小半夏汤多靶点防治化疗性恶心呕吐作用机制研究

发布时间：2018-10-07 19:48

【摘要】：目的:探讨小半夏汤多靶点防治化疗性恶心呕吐作用机制。方法:腹腔注射6mg/kg顺铂建立大鼠化疗性异食癖模型,测定大鼠摄食高岭土量作为其恶心呕吐程度指标。将Wistar大鼠随机分为正常对照组、小半夏汤正常对照组、顺铂模型组、昂丹司琼阳性药组、小半夏汤大剂量组和小半夏汤小剂量组。各组动物在造模前1h首次灌胃给药,之后每12h给药一次,昂丹司琼组、小半夏汤正常对照组、小半夏汤大、小剂量组每日给药剂量分别为2.6mg/kg昂丹司琼、1.6、3.2、1.6g/kg小半夏汤,正常对照组和模型组灌胃等容积蒸馏水。每12h称量并计算各组动物高岭土摄入量。分别于造模后24h和72h处理动物,ELISA法测定各组大鼠外周(血清、回肠)和中枢(延髓)5-HT与其代谢产物5-HIAA、DA与其代谢产物DOPAC、P物质含量以及回肠和延髓5-HT合成限速酶TPH、5-HT代谢关键酶MAOA、DA合成限速酶TH、DA代谢关键酶MAOB水平;免疫组织化学法检测各组大鼠回肠和延髓组织5-HT3A受体、NK1受体、D_2受体阳性细胞表达情况;Real-time PCR法测定各组大鼠回肠和延髓5-HT转运体(SERT)、5-HT3A受体、P物质前体前速激肽原A(PPTA)、NK1受体、D_2受体m RNA表达水平;Western Blotting法测定大鼠回肠和延髓5-HT3A受体、NK1受体和D_2受体蛋白表达变化。结果:模型组动物摄食高岭土量显著升高,小半夏汤大、小剂量均可抑制化疗大鼠摄食高岭土。小半夏汤大、小剂量均能够降低化疗大鼠24h、72h外周和中枢5-HT含量、增加5-HIAA含量、降低5-HT3A受体m RNA和蛋白表达水平,小半夏汤对化疗大鼠5-HT和5-HIAA作用与降低TPH水平、提高MAOA水平有关;小半夏汤大、小剂量均能够降低化疗大鼠24h、72h外周和中枢P物质含量、NK1受体m RNA和蛋白表达水平,小半夏汤对化疗大鼠P物质的抑制作用与降低PPTA m RNA表达有关;小半夏汤大、小剂量均能够降低化疗大鼠24h、72h外周和中枢DA含量、降低D_2受体m RNA和蛋白表达水平,但对DOPAC影响不大,小半夏汤对化疗大鼠DA的抑制作用与降低TH水平有关。结论:小半夏汤对CINV急性期和延迟期均有显著疗效,与对5-HT、P物质、DA多靶点作用有关。小半夏汤对CINV急性期的防治作用机制主要与抑制回肠和延髓5-HT合成、促进5-HT代谢以及下调5-HT3A受体m RNA和蛋白表达有关;小半夏汤对CINV延迟期的防治作用机制主要与抑制回肠和延髓P物质合成以及下调NK1受体m RNA和蛋白表达有关;另外,小半夏汤对CINV的防治作用还与抑制回肠和延髓DA合成以及下调D_2受体m RNA和蛋白表达有关。
[Abstract]:Objective: to investigate the mechanism of Xiao Banxia decoction (XBST) on preventing and treating nausea and vomiting induced by chemotherapy. Methods: the model of chemotherapia was established by intraperitoneal injection of 6mg/kg cisplatin in rats. The intake of kaolin was used as the index of nausea and vomiting in rats. Wistar rats were randomly divided into normal control group, small Banxia decoction normal control group, cisplatin model group, ondansetron positive drug group, small Banxia decoction large dose group and small Banxia decoction small dose group. The animals in each group were given orally for the first time 1 hour before the model was made, and then once every 12 hours. Ondansetron group, small Banxia decoction normal control group, small Banxia decoction, small dose group were given 2.6mg/kg ondansetron 1.6g / kg 1.6 g / kg small Banxia decoction, respectively. Normal control group and model group were fed with distilled water of equal volume. The intake of kaolin was calculated every 12 hours. The peripheral serum of rats in each group was determined by Elisa after 24 hours and 72 hours of treatment, respectively. Ileum) and central (medulla oblongata) 5-HT and its metabolite 5-HIAADA and its metabolite DOPAC,P, and the levels of MAOA,DA metabolism key enzyme TH,DA metabolic key enzyme MAOB of ileal and medulla 5-HT biosynthesis limiting enzyme TPH,5-HT metabolism key enzyme; Expression of 5-HT3A receptor NK1 receptor D2 receptor positive cells in ileum and medulla oblongata of rats detected by immunohistochemical method Real-time PCR method was used to detect the expression of pretachykininogen A (PPTA) NK1 in ileum and medulla oblongata 5-HT transporter (SERT) 5 HT3A receptor substance P Expression of D2 receptor m RNA in rat ileum and medulla oblongata were determined by Western Blotting. The expression of NK1 receptor and D2 receptor protein in rat ileum and medulla oblongata were determined. Results: in the model group, the intake of kaolin was significantly increased, and Xiaobanxia decoction was large, and small dose could inhibit the feeding of kaolin in chemotherapy rats. Xiaobanxia decoction could decrease the content of peripheral and central 5-HT, increase the content of 5-HIAA, decrease the expression of m RNA and protein of 5-HT3A receptor, and decrease the level of TPH in 5-HT and 5-HIAA of chemotherapeutic rats. Small Banxia decoction could decrease the expression of NK1 receptor m RNA and protein in peripheral and central substance P for 72 h after 24 h of chemotherapy in rats. The inhibitory effect of Xiao Banxia decoction on substance P in chemotherapeutic rats was related to the decrease of PPTA m RNA expression, and the large and low dose of Xiao Banxia decoction could decrease the contents of peripheral and central DA and the expression level of D2-receptor m RNA and protein in 24 h and 72 h after chemotherapy in rats. The inhibitory effect of Xiao Banxia decoction on DA in chemotherapeutic rats was related to the decrease of TH level. Conclusion: Xiao Banxia decoction has significant curative effect on acute and delayed stage of CINV, which is related to the multi target effect of 5 HT P substance DA. The mechanism of Xiao Banxia decoction in preventing and treating CINV in acute stage is mainly related to inhibiting the synthesis of 5-HT in ileum and medulla oblongata, promoting the metabolism of 5-HT and down-regulating the expression of m RNA and protein of 5-HT3A receptor. The preventive and therapeutic mechanism of Xiaobanxia decoction on CINV delayed phase is mainly related to inhibiting the synthesis of substance P in ileum and medulla oblongata and down-regulating the expression of m RNA and protein of NK1 receptor. The preventive and therapeutic effects of Xiao Banxia decoction on CINV were also related to the inhibition of DA synthesis in ileum and medulla oblongata, and the down-regulation of the expression of D _ 2 receptor m RNA and protein.
【学位授予单位】：山东中医药大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R730.53

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