Research progress on classical traditional Chinese medicine formula Baihe Zhimu (Lilium lancifolium bulb and Anemarrhena asphodeloides rhizome) decoction in the treatment of depression.

Depression is considered to be an "emotional disease" in ancient books of traditional Chinese medicine. Its clinical features are similar to those of "Lily disease" in the ancient Chinese medicine book Synopsis of the Golden Chamber written by Zhang Zhongjing in the Han Dynasty. Baihe Zhimu (Lilium lancifolium bulb and Anemarrhena asphodeloides rhizome) decoction (LBRAD) is the first prescription of "Lily Disease" in this book. It is also a special remedy for "Lily disease" after sweating. The classic recipe LBRAD consists of two herbs, fresh lily bulbs and dried Rhizoma Anemarrhena slice. It has the effect of supplementing nutrition and clearing heat, nourishing Yin and moistening. After more than two thousand years of clinical practice, it has been currently widely used in clinical treatment of depression. In this paper, the relationship between LBRAD and depression was systematically reviewed from both clinical and experimental studies, as well as the preparation, the clinical application, the pharmacological mechanism and the effective material basis for the treating depression of LBRAD. The core targets and biological processes of the depression treatment were explored through network pharmacological analysis, so as to speculate its potential mechanism. Finally, the association between LBRAD and post-COVID-19 depression was discussed. We concluded with a summary and future prospects. This review may provide a theoretical basis for the expansion of the clinical application of LBRAD and the development of new drugs for the treatment of depression, as well as new ideas for the secondary development of classical prescriptions.

Exploration on Anti-Depression Mechanism of Baihe Zhimu Decoction Based on Network Pharmacology and Molecular Docking.

OBJECTIVE: To analyze anti-depression mechanism of Baihe Zhimu decoction (BZD) based on network pharmacology method, which provides reference for the development of new drugs and the clinical application of classical prescriptions. METHOD: The main chemical components and targets of Baihe and Zhimu were obtained through traditional Chinese medicine pharmacology system technology platform (TCMSP) database, and the active components of TCM were filtered according to ADME; Major targets for anti-depression were get through Gencards, OMIM and DRUGBANK databases; Protein interaction analysis was performed using the String platform; Build PPI networks and mine potential protein functional modules in the network; The Metascape platform was used to analyze the "drug-ingredients-target" and its involved biological processes and pathways; Finally, the molecular docking validation was performed by Systems Dock Web Site. RESULTS: The core active ingredients of BZD treating depression are kaempferol and Stigmasterol, The core targets are AKT1, TNF, TP53, PTGS2, and CASP3. The biological pathway of the anti-depression mainly acts on Lipid and atherosclerosis, Chemical carcinogenesis and receptor activation. Molecular docking results showed that AKT1, TNF and TP53 have good affinity with components kaempferol and Stigmasterol. CONCLUSION: This study initially revealed the mechanism of multicomponent, multiple target and multiple pathway of anti-depression, which may be related to neuroactive ligand-receptor interaction, atherosclerotic, PI3K-Akt and TNF signaling pathway.

Uncovering the active components, prospective targets, and molecular mechanism of Baihe Zhimu decoction for treating depression using network pharmacology-based analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Baihe Zhimu decoction (BZD) is a classical traditional Chinese medicinal herbal formula. It consists of two herbal medicines, Rhizoma Anemarrhenae (Zhimu), the rhizomes of Anemarrhena asphodeloides Bge. (Liliaceae), and Bulbus Lilii (Baihe), the bulbs of Lilium brownii var. Viridulum Baker (Liliaceae). BZD has been widely used in China to treat depression and verified to be effective without evident side effects. AIM OF THE STUDY: The aim of this study was to elucidate the active components, potential targets, and molecular mechanism of Baihe Zhimu decoction for treating depression. MATERIALS AND METHODS: In this research, a chronic unpredictable mild stress (CUMS) mice was first established to evaluate the pharmacological effects of BZD for treating depression. A component database was then constructed for BZD. High-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS) technique was used to identify the components in BZD and blood-absorbed components. Further screening and validation of protein targets were performed by molecule docking. The component-target binding affinity was validated by surface plasmon resonance analysis (SPR) assay. The related pathways were predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Relative proteins in the predicted pathways were finally assessed by Western blot. RESULTS: The pharmacology evaluation experiment demonstrated that BZD could improve depressive-like behavior, inhibit the hippocampal secretion of pro-inflammatory cytokines and reduce neuronal apoptosis in CUMS mice model. A component database containing 163 components and a target database covering 1286 proteins were constructed. HPLC-QTOF-MS assay identified twenty-six components from BZD and ten components absorbed into rat plasma after an intragastric treatment with BZD. Next, 56 underlying targets were screened out by a virtual high-throughput screening approach. Twenty-seven of them were further screened out and confirmed by molecular docking. Afterward, a component-target network was established, and the component-protein binding affinities were validated by SPR assays. By KEGG pathway enrichment analysis, two signaling pathways PI3K/Akt and MAPK were predicted as the potential signaling cascades. Finally, Western blot showed that BZD dramatically reversed the suppression of PI3K/Akt/GSK-3ß pathway and the activation of MAPK pathway in CUMS mice model. CONCLUSIONS: BZD demonstrated a substantial pharmacological effect on CUMS mice model. Network pharmacology-based analysis predicted that ten blood-absorbed components can act on 27 target proteins. KEGG and Western blotting analysis suggested that BZD could exert antidepressant effects by regulating the PI3K/Akt and MAPK signaling pathways.

