The pharmacological mechanism of chaihu-jia-longgu-muli-tang for treating depression: integrated meta-analysis and network pharmacology analysis.

Aim: Chaihu-jia-Longgu-Muli-tang (CLM) is derived from "Shang Han Lun" and is traditionally prescribed for treating depression. However, there is still a lack of evidence for its antidepressant effects, and the underlying mechanism is also unclear. This study aimed to assess clinical evidence on the efficacy of CLM in patients with depression using a meta-analysis and to explore its underlying antidepressant molecular mechanisms via network pharmacology. Methods: Eight open databases were searched for randomized controlled trials (RCTs) comparing the effects of CLM alone or combined with serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) in patients with depression, evaluating the total effective rate of the treatment group (CLM alone or combined with SSRIs/SNRIs) and the control group (SNRIs or SSRIs), and comparing changes in depression scale, anxiety scale, sleep scale, inflammation indicators and adverse effects. Subsequently, the active ingredients and target genes of CLM were screened through six databases. Then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and protein-protein interaction (PPI) network and topology analysis were performed. Finally, Molecular docking was applied to evaluate the binding affinity between components and predicted targets. Results: Twenty-four RCTs with a total of 2,382 patients were included. For the efficacy of antidepression and adverse effects, whether CLM alone or in combination with SSRIs/SNRIs, the treatment group has no inferior to that of the control group. Additionally, the intervention of CLM + SSRI significantly improved the symptoms of anxiety and insomnia, and reduced serum IL-6 and TNF-α levels. For network pharmacology, a total of 129 compounds and 416 intersection targets in CLM were retrieved. The interaction pathway between CLM and depression is mainly enriched in PI3K-Akt, JAK-STAT, and NF-κB signaling pathway, PIK3R1, MAPK3, and AKT1 may be the potential targets of Stigmasterol, ß-stiosterol, coumestrol. Conclusion: Compared to SSRIs/SNRIs alone, CLM is more effective and safe in treating depression. It not only significantly alleviates depressive mood, but improves symptoms such as anxiety and insomnia, with fewer side effects, especially in combination with SSRI. Its antidepressant mechanism may be correlated with the regulation of the PI3K/Akt signaling pathway and inhibiting inflammatory response.

Effect and Mechanism of Chaihu Jia Longgu Muli Tang on Hippocampus of Rats with Chronic Stress Depression Based on BDNF/TrkB/CREB Pathway / 中国实验方剂学杂志

Objective:To explore the effect of Chaihu Jia Longgu Muli Tang on the hippocampus of rats with chronic stress depression based on the brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB)/cyclic adenosine phosphate response element-binding protein (CREB) pathway. Method:Sixty SD rats were divided into a blank group (<italic>n</italic>=10) and an experimental group (<italic>n</italic>=50) for the induction of the chronic stress depression model. The rats in the experimental group were further divided into the following five groups: a model group， a fluoxetine hydrochloride group (0.003 g·kg^-1), and low-(1.625 g·kg^-1), medium-(3.25 g·kg^-1), and high-dose (6.5 g·kg^-1) Chaihu Jia Longgu Muli Tang groups. The rats were administered correspondingly by gavage once a day for eight weeks. Behavioral tests were performed to evaluate the depression state of the rats before modeling， after modeling， and after drug administration. Hematoxylin-eosin (HE) staining was used to observe the morphological changes in the hippocampus of rats. The immunohistochemical (IHC) staining was used to quantitatively detect BDNF protein expression in the rat hippocampus. The mRNA and protein expression of BDNF， TrkB， and CREB in the rat hippocampus was detected by the real-time fluorescence-based quantitative PCR (Real-time PCR) and Western blot， respectively. Result:Compared with the blank group， the model group showed decreased sucrose preference rate (<italic>P</italic><0.05)， declining horizontal and vertical scores (<italic>P</italic><0.05)， and prolonged immobility time and floating time (<italic>P</italic><0.05). Additionally， HE staining results revealed that hippocampal neuron structure was damaged. IHC staining showed that the mRNA and protein expression of BDNF， TrkB， and CREB was significantly decreased (<italic>P</italic><0.05). Compared with the model group， the fluoxetine hydrochloride group and the Chaihu Jia Longgu Muli Tang groups displayed elevated sucrose preference rate (<italic>P</italic><0.05)， increased horizontal and vertical scores (<italic>P</italic><0.05)， and shortened immobility time and floating time (<italic>P</italic><0.05). Furthermore, the hippocampal neuron structure was significantly repaired. IHC staining showed that the mRNA and protein expression of BDNF， TrkB， and CREB was significantly increased (<italic>P</italic><0.05). Conclusion:Chaihu Jia Longgu Muli Tang can significantly improve the depression-like behaviors of rats after chronic stress stimulation and enhance the regeneration and repair of neurons in the hippocampus. The underlying mechanism may be related to the up-regulation of the BDNF/TrkB/CREB signaling pathway in the hippocampus of rats.

