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OBJECTIVE To explore the potential targets and mechanisms of the modified Baihe dihuang decoction （MBD/ BDD） applied in post-stroke depression （PSD）. METHODS Network pharmacology was used to mine the potential targets and key pathways of MBD/BDD in the treatment of PSD. PSD model rats were induced by focal cerebral ischemia surgery combined with chronic unforeseen mild stress， and then were randomly divided into PSD model group， MBD/BDD group （12.6 g/kg， by raw drug）， and fluoxetine hydrochloride （FLX） group （positive control， 2.3 mg/kg）； a blank control group was also set up， with 8 rats in each group. Each administration group was given a corresponding medication solution by gavage once a day for 21 consecutive days. The intervention effect of MBD/BDD on depression-like symptoms in model rats was evaluated by open field and forced swimming tests. The brain tissues of rats in each group were dissected and total RNA was extracted for transcriptome sequencing and bioinformatics analysis. The mRNA and protein expressions of genes with significant changes and common neurotrophic factors were verified based on the above results. RESULTS A total of 131 MBD/BDD antidepressant-related target genes were obtained （such as IL1B and AKT1， etc.）， which were closely related to neural active ligand-receptor interactions and cyclic adenosine monophosphate signaling pathway. MBD/BDD could significantly prolong or increase the total time spent and distance traveled in the central grid of qiangzhe@cqtcm.edu.cn PSD model rats， and significantly shorten the cumulative immobility time （P＜0.05）. After treatment with MBD/BDD， the number of genes that changed in rat brain tissue was much higher than that in the FLX group， and there were significant differences in gene profiles among the PSD model group， MBD/BDD group， and FLX group. There were 1 351 differentially expressed genes （DEGs） between the MBD/BDD group and the PSD model group， of which 178 were significantly down-regulated and 1 173 were significantly up-regulated （P＜0.05）. Above 1 351 DEGs were involved in neuronal differentiation， chemical synaptic transmission regulation. They were significantly enriched in axonal guidance， cholinergic synapses and neuroactive ligand-receptor interactions. The top 30 genes in terms of up-regulation in the brain tissue of rats of MBD/BDD group were all associated with neuronal proliferation， development， differentiation， and migration. After MBD/BDD intervention， the expressions of Fezf2， Arx， Ostn， Nrgn genes， brain-derived neurotrophic factor and tyrosine kinase receptor B protein in brain tissue of rats were significantly increased （P＜0.05）. CONCLUSIONS The anti-PSD effect of MBD/BDD may be related to the up-regulation of the expression of genes related to neuronal proliferation， development， differentiation and migration， as well as the promotion of neural structural and functional repair.
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OBJECTIVE To optimize the extraction process and to primarily evaluate the anti-anxiety and anti-depression efficacy of polysaccharide from Baihe dihuang decoction. METHODS Based on Plackett-Burman experimental design， using the comprehensive score of yield and content of polysaccharide as indicators， with extraction time， water amount， alcohol precipitation concentration as factors， Box-Behnken response surface methodology was used to optimize the extraction process of polysaccharide from Baihe dihuang decoction； and the validation test was conducted. Forty ICR mice were divided into control group， venlafaxine group [positive control， 13.5 mg/（kg·d）]， Baihe dihuang polysaccharide high-dose and low-dose groups [5.28， 2.64 g/（kg·d），by raw material]， with 10 mice in each group （half male and half female）. Administration groups were given corresponding drug solution intragastrically， and control group was given water 10 mL/kg intragastrically， once a day， for 7 test， forced swimming test and tail suspension test were used to evaluate the effects of the extract prepared by the optimal process on the anxiety-like and depression-like behavior of mice； enzyme-linked immunosorbent assay was used to detect the effects of the extract on the levels of neurotransmitter in cerebral tissue of mice. RESULTS The optimal extraction process of Baihe dihuang decoction was： the water amount of 25 times， extract time of 1.5 hours， and alcohol precipitation concentration of 70%. In 3 times of validation test， the average yield and content of polysaccharide were 33.10% and 0.62 mg/mg， the relative deviations of which from the predicted values （36.14% and 0.65 mg/mg） were 8.40% and 4.62% respectively （RSD＜2%， n＝3）. The polysaccharide extract of Baihe dihuang decoction could effectively increase the percentages of open-arms entry， the percentages of open-arms time， the total distance of voluntary activities and the activity distance in central area， and significantly shortened the immobility time of forced swimming test and tail suspension test （P＜0.05 or P＜0.01）. The polysaccharide extract could significantly increase the levels of 5-hydroxytryptamine， norepinephrine （except for the Baihe dihuang polysaccharide low-dose group） and gamma-aminobutyric acid in cerebral tissue of mice， while significantly decrease the levels of glutamic acid （except for the Baihe dihuang polysaccharide low-dose group） （P＜0.05 or P＜ 0.01）. CONCLUSIONS The optimized extraction process of polysaccharide from Baihe dihuang decoction is stable and feasible， and the obtained polysaccharide extract has obvious anti-anxiety and anti-depression effect in vivo.
