 1 mg/kg AM630). BDD: Baihe Dihuang decoction; CRS: chronic restraint stress; HE: hematoxylin and eosin; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling; DAPI: 4',6-diamidino-2-phenylindole; Iba-1: ionized calcium-binding adapter molecule 1; iNOS: inducible nitric oxide synthase; ARG-1: arginase-1; ANOVA: analysis of variance. Statistical significance was assessed using one way ANOVA, followed by pairwise comparisons between groups using the t-test. Data were presented as mean ± standard deviation (n = 3). aP < 0.01, vs the control group; bP < 0.01, dP < 0.05, vs the model group; cP < 0.01, eP < 0.05, vs the BDD-H group.
Figure 3 Effect of BDD on neuronal damage, apoptosis and microglial polarization in the amygdala A: representative images of HE staining showing neuronal morphology in the amygdala, scale bars: 100 μm; B: representative images of Nissl staining showing neuronal morphology in the amygdala, scale bars: 100 μm; C: representative images of TUNEL staining showing neuronal apoptosis in the amygdala (green: TUNEL, blue: DAPI), scale bars: 100 μm; D: number of TUNEL-positive cells in the amygdala; E: representative images of immunofluorescence staining for Iba-1 (green), iNOS (red) and DAPI (blue) in the amygdala, scale bars: 100 μm; F: representative images of immunofluorescence staining for Iba-1 (green), ARG-1 (red) and DAPI (blue) in the amygdala, scale bars: 100 μm; G: ratio of iNOS+/Iba-1+ positive cells in the amygdala; H: ratio of ARG-1+/Iba-1+ positive cells in the amygdala; A1, B1, C1, E1, F1: control group; A2, B2, C2, E2, F2: model group; A3, B3, C3, E3, F3: DZP group; A4, B4, C4, E4, F4: BDD-H group; A5, B5, C5, E5, F5: BDD-L group; A6, B6, C6, E6, F6: AM630 group. Ctrl: control group (distilled water); Model: model group (CRS + distilled water); DZP: diazepam group (CRS + 2 mg/kg diazepam); BDD-H: high dose of BDD group (CRS + 16 g/kg BDD); BDD-L: low dose of BDD group (CRS + 8 g/kg BDD); AM630: high dose of BDD combined with AM630 group (CRS + 16 g/kg BDD + 1 mg/kg AM630). BDD: Baihe Dihuang decoction; CRS: chronic restraint stress; HE: hematoxylin and eosin; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling; DAPI: 4',6-diamidino-2-phenylindole; Iba-1: ionized calcium-binding adapter molecule 1; iNOS: inducible nitric oxide synthase; ARG-1: arginase-1; ANOVA: analysis of variance. Statistical significance was assessed using one way ANOVA, followed by pairwise comparisons between groups using the t-test. Data were presented as mean ± standard deviation (n = 3). aP < 0.01, vs the control group; bP < 0.01, dP < 0.05, vs the model group; cP < 0.01, eP < 0.05, vs the BDD-H group.
Figure 4 BDD modulated CB2R expression and TLR4/MyD88/NF-κB signaling in the amygdala A: representative images of microglia immunofluorescence staining for CB2R (red) and DAPI (blue) in the amygdala, scale bars: 100 μm; A1: the control group; A2: model group; A3: DZP group; A4: BDD-H group; A5: BDD-L group; A6: AM630 group; B: CB2R average fluorescence density; C: protein electrophoresis of CB2R and TLR4/MyD88/NF-κB signaling molecules; D: protein expression of CB2R in the amygdala; E: protein expression of TLR4 in the amygdala; F: protein expression of MyD88 in the amygdala; G: protein expression of NF-κB in the amygdala. Ctrl: control group (distilled water); Model: model group (CRS + distilled water); DZP: diazepam group (CRS + 2 mg/kg diazepam); BDD-H: high dose of BDD group (CRS + 16 g/kg BDD); BDD-L: low dose of BDD group (CRS + 8 g/kg BDD); AM630: high dose of BDD combined with AM630 group (CRS + 16 g/kg BDD + 1 mg/kg AM630). BDD: Baihe Dihuang decoction; CB2R: cannabinoid type 2 receptor; TLR4: toll-like receptor 4; MyD88: myeloid differentiation primary response gene 88; DAPI: 4',6-diamidino-2-phenylindole; NF-κB: nuclear factor-kappa B; CRS: chronic restraint stress; ANOVA: analysis of variance. Statistical significance was assessed using one way ANOVA, followed by pairwise comparisons between groups using the t-test. Data were presented as mean ± standard deviation (n = 3). aP < 0.01, vs the control group; bP < 0.01, dP < 0.05, vs the model group; cP < 0.05 vs the BDD-H group.
