Study On The Multi-target Mechanisms Of Xiao-Ban-Xia-Tang In The Prevention And Treatment Of Chemotherapy-induced Nausea And Vomiting

Objective:To investigate the multi-target mechanisms of Xiao-Ban-Xia-Tang（XBXT） in the prevention and treatment of chemotherapy-induced nausea and vomiting. Methods:The chemotherapy rat pica model was established by intraperitoneal injection of 6 mg/kg cisplatin. The amount of kaolin consumption of rats was used as an indicator of nausea and vomiting. The Wistar rats were randomly divided into normal control group, XBXT normal control group, cisplatin model group, positive drug ondansetron group, XBXT high and low dose groups. The rats in ondansetron group, XBXT normal control group, XBXT high and low dose groups were respectively given 2.6mg/kg/d ondansetron, 1.6, 3.2 and 1.6g/kg/d XBXT by oral gavage before modeling 1h and then twice a day. The rats in normal control group and model group were gavaged with equal volume of distilled water. Kaolin consumptions were weighed and calculated once per 12 h. After modeling 24 h and 72 h, the contents of 5-HT and its metabolite 5-HIAA, DA and its metabolite DOPAC, substance P content in peripheral（serum, ileum） and central（medulla oblongata） tissues, and the levels of TPH, MAOA, TH and MAOB were measured by ELISA. The positive cells of 5-HT and 5-HT3 A receptor, P substance and NK1 receptor, DA and D₂ receptor in rat ileum and medulla oblongata were detected by immunohistochemistry method. The m RNA expression levels of SERT, 5-HT3 A receptor, substance P precursor（PPTA）, NK1 receptor and D₂ receptor in rat ileum and medulla oblongata were measured by Real-time PCR. The protein expression levels of 5-HT3 A receptors, NK1 receptors and D₂ receptor in rat ileum and medulla oblongata were measured by Western Blotting. Results: Kaolin consumptions in model group were significantly increased. The high and low dosages of XBXT could significantly inhibit kaolin consumptions in cisplatin-treated rats, and reduce 5-HT contents, increase 5-HIAA contents and reduce 5-HT3 A receptor m RNA and protein expression levels in rats at 24 h and 72 h after chemotherapy. The effects of XBXT on 5-HT and 5-HIAA in rats after chemotherapy were related to the reduction of TPH levels and the enhancement of MAOA levels. The high and low dosages of XBXT could significantly reduce substance P contents and NK1 m RNA and protein expression levels in rats at 24 h and 72 h after chemotherapy. The effect of XBXT on substance P was related to the reduction of PPTA m RNA expression levels. The high and low dosages of XBXT could also significantly reduce DA contents and D₂ receptor m RNA and protein expression levels in rats at 24 h and 72 h after chemotherapy, but could not significantly change DOPAC contents. The effect of XBXT on DA was related to the reduction of TH levels. Conclusion: XBXT has significant antiemetic effect in the acute phase and delayed phase of chemotherapy-induced nausea and vomiting. The mechanisms of XBXT in the prevention and treatment of chemotherapy-induced nausea and vomiting are related to the inhibition of 5-HT and 5-HT3 A receptor, substance P and NK1 receptor, DA and D₂ receptor. The main metabolism of XBXT on the prevention and treatment of acute CINV was related to the inhibition of 5-HT synthesis, the promotion of 5-HT metabolism and the down regulation of 5-HT3 A receptor m RNA and protein expression in chemotherapy rat ileum and medulla oblongata. The main mechanism of XBXT on the prevention and treatment of delayed CINV was related to the inhibition of substance P synthesis and the down regulation of NK1 receptor m RNA and protein expression in chemotherapy rat ileum and medulla oblongata. In addition, the metabolism of XBXT on the prevention and treatment of CINV was also related to inhibition of DA synthesis and the down regulation of D₂ receptor m RNA and protein expression in chemotherapy rat ileum and medulla oblongata.