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To explore the effect of Baihe Dihuang Decoction on the synaptic plasticity of hippocampal neurons in rats with anxious depression. Fifty SD rats were randomly divided into normal group, model group, venlafaxine group(6.75 mg·kg~(-1)), high-dose Baihe Dihuang Decoction group(8.64 g·kg~(-1)) and low-dose Baihe Dihuang Decoction group(4.32 g·kg~(-1)). Chronic restraint stress(6 h) combined with corticosterone(ih, 30 mg·kg~(-1)) was used to establish an anxious depression model, and 7 days after modeling, the administration started and continued for 21 days. The anxiety and depression-like behaviors of the rats were evaluated. Golgi-Cox staining and electron microscopy were used to observe the morphology and ultrastructural changes of synaptic dendrites. Immunofluorescence was used to detect the expression of hippocampal synaptic plasticity protein synapsin-1 and postsynaptic density protein 95(PSD-95). Western blot method was used to detect the expression of functional protein synaptophysin(SYP) and synaptic Ras GTPase activating protein(SynGap). The results showed that the rats in the model group had obvious anxiety and depression-like behaviors, the hip-pocampal dendritic spine density and branch length were reduced, the number of synapses was cut, and the internal structure was da-maged. The average fluorescence intensity of synapsin-1 and PSD-95 was significantly reduced and the expression of SYP and SynGap also decreased. High-dose Baihe Dihuang Decoction could significantly improve the anxiety and depression-like behaviors of model rats, relieve synaptic damage, and increase the expression of synapsin-1, PSD-95, SYP, and SynGap proteins. Therefore, we believe that Baihe Dihuang Decoction can improve anxiety and depression behaviors by regulating the synaptic plasticity of hippocampal neurons.
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Animals , Rats , Depression/drug therapy , Hippocampus , Neuronal Plasticity , Rats, Sprague-Dawley , SynapsesABSTRACT
Objective: To analyze the chemical composition and predict the pharmacological mechanism of Baihe Dihuang Decoction by chromatography-mass spectrometry and network pharmacology. Methods: LC/MS and GC/MS were used to analyze the chemical components of Baihe Dihuang Decoction. The target information of chemical components was collected by TCMSP database. TTD and CTD databases were used to collect diseases associated with targets, and depression was targeted for screening. Cytoscape software was carried out to draw “chemical composition-target-disease” network diagram, KEGG pathway analysis of target was performed by DAVID online analysis and its pharmacodynamic components and mechanism were explored. Results: A total of 52 chemical constituents were obtained by chromatography-mass spectrometry analysis. The 31 targets corresponding to 25 components in Baihe Dihuang Decoction by network pharmacology were associated with depression. Conclusion: Baihe Dihuang Decoction has the effect of “multi-directional pharmacology” and “superimposition” in the treatment of depression, reflecting the characteristics of the complex system of traditional Chinese medicine. It may play a role in the treatment of depression by acting on 31 targets, regulating the signaling pathway and participating in inflammatory reaction, apoptosis, and neurotransmitter regulation.
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Objective: To prepare substance benchmarks of Baihe Dihuang Decoction (BDD), and evaluate the scientificity and rationality of preparation process by analyzing the process quality. Methods: Fifteen batches of substance benchmarks were prepared according to the ancient method, the content of catalpol and acteoside in the preparation process was determined, and the transfer rate and extractum rate were calculated. Fingerprints of 15 batches of decoction pieces, decoction, concentrate and substance benchmarks were detected by HPLC, and the common peaks of fingerprints were attributed and identified; In addition, the similarity of fingerprints were evaluated. Results: In 15 batches of substance benchmarks, the transfer rates of catalpol and acteoside were 81.40%—92.88% and 28.90%—41.41% respectively, the extractum rate was 36.06%—41.71%, and without discrete data. During the process of decoction, concentration and freeze-drying, the transfer rates of effective components were stable. In the fingerprints of substance benchmarks, 16 common peaks were determined, of which six peaks belong to Lilii Bulbus, nine peaks belong to Rehmanniae Radix. Three peaks were identified. The similarity of fingerprints of decoction pieces, decoction, concentrate, and substance benchmarks were all over 0.9. The similarity of reference fingerprints of decoction, concentrate, and substance benchmarks were over 0.99. Conclusion: The fingerprint method is reasonable and feasible, which can be used for simultaneously determining the fingerprint of decoction pieces, intermediates and substance benchmarks. The preparation process is scientific and reasonable, and will not changes substance basis significantly. The paper establishes a foundation for the development of preparation of BDD, and provides a new idea for the evaluation of process and quality of the substance benchmarks of classical famous prescriptions.
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Baihe Dihuang Decoction (BDD) is a Chinese materia medica compound, and the formulation is relatively simple and widespread in clinical application. In ancient times, it is commonly used to treat lily disease, but for modern clinical application it is mainly used for the treatment of a variety of depression (such as subliminal depression, postpartum depression, menopausal depression, etc.), a variety of insomnia (such as menopausal insomnia, intractable insomnia, old age insomnia, etc.) anxiety, suboptimal health and so on. In this paper, the clinical and pharmacological effects of BDD decoction in neuropsychiatric system were summarized by literature analysis, in order to provide a reference for the clinical rational application and the study of modern pharmacological mechanism of BDD.