Efficacy and Safety of Modified Chaihu Jia Longgu Muli Tang in Treating Mild to Moderate Essential Hypertension Complicated with Depression and Liver-Yang Hyperactivity Syndrome / 中国实验方剂学杂志

Objective:To observe the clinical efficacy and safety of modified Chaihu Jia Longgu Muli Tang in treating mild to moderate essential hypertension complicated with depression and liver-Yang hyperactivity syndrome.Method:Totally 121 mild to moderate hypertensive patients complicated with depression in line with the inclusive criteria were randomized into treatment group and control group. All of the enrolled patients in treatment group and control group were treated with conventional therapy. In treatment group, patients were given modified Chaihu Jia Longgu Muli Tang, one dose per day. The treatment course lasted for 4 weeks. Blood pressure, patient health questionnaire-9 (PHQ-9) score, score of traditional Chinese medicine syndrome, C-reactive protein (CRP), endothelial-dependent vasodilation, and adverse effect were observed in this study.Result:Both systolic blood pressure and diastolic blood pressure were significantly lowered when compared to control group (P<0.05). PHQ-9 score was significantly improved in treatment group (P<0.05). The score of traditional Chinese medicine syndrome was significantly improved in treatment group compared to control group (P<0.05). CRP was significantly improved in treatment group compared with control group (P<0.05). Endothelial-dependent vasodilation was significantly improved in treatment group compared with control group (P<0.05). No severe adverse effect was observed in this research.Conclusion:Chaihu Jia Longgu Muli Tang has a creation clinical efficacy in the treatment of mild to moderate essential hypertension with depression. In addition to the effect in reducing both systolic and diastolic blood pressure, modified Chaihu Jia Longgu Muli Tang was also effective in improving depression, traditional Chinese medicine syndrome and endothelial-dependent vasodilation, and reducing the level of CRP with little adverse effect.

Chinese Herbal Products for Non-Motor Symptoms of Parkinson's Disease in Taiwan: A Population-Based Study.

Objective: Combinations of Chinese herbal products (CHPs) are widely used for Parkinson's disease (PD) in Taiwan. Thereby, we investigated the use of CHPs in patients with PD. Methods: This study was a population-based cohort study that analyzed the data of patients with PD from the National Health Insurance Research Database. A total of 9,117 patients were selected from a random sample of one million individuals included in this database. We used multiple logistic regression models to estimate the adjusted odds ratios of the demographic factors and analyzed the formula and single CHPs commonly used for PD. Results: Traditional Chinese medicine users were more commonly female, younger, of white-collar status, and residents of Central Taiwan. Chaihu-Jia-Longgu-Muli-Tang was the most commonly used formula, followed by Ma-Zi-Ren-Wan and then Shao-Yao-Gan-Cao-Tang. The most commonly used single herb was Uncaria tomentosa (Willd. ex Schult.) DC., followed by Gastrodia elata Blume and then Radix et Rhizoma Rhei (Rheum palmatum L., Rheum tanguticum Maxim. ex Balf., and Rheum officinale Baill.). Chaihu-Jia-Longgu-Muli-Tang and U. tomentosa (Willd. ex Schult.) DC. have shown neuroprotective effects in previous studies, and they have been used for managing non-motor symptoms of PD. Conclusion: Chaihu-Jia-Longgu-Muli-Tang and U. tomentosa (Willd. ex Schult.) DC. are the most commonly used CHPs for PD in Taiwan. Our results revealed the preferences in medication prescriptions for PD. Further studies are warranted to determine the effectiveness of these CHPs for ameliorating the various symptoms of PD, their adverse effects, and the mechanisms underlying their associated neuroprotective effects.

