Elsevier

Journal of Ethnopharmacology

Volume 150, Issue 3, 12 December 2013, Pages 1053-1061
Journal of Ethnopharmacology

A representative prescription for emotional disease, Ding-Zhi-Xiao-Wan restores 5-HT system deficit through interfering the synthesis and transshipment in chronic mild stress-induced depressive rats

https://doi.org/10.1016/j.jep.2013.10.018Get rights and content

Abstract

Ethnopharmacological relevance

Ding-Zhi-Xiao-Wan (DZ, also known as Kai-Xin-San) is a famous traditional Chinese medicine used for the treatment of emotional disease. Previously, we have found that in a variety of animal models of depression (such as tail suspension model, model of chronic fatigue and forced swimming model) DZ demonstrated significant antidepressant behavior and promoted the production of 5-hydroxytryptamine (5-HT). However, the mechanisms of 5-HT regulation are still unclear. Therefore, the current study is designed to further investigate the antidepressant effect of DZ by observing its influence on 5-HT synthesis, metabolism, transport and other key links, so as to clarify the molecular mechanism of its 5-HT regulation.

Materials and methods

Solitary rising combined with the chronic unpredictable mild stress (CMS) was used to establish the rat model of depression. The rats were given DZ for 3 weeks, the behavior change and the following items in hippocampus and prefrontal cortex were detected simultaneously: 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), tryptophan hydroxylase (TPH), aromatic amino acid decarboxylase (AADC), monoamine oxidase (MAO) and 5-HT transporter (5-HTT) were observed.

Results

Our results showed that treatment with the DZ significantly improved the behavior and simultaneously increased the 5-HT level in the hippocampus, prefrontal cortex tissues and hippocampus extracellular of depressive rats. In future studies revealed that DZ could significantly increase the protein and mRNA expression of the key enzymes TPH during the 5-HT synthesis process in the hippocampus and prefrontal cortex of the depressed rats, and suppress the expression of 5-HTT protein and mRNA at the same time. But it had no effects on MAO-A and MAO-B activities.

Conclusion

We believe that antidepressant effect of DZ is caused by the increase of 5-HT synthesis and reduction of 5-HT re-uptake, and eventually increase the content of 5-HT in the brain and the synaptic gaps.

Introduction

Depressive disorders are among the most prevalent psychiatric disorders, with a lifetime incidence of 15–25%. Ding-Zhi-Xiao-Wan (DZ) is a famous formula which was originally recorded in Chinese ancient book “Bei Ji Qian Jin Yao Fang” (means precious formulas for emergency) by Sun Simiao. “Ding-Zhi” means ameliorate or cure or recovery the moodiness, forgetfulness, learning and memory deficit and else induced by loneliness, pressure in traditional Chinese medical theory. DZ consists of Ginseng (Panax ginseng C.A. Meyer), hoelen (Wolf Poria cocos, Schw), polygala (Polygala tenuifolia Willd) and Acorus (Acorus tatarinowii Schott), the formula with a ratio of 3:3:2:2 has another name as Kai-Xin-San (KXS) in “Tai Ping Hui Min He Ji Ju Fang”. And it is a renowned Chinese herbal formula for anti-depression, and ameliorating the learning and memory deficits, such as desolation, moodiness, forgetfulness etc. for thousands years.

Our previous studies has indicated that DZ had the antidepressant-like effect in tail suspension test (TST) and forced swim test (FST), and could significantly elevate the contents of central monoamine neurotransmitter, 5-hydroxytryptamine (5-HT), dopamine (DA) and noradrenergic (NE) in mice (Hu et al., 2008, Zhou et al., 2012). Simultaneously, DZ could ameliorate chronic fatigue syndrome (CFS) by improving the proliferation of splenocyte from CFS mice and modulating the disturbance of cytokines induced by CFS (Cao et al., 2012). DZ exerts its antidepressant-like and nootropic effect in the chronic mild stress (CMS) model by modulating the HPA axis, monoamine neurotransmitter and cholinergic systems (Dang et al., 2009). However, the possible mechanisms of DZ on the regulation of 5-HT level in CMS rats have not been evaluated scientifically. The mechanisms of 5-HT synthesis, metabolism, and re-uptake is very complicated, affecting any one of the three links, will affect the content of 5-HT. So the present study aimed to explore the 5-HT up-regulation effects of DZ in the CMS rats, and detected the key protein or enzymes involved in the metabolism, synthesis and transshipment to determine whether DZ has excitatory or inhibitory actions on these paths above-mentioned.

Section snippets

Drug preparation

All medicines formulating DZ were purchased from the LvYe Medicinal Material Company, China; the quality of these crude drugs is controlled by the Chinese Pharmacopoeia (2010). The voucher specimen of each plant was registered under the numbers NU-90111, NU-82003, NU-79015, and NU-59012 respectively, and deposited in the Herbarium of Traditional Chinese Medicinal pharmacy. DZ was supplied in the form of a dried powder that had been manufactured as an aqueous extract of a mixture of ginseng,

Effects of DZ on behavioral index

The effects of DZ on sucrose-preference index and open-field test are presented in Fig. 1. After 4 weeks of stress, the CMS group was significantly different from the CON group, with a lower index of sucrose preference (p<0.05 vs. the normal control group). DZ oral administration treatment at 338, 676 mg/kg significantly increased the sucrose-preference index in comparison with the CMS group (p<0.05 vs. the CMS group). Likewise, an increase in the preference index was also noted in the

Discussion

The pathophysiology of depression is complex and involves several different biochemical pathways. Since 1965, the monoamine theory of depression advocates that mental depression is due to a deficiency in brain monoaminergic activity (Gesto et al., 2008). In particular, a great number of studies showed that serotonergic system is intimately linked to stress and anxiety responses (Graeff et al., 1996) and plays a major role in the onset and course of depression (Yi et al., 2008). 5-HT is one of

Conclusion

Ding-Zhi-Xiao-Wan could improve the depressive behavior via restore 5-HT system deficit in chronic mild stress-induced depressive Rats. The distinctly stimulatory on 5-HT level of DZ is caused by increasing the 5-HT synthesis, suppressing 5-HT re-uptake, and eventually increased the content of 5-HT in the brain and the synaptic gaps.

Acknowledgment

This work was supported by grants from the National Natural Science Foundation (No. 81173430).

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