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Serum Metabolic Profiling Reveals the Antidepressive Effects of the Total Iridoids of Valeriana jatamansi Jones on Chronic Unpredictable Mild Stress Mice.

ABSTRACT: Background:Depression is a long-term complex psychiatric disorder, and its etiology remains largely unknown. Valeriana jatamansi Jones ex Roxb (V. jatamansi) is used in the clinic for the treatment of depression, but there are insufficient reports of its antidepressive mechanisms and a poor understanding of its endogenous substance-related metabolism. The objective of this study was to identify biomarkers related to depression in serum samples and evaluate the antidepressive effects of the iridoid-rich fraction of V. jatamansi (IRFV) in a chronic unpredictable mild stress (CUMS) mouse model. Methods:Here, CUMS was used to establish a mouse model of depression. Behavioral and biochemical indicators were investigated to evaluate the pharmacodynamic effects. A comprehensive serum metabolomics study by nuclear magnetic resonance (NMR) approach was applied to investigate the pharmacological mechanism of IRFV in CUMS mouse. Subsequently, we used multivariate statistical analysis to identify metabolic markers, such as principal component analysis (PCA) and orthogonal projection to latent structure with discriminant analysis (OPLS-DA), to distinguish between the CUMS mouse and the control group. Results:After IRFV treatment, the immobility time, sucrose preference, and monoamine neurotransmitter were improved. PCA scores showed clear differences in metabolism between the CUMS group and control group. The PLS-DA or OPLS-DA model exhibited 26 metabolites as biomarkers to distinguish between the CUMS mice and the control mouse. Moreover, IRFV could significantly return 21 metabolites to normal levels. Conclusion:The results confirmed that IRFV exerted an antidepressive effect by regulating multiple metabolic pathways, including the tricarboxylic acid cycle, the synthesis of neurotransmitters, and amino acid metabolism. These findings provide insights into the antidepressive mechanisms of IRFV.

SUBMITTER: Li Y

PROVIDER: S-EPMC7099651 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Serum Metabolic Profiling Reveals the Antidepressive Effects of the Total Iridoids of <i>Valeriana jatamansi</i> Jones on Chronic Unpredictable Mild Stress Mice.

Li Yongbiao Y Wu Lanlan L Chen Chang C Wang Liwen L Guo Cong C Zhao Xiaoqin X Zhao Tingting T Wang Xinyi X Liu An A Yan Zhiyong Z

Frontiers in pharmacology 20200320

<h4>Background</h4>Depression is a long-term complex psychiatric disorder, and its etiology remains largely unknown. <i>Valeriana jatamansi</i> Jones ex Roxb (V. <i>jatamansi)</i> is used in the clinic for the treatment of depression, but there are insufficient reports of its antidepressive mechanisms and a poor understanding of its endogenous substance-related metabolism. The objective of this study was to identify biomarkers related to depression in serum samples and evaluate the antidepressiv ...[more]