Figure 4 BDD modulated CB2R expression and TLR4/MyD88/NF-κB signaling in the amygdala A: representative images of microglia immunofluorescence staining for CB2R (red) and DAPI (blue) in the amygdala, scale bars: 100 μm; A1: the control group; A2: model group; A3: DZP group; A4: BDD-H group; A5: BDD-L group; A6: AM630 group; B: CB2R average fluorescence density; C: protein electrophoresis of CB2R and TLR4/MyD88/NF-κB signaling molecules; D: protein expression of CB2R in the amygdala; E: protein expression of TLR4 in the amygdala; F: protein expression of MyD88 in the amygdala; G: protein expression of NF-κB in the amygdala. Ctrl: control group (distilled water); Model: model group (CRS + distilled water); DZP: diazepam group (CRS + 2 mg/kg diazepam); BDD-H: high dose of BDD group (CRS + 16 g/kg BDD); BDD-L: low dose of BDD group (CRS + 8 g/kg BDD); AM630: high dose of BDD combined with AM630 group (CRS + 16 g/kg BDD + 1 mg/kg AM630). BDD: Baihe Dihuang decoction; CB2R: cannabinoid type 2 receptor; TLR4: toll-like receptor 4; MyD88: myeloid differentiation primary response gene 88; DAPI: 4',6-diamidino-2-phenylindole; NF-κB: nuclear factor-kappa B; CRS: chronic restraint stress; ANOVA: analysis of variance. Statistical significance was assessed using one way ANOVA, followed by pairwise comparisons between groups using the t-test. Data were presented as mean ± standard deviation (n = 3). aP < 0.01, vs the control group; bP < 0.01, dP < 0.05, vs the model group; cP < 0.05 vs the BDD-H group.
Table 2 CB2R and TLR4/MyD88/NF-κB signaling molecules mRNA levels in the amygdala ($\bar{x}±s$)
| Group | n | CB2R | TLR4 | MyD88 | NF-κB |
|---|---|---|---|---|---|
| Ctrl | 3 | 1.081±0.068 | 1.005±0.061 | 1.056±0.050 | 1.018±0.016 |
| Model | 3 | 0.504±0.049a | 1.620±0.233a | 1.560±0.242a | 1.294±0.148 |
| DZP | 3 | 0.828±0.148b | 1.043±0.178b | 0.949±0.269b | 0.958±0.045 |
| BDD-H | 3 | 0.936±0.039c | 0.979±0.170b | 0.960±0.109b | 0.931±0.280 |
| BDD-L | 3 | 0.884±0.157c | 1.102±0.177d | 1.007±0.125d | 1.057±0.265 |
| AM630 | 3 | 0.607±0.026d | 1.448±0.112e | 1.464±0.157e | 1.374±0.098e |
Table 2 CB2R and TLR4/MyD88/NF-κB signaling molecules mRNA levels in the amygdala ($\bar{x}±s$)
| Group | n | CB2R | TLR4 | MyD88 | NF-κB |
|---|---|---|---|---|---|
| Ctrl | 3 | 1.081±0.068 | 1.005±0.061 | 1.056±0.050 | 1.018±0.016 |
| Model | 3 | 0.504±0.049a | 1.620±0.233a | 1.560±0.242a | 1.294±0.148 |
| DZP | 3 | 0.828±0.148b | 1.043±0.178b | 0.949±0.269b | 0.958±0.045 |
| BDD-H | 3 | 0.936±0.039c | 0.979±0.170b | 0.960±0.109b | 0.931±0.280 |
| BDD-L | 3 | 0.884±0.157c | 1.102±0.177d | 1.007±0.125d | 1.057±0.265 |
| AM630 | 3 | 0.607±0.026d | 1.448±0.112e | 1.464±0.157e | 1.374±0.098e |
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