Uncovering pharmacological mechanisms of Zhi-Zi-Hou-Po decoction in chronic unpredictable mild stress induced rats through pharmacokinetics, monoamine neurotransmitter and neurogenesis.

Zhi-Zi-Hou-Po decoction (ZZHPD), a classical Chinese prescription, has been reported to improve depressive behaviors in clinic. However, definite pharmacological effects and mechanisms of ZZHPD on monoaminergic system and hippocampal neurogenesis are ambiguous. It need to be further illuminated. Our study is designed to reveal pharmacological mechanisms of ZZHPD on depression through pharmacokinetics, monoamine neurotransmitters and neurogenesis. Chronic unpredictable mild stress (CUMS) is used to establish rats model of depression. Then, the antidepressant effects of ZZHPD are evaluated by detecting body weight, sucrose preference and forced swimming test. The regulatory functions of ZZHPD on monoaminergic system are assessed by measuring monoamine neurotransmitters, neurotransmitter precursor substances, synthesized rate-limiting enzymes and transporters. Finally, potential molecular mechanism of ZZHPD on hippocampal neurogenesis is evaluated by investigating newborn immature neuron and newborn mature neuron. Our results show that ZZHPD remarkably normalizes CUMS-induced decline in weight gain, decrease of sucrose consumption rate in sucrose preference test and increase of immobility time in forced swimming test. Moreover, ZZHPD significantly reverses CUMS-induced reduction of 5-hydroxytryptamine (5-HT), dopamine (DA), tryptophan (Trp), tyrosine (Tyr), tryptophan hydroxylase2 (TPH2) and tyrosine hydroxylase (TH), whereas decreases level of serotonin transporter (SERT) in CUMS-induced rats. Finally, ZZHPD obviously improves CUMS-induced decrease of newborn immature neuron and newborn mature neuron in dentate gyrus of hippocampus. This study demonstrates that ZZHPD can alleviate CUMS-induced depression-like behaviors. It is probably attributed to the fact that ZZHPD could enhance monoaminergic system and hippocampal neurogenesis. Our findings provide the new perspectives on molecular targets of ZZHPD, and it will facilitate its clinical application.

Xing H ，Zhang X ，Xing N ，Qu H ，Zhang K ... -  《-》

Antidepressant-like effect of the water extract of the fixed combination of Gardenia jasminoides, Citrus aurantium and Magnolia officinalis in a rat model of chronic unpredictable mild stress.

Water extract of the fixed combination of Gardenia jasminoides Ellis fruit, Citrus aurantium L. fruit and Magnolia officinalis Rehd. et Wils. bark, traditional name - Zhi-Zi-Hou-Po (ZZHPD) is used for treatment of depressive-like symptoms in traditional Chinese medicine for centuries. The present study aimed to explore antidepressant-like effects and potential mechanisms of ZZHPD in a rat model of chronic unpredictable mild stress (CUMS). Antidepressant-like effects of ZZHPD were investigated through behavioral tests, and potential mechanism was assessed by neuroendocrine system, neurotrophin and hippocampal neurogenesis. Antidepressant-like effects of ZZHPD (3.66, 7.32 and 14.64 g/kg/day) were estimated through coat state test, sucrose preference test, forced swimming test and open-field test. Effects of ZZHPD on hypothalamic-pituitary-adrenal (HPA) axis were evaluated by hormones measurement and dexamethasone suppression test. In addition, the expression of brain-derived neurotrophic factor (BDNF) in hippocampus was measured, as well as hippocampal neurogenesis was investigated by doublecortin (DCX) and 5-bromo-2-deoxyuridine/neuronal nuclei (BrdU/NeuN). The results demonstrated that ZZHPD significantly reversed the depressive-like behaviors, normalized the levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT), restored the negative feedback loop of HPA axis and improved the levels of BDNF, DCX and BrdU/NeuN compared with those in CUMS-induced rats. The above results revealed that ZZHPD exerted antidepressant-like effects possibly by normalizing HPA axis function, increasing expression of BDNF in hippocampus and promoting hippocampal neurogenesis.

Xing H ，Zhang K ，Zhang R ，Shi H ，Bi K ，Chen X ... -  《-》

Effect of aqueous extract and fractions of Zhi-Zi-Hou-Pu decoction against depression in inescapable stressed mice: Restoration of monoamine neurotransmitters in discrete brain regions.

Yao AM ，Ma FF ，Zhang LL ，Feng F ... -  《-》

Xiaochaihutang attenuates depressive/anxiety-like behaviors of social isolation-reared mice by regulating monoaminergic system, neurogenesis and BDNF expression.