Immediate and persistent antidepressant-like effects of Chaihu-jia-Longgu-Muli-tang are associated with instantly up-regulated BDNF in the hippocampus of mice.

Conventional antidepressants have a disadvantage in delayed onset of efficacy. Here, we aimed to evaluate the immediate and persistent antidepressant-like action of a classic herbal medicine Chaihu-jia-Longgu-Muli decoction (CLM) as well as the action of CLM on hippocampal brain-derived neurotrophic factor (BDNF) over time. CLM consists of Xiaochaihu decoction (XchD), Longgu-Muli (LM) and several other herbs. The contribution of constituent herbal formula XchD and other parts of CLM was also assessed. Following a single dose of CLM, tail suspension test (TST), forced swim test (FST), and novelty-suppressed feeding test (NSF) were performed. The antidepressant activity of XchD, its interaction with LM or remaining parts of CLM was also examined after a single administration. BDNF expression in the hippocampus was examined at 30 min and 24 hr post a single CLM. A single administration of half of clinical dose of CLM elicited antidepressant effects at TST 30 min post administration, and lasted for 72 hr. Furthermore, CLM also reduced the latency to eat in NSF test. A single proportional dose of XchD induced antidepressant effects at 30 min and lasted for 48 hr, whereas the effect lasted for 72 hr when combined with either LM or the remaining parts of CLM. BDNF expression increased at 30 min and persisted at least for 24 hr after a single dose of CLM. The results support that Chaihu-jia-Longgu-Muli decoction was capable to immediately and enduringly elicit antidepressant activity via enhancement of hippocampal BDNF expression, in which the constituent Xiaochaihu decoction played the primary role.

[Analysis of protective effects of Chaihu Jia Longgu Muli Tang against ischemic stroke by combining traditional Chinese medicine pathogenesis and efficacy with modern pathology and pharmacology].

Chaihu Jia Longgu Muli Tang is a classical Chinese formulas treating Shaoyang syndrome complicated with Yangming syndrome according to Treatise on Febrile Diseases. This formula is used in mental disorder, nervous system, gynecologic, andrologic, and cardiovascular disease. However, its therapeutic effect on ischemia stroke and its mechanism is far from clear. In clinical practice, we have found that this formula is effective in treating ischemic stroke, which can shorten the course of the disease and reduce recurrence. The characteristics of this formula include: Shaoyang cardinal disadvantageous syndrome, mental and nervous symptoms, retained fluid punched upward syndrome and accumulation of heat in the stomach and intestines. By combining traditional Chinese medicine (TCM) pathogenesis and efficacy with modern pathology and pharmacology, we proposed that the TCM pathogenesis of stroke, which is characterized by hyperactivity of heat combining with phlegm, stasis and water drink, is consistent with syndromes and corresponding pathology targeted by Chaihu Jia Longgu Muli Tang, including the stress brain edema zone around the ischemic lesion, the increase of intracranial pressure, the excitement of sympathetic nerve, the release of monoamine neurotransmitter, the hypofunction of autonomic nervous system after stroke, and gastrointestinal stress response. Furthermore, the pharmacological mechanism of Chaihu Jia Longgu Muli Tang is concentrated on regulation the neuroendocrinology system centered by hypothalamic-pituitary-adrenal axis (HPA), participating in the process of neuron regeneration and apoptosis, oxidative stress, hyperactivity of sympathetic nerve, and inflammatory reaction. These pathological processes are consistent with the pathological changes after ischemic stroke. Therefore, Chaihu Jia Longgu Muli Tang is a key formula for treating ischemic stroke.

