Purpose [6]-gingerol is a bioactive compound extracted from ginger, a traditional anti-emetic herb in Chinese medicine. Previous studies have demonstrated that [6]-gingerol can ameliorate chemotherapy-induced pica in rats, although the underlying mechanism has not been elucidated. This study is designed to investigate [6]-gingerol’s antiemetic mechanism focusing on the 5-hydroxytryptamine (serotonin, 5-HT) system by evaluating the synthesis, metabolism and reuptake of 5-HT, as well as the mechanism of 5-hydroxytryptamine type 3 receptor (5-HT 3 receptor), in a cisplatin-induced pica model of rats. Methods Rats were randomly divided into control group (vehicle + saline, Con), [6]-gingerol control group (50 mg/kg [6]-gingerol + saline, G-con), ondansetron control group (2.6 mg/kg ondansetron + saline, O-con), cisplatin model group (vehicle + cisplatin, Model), ondansetron-treated group (2.6 mg/kg ondansetron + cisplatin, O-treated), high dosage of [6]-gingerol-treated group (100 mg/kg [6]-gingerol + cisplatin, GH-treated), and low dosage of [6]-gingerol-treated group (50 mg/kg [6]-gingerol + cisplatin, GL-treated). The rats were administered with [6]-gingerol, ondansetron, and vehicle (3% Tween-80) by gavage twice (7:00 AM and 7:00 PM). One hour after the first treatment (8:00 AM), rats in groups Model, O-treated, GH-treated and GL-treated were injected intraperitoneally (i.p.) with 6 mg/kg cisplatin, and the other groups were injected i.p. with saline of equal volume. The consumption of kaolin of the rats were measured. All the rats were anesthetized by i.p. injection of pentobarbital sodium at 24 h post-cisplatin. After blood samples were taken, medulla oblongata and ileum were removed. The levels of 5-HT and its metabolite 5-HIAA in ileum, medulla oblongata and serum were determined using high-performance liquid chromatography with electrochemical detection (HPLC-ECD). The mRNA expression levels of 5-HT 3 receptor, tryptophan hydroxylase (TPH), monoamine oxidase A (MAO-A) and serotonin reuptake transporter (SERT) were detected by real-time PCR. The protein expression levels and distribution of 5-HT 3 receptor, TPH and MAO-A in the medulla oblongata and ileum were measured by Western blotting and immunohistochemistry, respectively. Results [6]-gingerol treatment significantly reduced the kaolin ingestion and the increase in 5-HT concentration in rats induced by cisplatin. TPH, MAO-A, SERT, and 5-HT 3 receptor are important in 5-HT metabolism, and cisplatin-induced alterations in the associated protein/mRNA levels were restored when treated with [6]-gingerol. Conclusion This suggests that the antiemetic effect of [6]-gingerol against cisplatin-induced emesis may be due to 5-HT attenuation via modulating the TPH/MAO-A/SERT/5-HT/5-HT 3 receptor system.
Purpose [6]-gingerol is one of the main components of ginger with many biological activities. In this study, the effects of ondansetron and [6]-gingerol on pica and gut microbiota in rats injected with cisplatin were evaluated. Materials and methods Rat model of cisplatin-induced pica was established, and the effects of ondansetron and [6]-gingerol on the gut microbiota were further studied by 16S rDNA gene analysis. Results The results showed that the total intake of kaolin of the rats injected with cisplatin was significantly increased, and treatment of ondansetron and [6]-gingerol in advance could significantly ameliorate the pica induced by cisplatin. The body weight of the rats injected with cisplatin was decreased compared with the control group. The 16S rDNA gene analysis has shown that ondansetron, [6]-gingerol and cisplatin could increase the relative abundance of Bacteroidetes and decrease Firmicutes on phylum level. Conclusion [6]-gingerol was as effective as ondansetron in the treatment of pica induced by cisplatin in rats, and it seemed that [6]-gingerol had the potential to ameliorate the alteration of gut microbiome, but it needs further study.
Xiao-Ban-Xia-Tang (XBXT), a traditional Chinese medicine formula, has been used for the treatment of emesis for nearly 2000 years, but its underlying mechanism is not yet fully clarified. The purpose of this study is to reveal the antiemetic mechanisms of XBXT by focusing on the NLRP3 inflammasome pathway in a chemotherapy-induced rat pica model. The pica model was generated by a single intraperitoneal injection of cisplatin in this study. Consumption of kaolin (a type of clay) and food and body weight were recorded every 24 hours. Cisplatin-induced increase in kaolin consumption (pica) was used to quantify chemotherapy-induced nausea and vomiting (CINV). Tissue from the ileum and antrum was stained with hematoxylin eosin (HE) to observe pathological changes. The levels of reactive oxygen species (ROS) and inflammatory cytokines, including IL-1β and IL-18 in serum, were detected by ELISA. In addition, changes in the NLRP3 inflammasome activation in the ileum and antrum were investigated using western blot and immunofluorescence microscopy. The results showed that oral administration of XBXT and ondansetron inhibited acute and delayed pica and significantly protected against the gastrointestinal pathological injury induced by cisplatin. The levels of ROS, IL-1β, and IL-18 in the serum of cisplatin-treated rats were also remarkably decreased by XBXT and ondansetron. Moreover, we found that XBXT can inhibit cisplatin-induced NLRP3 inflammasome activation. The present study indicates that the inhibition of the NLRP3 inflammasome activation might be one of the potential mechanisms for the therapeutic effects of XBXT against CINV.
Background: Xiao-Ban-Xia-Tang (XBXT) formula is a traditional Chinese herbal formula for treating emesis. Chemotherapy-induced nausea and vomiting (CINV) are serious side effects of chemotherapy, which was closely related to the activation of 5-hydroxytryptamine 3 receptor (5-HT3R). In this paper, the effect of XBXT on cisplatin- and 1-phenylbiguanide hydrochloride (1-PBG, a selective 5-HT3R agonist)- induced pica behavior in male Wistar rats and inhibition of calmodulin/calmodulin-dependent protein kinase II/extracellular signal-regulated kinase 1/2 (CaM/CaMKII/ERK1/2) signaling pathway were investigated. Methods: XBXT (1.6 g/kg, twice daily) was orally administered from day 1 after intraperitoneal injection of cisplatin (6 mg/kg) and 1-PBG (25 mg/kg) to day 3. Pica behavior (consumption of kaolin, a type of clay) was recorded every 24 h. The expression and co-localization of CaM and 5-HT3R in small intestine and brain were detected by immunofluorescence. The expression of CaMKII, pCaMKII, ERK1/2, and pERK1/2 proteins were detected by Western blot. Results: XBXT treatment significantly decreased kaolin ingestion (pica) of rats after treatment of cisplatin and 1-PBG during both 0 - 24 h (respectively, from 1.57 g to 0.87 g; from 1.04 g to 0.11 g) and 0 - 72 h (respectively, from 2.98 g to 1.85 g; from 2.29 g to 0.35 g) periods. The fluorescence expression of CaM and 5-HT3R and expression of CaMKII, pCaMKII, ERK1/2 and pERK1/2 in the small intestine and brain of cisplatin- and 1-PBG-treated rats were remarkably suppressed by XBXT.Conclusions: The present study implies that inhibiting CaM/CaMKII/ERK1/2 signaling is an underlying mechanism of XBXT for treating CINV. These insights provide an experimental basis of XBXT for the clinical treatment of CINV.
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