Xiaochaihutang (XCHT), as a classical herbal formula for the treatment of "Shaoyang syndrome" has been demonstrated to exert an antidepressant effect in multiple animal models of depression as shown in our previous studies. However, the effects of XCHT on social isolation (SI)-reared mice have not been investigated. This study aims to explore the effects of XCHT on depressive/anxiety-like behaviors of SI-reared mice, and its implicated mechanisms, including alterations in the monoaminergic system, neurogenesis and neurotrophin expression. Male C57 BL/6J mice (aged 4 weeks after weaning) were reared isolatedly for 8 weeks and XCHT (0.8, 2.3, 7.0g/kg) were given by gavage once a day. Forced swimming test (FST), tail suspension test (TST), open field test (OFT), elevated-plus maze test (EPM) and intruder-induced aggression test were used to explore the effects of XCHT on depressive/anxiety-like behaviors of SI-reared mice after administration of XCHT for 6 weeks. HPLC-MS/MS was performed to quantify the levels of neurotransmitters in the hippocampus by in vivo microdialysis, while western immunoblotting was used to evaluate the action of XCHT on the synthesis, transport and degradation of monoamine neurotransmitters. Immunofluorescence was used to study the effects of XCHT on neurogenesis and neurotrophin expression, including Ki-67, DCX, BrdU and BDNF. Our results showed that administration of XCHT (0.8, 2.3 and 7.0g/kg) for 6 weeks significantly attenuated the increase in immobility time in TST and FST, improved the anxiety-like behaviors in OFT and EPM, and improved the aggressive behaviors of SI-reared mice. XCHT significantly elevated monoamine neurotransmitters levels and inhibited 5-HT turnover (5-HIAA/5-HT) in hippocampal microdialysates of SI-reared mice. In addition, we found XCHT enhanced monoamine neurotransmitter synthesis enzymes (TPH2 and TH) expressions, inhibited serotonin transporter (SERT) expression and decreased monoamine neurotransmitter degradation enzyme (MAOA) expression in the hippocampus of SI-reared mice for the first time. Moreover, XCHT significantly augmented hippocampal neurogenesis and BDNF expression in hippocampus of SI-reared mice. Our results showed for the first time that XCHT improved depressive/anxiety-like behaviors of SI-reared mice by regulating the monoaminergic system, neurogenesis and neurotrophin expression. The findings indicate that XCHT may have a therapeutic application for early-life stress model of depression and in turn provide further evidence supporting XCHT a novel potential antidepressant from a distinct perspective.

Ma J ，Wang F ，Yang J ，Dong Y ，Su G ，Zhang K ，Pan X ，Ma P ，Zhou T ，Wu C ... -  《-》

Zhi-Zi-Hou-Po decoction alleviates depressive-like behavior and promotes hippocampal neurogenesis in chronic unpredictable mild stress induced mice via activating the BDNF/TrkB/CREB pathway.

Zhi-Zi-Hou-Po decoction (ZZHP), a traditional Chinese medicine (TCM) classic recipe, has been extensively applied for the remedy of depression. However, the underlying mechanism of ZZHP hasn't been fully elucidated and it needs to be further clarified. The aim of the study is to uncover the mechanisms of ZZHP's effect on depression. C57BL/6 mice were employed to establish Chronic Unpredictable Mild Stress (CUMS) models. Behavioral tests were conducted for evaluating the antidepressant effects of ZZHP. Then, the monoamine neurotransmitters in the hippocampus through High Performance Liquid Chromatography Electrochemical Detection (HPLC-ECD) were utilized to assess the effect of ZZHP on the maintenance of monoamine neurotransmitter homeostasis. Immunofluorescence staining and Golgi staining were detected to analyze the effects of ZZHP on neuroplasticity in the hippocampus. Western Blot (WB) was utilized to examine the effects of ZZHP on BDNF/TrkB/CREB pathways. Finally, behavioral tests, WB and immunofluorescence staining were repeated after TrkB receptor antagonist was added to further confirm the underlying mechanism. Our results shown that ZZHP attenuated depressive-like symptoms in CUMS mice. Moreover, ZZHP remarkably reversed the reduction and maintained the homeostasis of monoamine neurotransmitters in the hippocampus. Simultaneously, ZZHP protected neuronal synaptic plasticity and promoted hippocampal neurogenesis. Furthermore, ZZHP stimulated the BDNF/TrkB/CREB pathway in the hippocampus. The addition of TrkB receptor antagonist inhibited the antidepressant effects of ZZHP, suggesting that ZZHP could not work without triggering the BDNF/TrkB/CREB pathway. This study demonstrates that ZZHP can alleviate depressive-like behavior and promote hippocampal neurogenesis in CUMS mice via activating the BDNF/TrkB/CREB pathway.

Ye Z ，Wang J ，Fang F ，Wang Y ，Liu Z ，Shen C ，Hu Y ... -  《-》