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Potential Anti-Depressive Effects and Mechanisms of Zhi-Zi Hou-Po Decoction Using Behavioral Despair Tests Combined With in Vitro Approaches.

ABSTRACT: Zhi-Zi Hou-Po Decoction (ZHD) has been widely used in the treatment of depression for centuries. This study aimed to investigate the antidepressant effects of the water extract of ZHD (ZHD-WE) and ethanol extract of ZHD (ZHD-EE) using behavioral despair tests in mice, and to further explore the neuroprotective effects in a PC12 cell injury model induced by corticosterone (CORT). Mice were divided into a control group (normal saline), ZHD-WE groups (4, 8, and 16 g kg^-1), ZHD-EE groups (4, 8, and 16 g kg^-1) and the fluoxetine group (20 mg kg^-1). The forced swimming test (FST) and tail suspension test (TST) were used to screen the antidepressant effects of ZHD-WE and ZHD-EE after oral administration for seven consecutive days. The level of brain-derived neurotrophic factor (BDNF) in the hippocampus was determined by ELISA. The MTT, lactate dehydrogenase (LDH) and flow cytometry analysis were performed to elucidate the neuroprotective effect of ZHD-EE on a PC12 cell injury model. Additionally, the mRNA and proteins expression of apoptotic molecules Bax, Bcl-2 and BDNF were detected by RT-PCR and western blot assay. It showed that ZHD-EE at concentrations of 8 and 16 g kg^-1 significantly decreased the immobility time in the TST and FST, and increased the BDNF levels in the hippocampus. While ZHD-WE at concentrations of 4, 8, and 16 g kg^-1 had no significant effect on the immobility time in the TST, and only the 16 g kg^-1 of extract group significantly decreased the immobility time in the FST. In vitro, the obtained results showed that PC12 cells pre-incubated with ZHD-EE at concentrations of 100 and 400 μg ml^-1 improved cell viability, decreased LDH release, and reduced apoptosis rate of PC12 cells. Moreover, ZHD-EE significantly increased the mRNA and proteins expression of Bcl-2 and BDNF, while decreased the mRNA and protein expression of Bax. ZHD-EE significantly improved despair-like behavior in mice, and its mechanism may be related to BDNF upregulation in the hippocampus. This study also showed that ZHD-EE had a protective effect on CORT-induced injury in PC12 cells by upregulating the expression of BDNF and restoring Bcl-2/Bax balance.

SUBMITTER: Bai Y

PROVIDER: S-EPMC9298739 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Potential Anti-Depressive Effects and Mechanisms of Zhi-Zi Hou-Po Decoction Using Behavioral Despair Tests Combined With <i>in Vitro</i> Approaches.

Bai Yongtao Y Dai Guoliang G Song Lihua L Gu Xiaolei X Ba Ning N Ju Wenzheng W Zhang Wenzhou W

Frontiers in pharmacology 20220706

Zhi-Zi Hou-Po Decoction (ZHD) has been widely used in the treatment of depression for centuries. This study aimed to investigate the antidepressant effects of the water extract of ZHD (ZHD-WE) and ethanol extract of ZHD (ZHD-EE) using behavioral despair tests in mice, and to further explore the neuroprotective effects in a PC12 cell injury model induced by corticosterone (CORT). Mice were divided into a control group (normal saline), ZHD-WE groups (4, 8, and 16 g kg<sup>-1</sup>), ZHD-EE groups ...[more]

PMID: 35873590

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Project description:To reveal the pharmacokinetic process of narirutin, naringin, and honokiol in normal and different courses of liver-stagnation and spleen-deficiency syndrome depressive rats after intragastric administration of Zhi-Zi-Hou-Po decoction (ZZHPD), a rapid ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) method was proposed in this study. Chronic unpredictable mild stress (CUMS) rat was employed as the depression model. Acetonitrile solution containing 0.1% acetic acid and methyl alcohol-water (50 : 50, v/v) was chosen as the protein precipitant and redissolve solution severally; a Shim-pack GISS C18 column coupled with 0.1% aqueous acetic acid-acetonitrile in gradient elution was employed to separate the mixed constituents in plasma. The WinNonLin software (version 6.1) was chosen as the analytical tool for the pharmacokinetic parameters. The results indicated that compared with rats in the control group, the sucrose preference, scores in the open-field test, and the concentration of 5-HT in plasma of rats in CUMS and CUMS + ZZHPD treatment groups were lower, while the immobility time in the forced swimming test of rats in these two groups was longer, which implied that the depression model was successful. These behavioral and biochemical indexes of rats above in the CUMS + ZZHPD treatment group were improved after oral administration of ZZHPD, which indicated that the antidepressant effect of ZZHPD was definite. The UHPLC-MS/MS method was stabilized, sensitive, and exclusive, and the extraction recovery and matrix effect of three analytes were all above 89%. The T max, AUC, and Cmax of three ingredients in CUMS-induced depression rats were significantly larger than control rats, while these pharmacokinetic parameters in CUMS + ZZHPD treatment rats were decreased significantly compared with CUMS-induced depression rats, which may relate with the changes in physiological function of the gastrointestinal tract and liver in CUMS-induced liver-stagnation and spleen-deficiency syndrome depressive rats. This study provided important information for the clinical rational use of ZZHPD in antidepressant treatment.

