摘要
目的：生姜作为“呕家圣药”在我国应用历史悠久,可用于妊娠、术后及化疗引起的呕吐。姜辣素是从生姜中提取的活性成分,可对抗顺铂引起的呕吐。本文应用新型水貂呕吐模型,开展对姜辣素抗阿扑吗啡、洛哌丁胺和硫酸铜诱导的呕吐作用及其机制的研究。
方法：
1.姜辣素在阿扑吗啡诱导的水貂呕吐模型抗呕吐作用研究
将雄性水貂随机分为：①空白对照组、②阿扑吗啡组、③姜辣素低、中、高剂量组,每组6只。空白对照组和阿扑吗啡组分别给以生理盐水和1%西黄耆胶5ml·kg-1ig预处理；姜辣素低、中、高剂量组分别予姜辣素20mg·kg-1ig、100mg·kg-1ig、200mg·kg-1ig预处理。除空白对照组外,其余水貂在预处理30min后给予阿扑吗啡0.5mg·kg-1sc,观察水貂在给阿扑吗啡后的呕吐反应,记录呕吐潜伏期,干呕,呕吐次数。2h观察期结束后,处死水貂,取极后区,一部分置4%甲醛中固定,备测SP、c-fos的免疫组化表达;另一部分置于-80℃冰箱中冷冻,备用Western-blot法检测NK1受体表达。
2.姜辣素在洛哌丁胺诱导的水貂呕吐模型抗呕吐作用研究
将雄性水貂随机分为：①空白对照组、②洛哌丁胺组、③姜辣素低、中、高剂量组,每组6只。空白对照组和洛哌丁胺组分别给以生理盐水和1%西黄耆胶5ml·kg-1ig预处理；姜辣素低、中、高剂量组分别予以姜辣素50mg·kg-1ig、100mg·kg-1ig、200mg·kg-1ig预处理。除空白对照组外,其余水貂在预处理30min后给予洛哌丁胺0.5mg·kg-1sc,观察水貂在给洛哌丁胺后的呕吐反应,记录呕吐潜伏期,干呕,呕吐次数。观察2h后,处死水貂,取极后区,备测SP、c-fos NK1受体表达。
3.姜辣素在硫酸铜诱导的水貂呕吐模型抗呕吐作用研究
将雄性水貂随机分为：①空白对照组、②硫酸铜组、③姜辣素低、中、高剂量组,每组6只。空白对照组和硫酸铜组分别给以生理盐水和1%西黄耆胶5ml·kg-1ig预处理；姜辣素低、中、高剂量组分别用姜辣素50mg·kg-1ig、100mg·kg-1ig、200mg·kg-1ig预处理。除空白对照组外,其余水貂在预处理30min后给予硫酸铜40mg·kg-1ig,2h观察期内记录呕吐潜伏期,干呕,呕吐次数。处死水貂,取极后区和回肠组织,一部分置4%甲醛中,备测SP、c-fos的免疫组化表达；另一部分置于-80。C冰箱中冷冻,备测NK1受体表达及cGMP、cAMP、IP3和DAG/DG的含量。
结果：1.姜辣素在阿扑吗啡诱导的水貂呕吐模型抗呕吐作用研究表明：
皮下注射阿扑吗啡后,阿扑吗啡组6只水貂均发生呕吐,呕吐潜伏期短,干呕及呕吐次数均增加；而姜辣素低、中、高剂量组与阿扑吗啡组比较,干呕及呕吐次数减少(26.5±2.1b,15.2±4.3b,9.2±11.7b vs31.7±12.5；3.7±0.5c,3.0±0.6b,2.0±0.9b vs4.7±0.8,bP<0.01,cP0.05),呕吐潜伏期延长(50.7±5.7min vs29.3±3.8b min,bP<0.01),并有量效关系。
免疫组化结果显示：SP、c-fos免疫反应阳性产物呈现棕黄色颗粒,在阿扑吗啡组极后区阳性颗粒最多,着色最深,随姜辣素剂量增大,阳性反应颗粒减少,着色变浅,表达受到抑制。免疫组化阳性评分结果显示.阿扑吗啡组水貂脑组织极后区中SP、c-fos表达明显增高,与空白对照组比较有差异(4.2±0.9a vs0.7±0.5；4.5±1.2avs1.7±0.7,aP<0.01)；姜辣素低、中、高剂量组SP、c-fos表达水平与阿扑吗啡组比较降低(2.8±0.8b,2.3±0.5c,1.5±0.6c vs4.2±0.9；3.8±1.7,2.8±0.7b,2.0±0.9c vs4.5±1.2,bP<0.05,cP<0.01)。
