In vitro and in vivo metabolism of Cistanche tubulosa extract in normal and chronic unpredictable stress-induced depressive rats
Introduction
Cistanches Herba is officially recorded as the dried succulent stems of Cistanche deserticola (Y. C. Ma) and C. tubulosa (Schrenk), which is used to treat kidney deficiency, impotence, female infertility, morbid leucorrhea, profuse metrorrhagia, and senile constipation [1]. Modern pharmacological studies have shown that Cistanches Herba possesses various biological activities such as anti-neurodegeneration, immunoregulation, and anti-inflammation [2,3]. Our previous investigations have verified that C. tubulosa extract (CTE), which are consisted of 48.6% phenylethanoid glycosides (PhGs), 6.9% iridoid glycosides, and 20.0% total saccharides, could markedly alleviate depressive symptoms of chronic unpredictable stress (CUS)-induced depressive rats by restoring homeostasis of gut microbiota [4]. Recent studies indicate that changes in the intestinal microbiota composition were associated with the development and progression of depression [5,6]. The relative abundances of the microbial genera were markedly disturbed in CUS depressive model rats compared with normal controls [7]. In depressed patients, the diversity and richness of intestinal microbiota were also significantly altered [8]. Moreover, various compounds including phenylethanoid glycosides (PhGs) and iridoid glycosides were considered as the main constituents of Cistanches Herba [2,3], which were easily metabolized into their secondary glycosides and aglycones including hydroxytyrosol (HT), 3,4-dihydroxyphenethyl glycoside, deglycosylated geniposidic acid etc. by human intestinal microbiota. These metabolites are more easily absorbed through the intestine and exert biological activity consistent with the prototype component [[9], [10], [11]]. Thus, we believe that during the occurrence and development of depression, the disturbance of intestinal microflora structure will inevitably affect the metabolism of oral traditional Chinese medicines (TCMs) in the gastrointestinal tract, in addition to affecting the physiological state of the host. Most of the existing metabolic data of Cistanches Herba come from metabolic studies on healthy animals [[12], [13], [14], [15]]. Therefore, it would be of more clinical significance to investigate the metabolic profile of CTE in the pathological state in elucidating its bioactive components and understanding the mechanism of action for its anti-depressive efficacy.
In the current study, we aim to characterize the metabolic profiles of CTE in both healthy and CUS-induced depressive model rats by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Gastric juice, intestinal fluid, and microbiota of normal and depressive pathological rats are used to simulate the metabolic process of CTE in the gastrointestinal tract in vitro, independently and sequentially. In vivo metabolites are also elucidated after oral administration of CTE in normal and CUS rats. This study provides new insights into the metabolism and active metabolites of CTE for depression.
Section snippets
Material
Dried stems of C. tubulosa were collected from Hetian County (Xinjiang, China). The voucher specimen samples were authenticated by Prof. Xiaobo Li and deposited at the herbarium of the School of Pharmacy, Shanghai Jiao Tong University (Shanghai, China). The extraction method used was specified in our previous publication [4]. The C. tubulosa extract (CTE) samples were stored at 4 °C and re-dissolved with sterile water before use. The sterile water solutions of CTE sample were then filtered
Behavioral changes in the CUS induced depression rat
The rats with CUS-induced depressive symptom were assessed by behavioral tests including sucrose preference test, open-field test, and novelty-suppressed feeding test. Student's t-test revealed that sucrose preference in sucrose preference test (p < .001), total distance covered in open-field test (p < .001), and latency to eat in novelty-suppressed feeding test (p < .01) were significantly different compared with the control group after 4-week CUS treatment (Fig. 1). These findings indicated
Discussion
In this study, three in vitro incubation models including gastric juice, intestinal juice, normal and CUS rat intestinal microbiota were employed independently and sequentially to investigate the gastrointestinal metabolic profile of CTE in vitro. It was found that PhGs and iridoid glycosides in CTE were readily metabolized to their secondary glycosides and aglycones by CUS-induced depressive rat intestinal microbiota. After that, in vivo metabolism of CTE in normal and CUS rats were also
Conclusion
In the present study, UPLC-Q-TOF-MS technique was established and applied to screen and identify metabolites of Cistanche tubulosa extract in normal and CUS depressive rats in vitro and in vivo. The results showed that CTE was metabolized to aglycones and degradation products of PhGs and iridoid glycosides by both healthy and depressed rat intestinal microbiota. After oral administration of CTE, phase II metabolites of aglycones and degradation products of PhGs and iridoid glycosides were
Acknowledgements
This work was supported by grants from National Key Research and Development Program of China (2017YFC1702400).
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