PMID: 32265710

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Project description:The roots and rhizomes of Valeriana jatamansi have long been used as folk medicine in Asia and usually named as "Zhizhuxiang" in Chinese for the treatment of abdominal distention and pain. However, its active ingredients and molecular targets for treatment of abdominal pain remain unrevealed. Inhibitors of Cav2.2 N-type voltage-gated calcium channels (VGCCs) are actively sought after for their potential in treating pain, especially chronic pain. As far as we know, the method used for seeking analgesic active ingredient from plant material has rarely been reported. The analgesic potentials of the EtOH extract (0.01 mg/ml) of the roots and rhizomes of V. jatamansi and its EtOAc, n-BuOH and H2O soluble parts (0.01 mg/ml, respectively) were tested herein on Cav2.2, using whole-oocyte recordings in vitro by tow-electrode voltage clamp. The results indicated that the EtOAc-soluble part exhibited the most potent inhibition of Cav2.2 peak current (20 mv). The EtOAc-soluble part was then subjected to silica gel column chromatography (CC) and giving 9 fractions. Phytochemical studies were carried out by repeated CC and extensive spectroscopic analyses after the fraction (0.01 mg/ml) was identified to be active and got seventeen compounds (1-17). All isolates were then sent for further bioactive verification (1 and 3 at concentration of 10 μM, others at 30 μM). In addition, the selectivity of the active compounds 1 and 3 were tested on various ion channels including Cav1.2, Cav2.1 and Cav3.1 VGCCs and Kv1.2, Kv2.1, Kv3.1 and BK potassium channels. The results indicated that compound 1 and 3 (an abundant compound) inhibited Cav2.2 with an EC50 of 3.3 and 4.8 μM, respectively, and had weaker or no effect on Cav1.2, Cav2.1 and Cav3.1 VGCCs and Kv1.2, Kv2.1, Kv3.1 and BK potassium channels. Compounds 1 and 3 appear to act as allosteric modulators rather than pore blockers of Cav2.2, which may play crucial role in attenuating nociception. The results of present research indicated that the ethnopharmacological utilization of V. jatamansi for relieving the abdominal distention and pain may mediate through Cav2.2 channel. Our work is the first demonstration of inhibition of Cav2.2 by iridoids, which may provide a fresh source for finding new analgesics.

Project description:Zhi zhu xiang (ZZX) is the root and rhizome of Valeriana jatamansi Jones ex Roxb. Recent studies have shown that ZZX can exert antianxiety, antidepressant, and sedative effects. Because post-traumatic stress disorder (PTSD) is similar to depression and anxiety in terms of its etiology, pathogenesis, and clinical manifestations, it is possible that ZZX may also be useful for the prevention and treatment of PTSD. In this study, a mouse model of PTSD was established and used to study the pharmacological action of a 95% ethanol extract of ZZX on PTSD via a series of classic behavioral tests. We found that a 95% ethanol extract of ZZX was indeed effective for relieving the symptoms of PTSD in mice. Moreover, network pharmacology analysis was used to predict the potential active ingredients, targets, and possible pathways of ZZX in the treatment of PTSD. The neurotransmitter system, the hypothalamic-pituitary-adrenal (HPA) axis, and the endocannabinoid (eCB) system were identified to be the most likely pathways for anti-PTSD action in ZZX. Due to the lack of a falsification mechanism in network pharmacology, in vivo tests were carried out in mice, and the expression levels of neurotransmitters, hormones, and genes of key targets were detected by enzyme-linked immunosorbent assay and real-time PCR to further verify this inference. Analysis showed that the levels of norepinephrine, 5-hydroxytryptamine, and glutamic acid were increased in the hippocampus, prefrontal cortex, and amygdala of PTSD mice, while the levels of dopamine and γ-aminobutyric acid were decreased in these brain regions; furthermore, ZZX could restore the expression of these factors, at least to a certain extent. The levels of adrenocorticotropic hormone, corticosterone, and corticotropin-releasing hormone were increased in these different brain regions and the serum of PTSD mice; these effects could be reversed by ZZX to a certain extent. The expression levels of cannabinoid receptor 1 and diacylglycerol lipase α mRNA were decreased in PTSD mice, while the levels of fatty acid amide hydrolase and monoacylglycerol lipase mRNA were increased; these effects were restored by ZZX to a certain extent. In conclusion, our findings suggest that ZZX may provide new therapeutic pathways for treating PTSD by the regulation of neurotransmitters, the HPA, and expression levels of eCB-related genes in the brain.

Dataset Information

Serum Metabolic Profiling Reveals the Antidepressive Effects of the Total Iridoids of Valeriana jatamansi Jones on Chronic Unpredictable Mild Stress Mice.

Publications

Serum Metabolic Profiling Reveals the Antidepressive Effects of the Total Iridoids of <i>Valeriana jatamansi</i> Jones on Chronic Unpredictable Mild Stress Mice.

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