积雪草总苷对老年消化不良模型大鼠胃肠动力及肠神经系统的保护作用量效关系及机制研究
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篇名: 积雪草总苷对老年消化不良模型大鼠胃肠动力及肠神经系统的保护作用量效关系及机制研究
TITLE: Study on Dose-effect Relationship and Mechanism of Protective Effects of Total Asiaticoside on Gastrointestinal Motility and Enteric Nervous System in Aged Functional Dyspepsia Model Rats
摘要: 目的:探究积雪草总苷对老年消化不良(FD)模型大鼠胃肠动力及肠神经系统(ENS)保护作用的量效关系及机制。方法:将16月龄老年雄性SD大鼠随机分为空白对照组、模型组和积雪草总苷低、中、高剂量组(15、30、60mg/kg),每组8只。采用夹尾刺激联合不规则饮食法持续4周以建立老年大鼠FD模型。造模完成后隔日,给药组大鼠灌胃相应剂量积雪草总苷药液,对照组和模型组大鼠灌胃等容生理盐水,每日1次,连续15d。采用酶联免疫吸附测定法检测大鼠血清中胃动素(MTL)、血管活性肠肽(VIP)的含量;测定大鼠胃排空率和小肠推进比;采用免疫荧光法和免疫组织化学法检测大鼠胃窦组织中ENS标志物[中枢神经特异性蛋白(S100β)和胶质细胞源性神经营养因子(GDNF)]的表达情况;采用Westernblotting法检测胃窦组织中S100β、胶质细胞原纤维酸性蛋白(GFAP)、蛋白基因产物9.5(PGP9.5)、GDNF、磷酸化丝裂原活化蛋白激酶激酶(p-MEK)以及磷酸化细胞外信号调节激酶1/2(p-ERK1/2)蛋白的表达水平。结果:与空白对照组比较,模型组和积雪草总苷低、中剂量组大鼠胃排空率和小肠推进比以及血清中MTL含量和胃窦组织中PGP9.5蛋白表达水平显著降低,血清中VIP含量和胃窦组织中S100β、GFAP、GDNF、p-MEK、p-ERK1/2蛋白表达水平均显著升高(P<0.05)。与模型组比较,积雪草总苷各剂量组大鼠胃排空率和小肠推进比均显著升高(P<0.05);除积雪草总苷低剂量组GFAP蛋白表达水平变化不显著(P>0.05)外,各剂量组大鼠血清中MTL含量和胃窦组织中PGP9.5蛋白表达水平均显著升高,血清中VIP含量和胃窦组织中S100β、GFAP、GDNF、p-MEK、p-ERK1/2蛋白表达水平均显著降低(P<0.05)。上述胃肠动力指标含量和相关因子蛋白表达水平有部分或大多数在积雪草总苷不同剂量组之间有显著差异(P<0.05),且高剂量组各指标可恢复至与空白对照组无显著差异的水平(P>0.05)。结论:积雪草总苷能剂量依赖性地改善老年FD模型大鼠的胃肠动力不足、ENS功能异常,且以高剂量组(60mg/kg)的作用效果最明显;其机制可能与促进内源性MTL释放并抑制VIP分泌、抑制GDNF及下游信号通路激活并促进ENS和肠神经元修复有关。
ABSTRACT: OBJECTIVE:To explo re the dose-effect relationship and mechanism of protective effects of total asiaticoside (TA) on gastrointestinal motility and enteric nervous system (ENS)in aged functional dyspepsia (FD)model rats. METHODS :Aged male SD rats of 16 months old were randomly divided into blank control group ,model group ,TA low dose ,medium dose and high dose groups (15,30,60 mg/kg),with 8 rats in each group. FD model was established by tail-stimulation combined with irregular diet for 4 weeks. The next day after modeling ,administration groups were given relevant doses of TA solution intragastrically ; control group and model group were given constant volume of normal saline intragastrically ,once a day ,for consecutive 15 d. Gastric emptying rate and small intestinal propulsion rate of rats were examined. ELISA were used to detect serum contents of MTL and VIP. Immunofluorescence and immunohistochemistry were proposed to measure the expression of ENS marker (S100β and GDNF)in gastric antrum tissue. The protein expression of S 100β,GFAP,PGP9.5,GDNF,p-MEK and p-ERK 1/2 in gastric antrum tissue were measured by Western blotting assay. RESULTS :Compared with blank control group ,gastric emptying rate and small intestinal propulsion rate ,serum MTL content and protein expression of PGP 9.5 in gastric antrum tissue of model and TA low,medium dose group were decreased significantly ,while serum VIP content ,protein expressions of S 100β,GFAP,GDNF, p-MEK and p-ERK 1/2 in gastric tissue were increased significantly (P<0.05). Compared with model group ,gastric emptying rate and small intestinal propulsion rate of TA groups were increased significantly (P<0.05);except for GFAP protein in TA low dose group(P>0.05),the serum MTL content and the expression of PGP 9.5 protein in gastric antrum tissue of rats in TA groups were increased significantly ,while serum VIP content ,protein expression of S 100β,GFAP,GDNF,p-MEK and p-ERK 1/2 in gastric antrum tissue were decreased significantly (P<0.05). Some or most of the content of gastrointestinal motility indexes and related factor protein expression were significantly different among TA groups (P<0.05),and the indexes in TA high dose group could recover to the levels which were not significantly different with blank control group (P>0.05). CONCLUSIONS :TA can dose-dependently improve the gastrointestinal motility deficiency and ENS dysfunction in aged FD model rats ,especially in high dose(60 mg/kg)of TA group. Its mechanism may be related with promoting the release of endogenous MTL ,inhibiting the secretion of VIP ,expression of GDNF and the activation of downstream signaling pathway ,and promoting the repair of ENS and intestinal neurons.
期刊: 2020年第31卷第12期
作者: 田徐露,蓝程,岑运光,王太昊,崔晓燕
AUTHORS: TIAN Xulu,LAN Cheng ,CEN Yunguang ,WANG Taihao ,CUI Xiaoyan
关键字: 积雪草总苷;消化不良;胃肠动力;肠神经系统;胶质细胞源性神经营养因子;机制;量效关系;老年大鼠
KEYWORDS: Total asiaticoside ;Functional dyspepsia ;Gastrointestinal motility ;Enteric nervous system ;GDNF;Mechanism;
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