Western-blot检测结果显示：皮下注射阿扑吗啡会引起水貂极后区NK1受体表达增高,姜辣素低、中、高剂量组均能抑制NK1受体表达,且随剂量增加,抑制作用增强。半定量结果显示：阿扑吗啡组NK1受体表达,与空白对照组比较有差异(0.7±0.08a vs0.20±0.03,aP<0.01)；姜辣素低、中、高剂量组NK1受体表达水平,与阿扑吗啡组比较降低(0.46±0.04b,0.39±0.05b,0.27±0.03b vs0.70±0.08,bP<0.01)。
2.姜辣素在洛哌丁胺诱导的水貂呕吐模型抗呕吐作用研究表明：
洛哌丁胺可成功复制水貂呕吐模型,皮下注射洛哌丁胺后,洛哌丁胺组6只水貂均发生呕吐,呕吐潜伏期短,干呕及呕吐次数均增加；而姜辣素具有明显的抗呕吐作用,姜辣素组水貂呕吐潜伏期较洛哌丁胺组延长(45.2±12.7b min vs26.9±7.8min,bP<0.01)。0-2h观察期内,姜辣素低、中、高剂量组干呕和呕吐次数较洛哌丁胺组显著减少(30.5±4.3b,25.3±3.0b,200±2.5b vs51.7±13.2；4.5±1.0,3.7±0.5c,2.8±0.7bvs5.3±1.0, bP<0.01,cP<0.05)。
免疫组化染色显示,SP、c-fos免疫反应阳性产物在洛哌丁胺组极后区阳性颗粒最多,着色最深,而姜辣素组随剂量增大,阳性反应颗粒减少,着色变浅。免疫组化阳性评分结果显示,洛哌丁胺使水貂极后区SP及c-fos表达增加(3.3±0.5a vs0.7±0.5；3.7±0.5a vs0.3±0.5,aP<0.01)姜辣素低、中、高剂量组水貂极后区SP及c-fos表达显著少于洛哌丁胺组(2.3±0.5“,1.7±0.5b,0.8±0.4b vs3.3±0.5；3.2±0.7,2.7±0.5b1.5±0.6b vs3.7±0.5,bP<0.01)
Western-blot检测结果显示：与空白对照组比,洛哌丁胺组水貂极后区NK1受体表达增高(0.63±0.04a vs0.16±0.04,aP<0.01)：姜辣素低、中、高剂量组NK1受体表达水平与洛哌丁胺组比降低(0.39±0.03b,0.32±0.05b,0.24±0.06b vs0.63±0.04, bP<0.01)。
3.姜辣素在硫酸铜诱导的水貂呕吐模型抗呕吐作用研究表明：
硫酸铜40mg·kg-1灌胃后水貂有明显的干呕和呕吐反应。与硫酸铜组相比,姜辣素组水貂呕吐潜伏期延长,干呕及呕吐次数减少(22.3±2.1b,18.5±1.4b,7.5±1.5b vs31.5±2.5；4.8±0.7c,4.0±0.6b,2.3±0.8b vs6.3±1.2bP<0.01,cP<0.05)。
免疫组化方法显示：SP免疫反应阳性产物在硫酸铜组回肠组织和极后区阳性颗粒最多,着色最深,而随姜辣素剂量增大,阳性反应颗粒减少,着色变浅。免疫组化阳性评分结果显示,硫酸铜组水貂回肠组织和极后区SP表达明显增加(3.0±0.6a vs0.7±0.5；2.5±0.5a vs0.5±0.5,aP<0.01),而姜辣素低、中、高剂量组回肠及极后区SP表达水平,与硫酸铜组比较降低(2.3±0.5,1.5±0.5b,1.3±0.5b vs3.0±0.6；2.2±0.4,1.3±0.5b,0.8±0.4b vs2.5±0.5,b P<0.01)。
免疫组化阳性评分结果显示,硫酸铜组水貂回肠组织和极后区c-fos表达明显增加(3.1±0.7a vs0.7±0.5；2.8±0.8a vs0.5±0.5,aP<0.01),而姜辣素低、中、高剂量组外周及中枢组织中c-fos表达水平,与硫酸铜组比较降低(2.5±0.5,1.7±0.5b,1.4±0.4b vs3.1±0.7;2.4±0.6,1.7±0.8b,1.2±0.4b vs2.8±0.8,bP<0.01)
Western-blot检测结果显示：硫酸铜组水貂回肠和极后区NK1受体表达明显增高,与空白对照组比较有差异(0.73±0.03a vs0.32±0.04；0.52±0.03a vs0.29±0.02,aP<0.01)；姜辣素低、中、高剂量组NKl受体表达水平,与硫酸铜组比较降低(0.55±0.03b,0.42±0.04b,0.32±0.04b vs0.73±0.03：0.47±0.03c,0.36±0.05b,0.31±0.05b vs0.52±0.03,bP<0.01,cP<0.05)