Involvement of NMDA-AKT-mTOR Signaling in Rapid Antidepressant-Like Activity of Chaihu-jia-Longgu-Muli-tang on Olfactory Bulbectomized Mice.

Background: Fast-onset antidepressants are urgently needed. Chaihu-jia-Longgu-Muli-tang (CLM), a classic Chinese herbal medicine, has been used for antidepressant treatment with long history. Olfactory bulbectomization (OB) model is validated for identification of rapid antidepressant efficacy. Here we used OB model for investigating the rapid onset activity of CLM in mice, and also tested the involvement of prefrontal Akt-mTOR and associated AMPA/NMDA receptors as well as hippocampal BDNF in the rapid antidepressant-like effect of CLM. Methods: The OB model was first characterized with depression-like behaviors and the time course changes of the behaviors. The fast onset of antidepressant effect of CLM was evaluated using sucrose preference test, tail suspension test and forced swim test in OB mice after a single administration. The expression of synaptic proteins of AMPA and NMDA subunits as well as Akt/mTOR signaling in the prefrontal cortex, and hippocampal BDNF was evaluated with the immunoblotting method. Results: A single dose of CLM significantly improved the deficiency in the sucrose preference and decreased the immobility time in the tail suspension test in OB mice. In the prefrontal cortex (PFC) in OB mice, there was lower expression level of the AMPA receptor subunit GluR1, rescued by a single dose of CLM. Additionally, the expression of NMDA subunit NR1 was up-regulated in OB mice, whereas mTOR and its upstream Akt signalings were both down-regulated. These deficiencies were reversed by a single dose of CLM. The CLM treatment also attenuated the expressions of NMDA receptor subunits NR2A and NR2B, which did not change in OB mice. In the hippocampus, expressions of GluR1 and brain derived neurotrophic factor (BDNF) were both up-regulated in OB mice, although CLM increased GluR1, but not BDNF. Conclusion: CLM elicited rapid antidepressant-like effects in the OB model mice, and CLM reversal of the abnormality in PFC expression of AMPA and NMDA receptors and associated Akt-mTOR signaling may underlie the effects.

Analysis of protective effects of Chaihu Jia Longgu Muli Tang against ischemic stroke by combining traditional Chinese medicine pathogenesis and efficacy with modern pathology and pharmacology / 中国中药杂志

Chaihu Jia Longgu Muli Tang is a classical Chinese formulas treating Shaoyang syndrome complicated with Yangming syndrome according to Treatise on Febrile Diseases. This formula is used in mental disorder, nervous system, gynecologic, andrologic, and cardiovascular disease. However, its therapeutic effect on ischemia stroke and its mechanism is far from clear. In clinical practice, we have found that this formula is effective in treating ischemic stroke, which can shorten the course of the disease and reduce recurrence. The characteristics of this formula include: Shaoyang cardinal disadvantageous syndrome, mental and nervous symptoms, retained fluid punched upward syndrome and accumulation of heat in the stomach and intestines. By combining traditional Chinese medicine (TCM) pathogenesis and efficacy with modern pathology and pharmacology, we proposed that the TCM pathogenesis of stroke, which is characterized by hyperactivity of heat combining with phlegm, stasis and water drink, is consistent with syndromes and corresponding pathology targeted by Chaihu Jia Longgu Muli Tang, including the stress brain edema zone around the ischemic lesion, the increase of intracranial pressure, the excitement of sympathetic nerve, the release of monoamine neurotransmitter, the hypofunction of autonomic nervous system after stroke, and gastrointestinal stress response. Furthermore, the pharmacological mechanism of Chaihu Jia Longgu Muli Tang is concentrated on regulation the neuroendocrinology system centered by hypothalamic-pituitary-adrenal axis (HPA), participating in the process of neuron regeneration and apoptosis, oxidative stress, hyperactivity of sympathetic nerve, and inflammatory reaction. These pathological processes are consistent with the pathological changes after ischemic stroke. Therefore, Chaihu Jia Longgu Muli Tang is a key formula for treating ischemic stroke.