Project description:Background and objectiveThe multi-targets and multi-components of Traditional Chinese medicine (TCM) coincide with the complex pathogenesis of depression. Zhi-Zi-Hou-Pu Decoction (ZZHPD) has been approved in clinical medication with good antidepression effects for centuries, while the mechanisms under the iceberg haven't been addressed systematically. This study explored its inner active ingredients - potent pharmacological mechanism - DDI to explore more comprehensively and deeply understanding of the complicated TCM in treatment.MethodsThis research utilized network pharmacology combined with molecular docking to identify pharmacological targets and molecular interactions between ZZHPD and depression. Verification of major active compounds was conducted through UPLC-Q-TOF-MS/MS and assays on LPS-induced neuroblastoma cells. Additionally, the DDIMDL model, a deep learning-based approach, was used to predict DDIs, focusing on serum concentration, metabolism, effectiveness, and adverse reactions.ResultsThe antidepressant mechanisms of ZZHPD involve the serotonergic synapse, neuroactive ligand-receptor interaction, and dopaminergic synapse signaling pathways. Eighteen active compounds were identified, with honokiol and eriocitrin significantly modulating neuronal inflammation and promoting differentiation of neuroimmune cells through genes like COMT, PI3KCA, PTPN11, and MAPK1. DDI predictions indicated that eriocitrin's serum concentration increases when combined with hesperidin, while hesperetin's metabolism decreases with certain flavonoids. These findings provide crucial insights into the nervous system's effectiveness and potential cardiovascular or nervous system adverse reactions from core compound combinations.ConclusionsThis study provides insights into the TCM interpretation, drug compatibility or combined medication for further clinical application or potential drug pairs with a cost-effective method of integrated network pharmacology and deep learning.

Project description:BackgroundThe microbiota-gut-brain axis plays a critical role in neuropsychiatric disorders, particularly anxious depression, and attracts more attention gradually. Zhi Zi Chi decoction (ZZCD) consisting of Gardenia jasminoides J. Ellis and Glycine max (L.) Merr, is a classic formula in clinic and widely applied in anxiety and depression treatment. However, the underlying mechanisms of regulating microbiota-gut-brain axis in the treatment of anxious depression by oral administration of ZZCD remain elusive.Materials and methodsIn this project, we clarified the origin and preparation methods of the Gardenia jasminoides J. Ellis and Glycine max (L.) Merr and examined the chemical ingredients of ZZCD by liquid chromatograph mass spectrometer. Then, corticosterone combined with chronic restraint stress was applied to establish an anxious depression model. After treated with ZZCD standard decoction, based on enzyme-linked immunosorbent assay (ELISA), 16S rRNA technology, high-throughput sequencing, quantitative RT-PCR and fecal microbiota transplantation (FMT), the multiple associations between nucleus accumbens and intestinal flora in anxious depression mice were determined to clarify the mechanism of ZZCD in the treatment of anxiety and depression disorder.ResultsWe found various substances with antidepressant and antianxiety properties in ZZCD such as rosiridin and oleanolic acid. ZZCD could alleviate depressive and anxiety behaviors in anxious depression mice via regulating the disturbance of gut microbiota. Meanwhile, the bioactive compounds of ZZCD might directly active on neurodevelopment and neuroimmune-related genes. Furthermore, the secretion of prolactin and estrogen, and interfering with mitogen-activated protein kinase (MAPK) and tumor necrosis factor (TNF) signaling pathways were mainly involved in the multi-target therapeutic effects of ZZCD against anxiety and depression.ConclusionsThese findings suggested that ZZCD exerts antidepressant effects pleiotropically through modulating the microbiota-gut-brain.

Dataset Information

Potential Anti-Depressive Effects and Mechanisms of Zhi-Zi Hou-Po Decoction Using Behavioral Despair Tests Combined With in Vitro Approaches.

Publications

Potential Anti-Depressive Effects and Mechanisms of Zhi-Zi Hou-Po Decoction Using Behavioral Despair Tests Combined With <i>in Vitro</i> Approaches.

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