Identifying the active components of Baihe-Zhimu decoction that ameliorate depressive disease by an effective integrated strategy: a systemic pharmacokinetics study combined with classical depression model tests.

BACKGROUND: Modern pharmacological studies have demonstrated that Baihe-Zhimu decoction (BZD) has antidepressant effects. However, the complex composition and lack of clear evaluation standards for BZD make it less likely to be understood and accepted than evidence-based active natural compounds. METHODS: In this study, an effective method for the identification of antidepressant components was demonstrated and applied to BZD. The first step was to evaluate the efficacy of BZD by the forced swimming test (FST) and the tail suspension test (TST), followed by successive quantitative analyses of the absorbed constituents at different stages, such as before hepatic disposition, liver distribution, after hepatic disposition and brain distribution after the oral administration of BZD. Finally, the compounds detected in the brain were confirmed by activity testing. RESULTS: Our investigation observed that timosaponin BII and timosaponin BIII were accurately determined in the brain after oral administration of BZD, and they were further confirmed to reduce the immobility time in the FST and TST. As described above, timosaponin BII and timosaponin BIII were used to scientifically and reasonably explain the effective chemical basis of the effect of BZD on depression. CONCLUSIONS: This research affords an effective method to discover lead molecules for antidepressants from traditional Chinese medicine.

Pharmacokinetic comparison of seven major bioactive components in normal and depression model rats after oral administration of Baihe Zhimu decoction by liquid chromatography-tandem mass spectrometry.

A simple and rapid liquid chromatography-tandem mass spectrometry method was firstly developed for simultaneous quantification of neomangiferin, mangiferin, regaloside A, regaloside I, timosaponin BII, anemarsaponin E and timosaponin AIII in rat plasma after oral administration of Baihe Zhimu decoction, which plays an important role for the treatment of depression. The plasma samples were pretreated by a one-step direct protein precipitation with methanol. Separation of the seven components and scutellarin (IS) from endogenous components with high selectivity and sensitivity (LLOQ, 0.1-1.0ng/mL) was achieved within 10min using Poroshell 120 EC-C18 column (150mm×3.0mm, 2.7µm). A gradient mobile phase consisting of acetonitrile and water (containing 5mM ammonium acetate) was applied at a flow rate of 0.4mL/min. Detection and measurement were performed on an AB Sciex QTRAP® 5500 mass spectrometer in multiple reactions monitoring mode. The intra- and inter-day precisions were all within 15% and the accuracies were in the range of -10.4% to 14.5%. The recovery ranged from 90.8 to 113.8%. The validated method was successfully applied to pharmacokinetic study of the seven components in normal and chronic unpredicted mild stress-induced depression model rats.

Chemical interaction between Lilium brownii and Rhizoma Anemarrhenae, the herbal constituents of Baihe Zhimu decoction, by liquid chromatography coupled to hybrid triple quadrupole linear ion trap mass spectrometer.

During the course of decoction, the components of herbal formula interact with each other, such that chemical extraction characteristics are altered. The crude drugs, Lilium brownii (Baihe) and Rhizoma Anemarrhenae (Zhimu), are the herbal constituents of Baihe Zhimu decoction, a traditional herbal formula. To investigate the chemical interaction between Baihe and Zhimu when decocting together, eight marker components in Baihe Zhimu decoction were simultaneously characterized and quantified in one run by a hybrid triple quadrupole linear ion trap mass spectrometer in the multiple reactions monitoring-information dependent acquisition-enhanced product ion mode. The results showed that Zhimu significantly suppressed the extraction of phenolic glycosides (the components from Baihe) when co-decocting, and Baihe clearly suppressed the extraction of xanthones and steroidal saponins (the components from Zhimu). Overall, the presently developed method would be a preferred candidate for the investigation of the chemical interaction between herbal medicines.