酶联免疫法实验结果表明：硫酸铜组水貂回肠组织与极后区脑组织中cGMP含量有明显降低,与空白对照组比较有差异(26.82±5.93a vs42.37±10.84；25.60±7.44a vs40.18±12.03,aP<0.01)。姜辣素低、中、高剂量组回肠与极后区cGMP含量较硫酸铜组均升高(35.43±6.26b,37.92±7.23b,40.50±7.25b vs26.82±5.93；32.62±8.55b,35.12±3.76b,39.48±5.93b vs25.60±7.44,bP<0.01)。与空白对照组比较,模型组的cAMP、IP3和DAG/DG没有统计学意义,与硫酸铜组相比,姜辣素组cAMP、IP3和DAG/DG水平未见显著差异。
结论：在水貂呕吐模型,姜辣素可抑制阿扑吗啡、洛哌丁胺、硫酸铜诱导的呕吐,其机制与抑制了NK1受体的异常表达有关。
Objective:
Ginger (Zingiber officinale) has been used extensively as a treatment for nausea and vomiting for more than2500years in China. The effectiveness of ginger in emesis due to hyperemesis gravidarum, post-operation and cancer chemotherapy. It was reported that ginerols, the pungent constituents of ginger, inhibited cisplatin-induced emesis in minks possibly by inhibiting central or peripheral increase ofsubstance P and NK1receptors. The present study in minks was designed to investigate the anti-emetic efficacy and the mechanisms of ginerols, inhibiting emesis induced by a wide variety of emetogens such as apomorphine, loperamide and copper sulfate.
Methods:
1. Antiemetic effect of ginerols on apomorphine-induced emesis in minks
30minks were randomly divided into the following five groups (n=6):the blank control group, the apomorphine group, and three ginerols groups. The blank control group were pretreated with sterile saline, the apomorphine group were preadministered with vehicle (1%tragacanth,5ml·kg-1, ig), the ginerols groups were preadminstered with ginerols (50mg·kg-1,100mg·kg-1or200mg·kg-1, ig), which was dissolved in1%tragacanth. Apomorphine (0.25mg·kg-1, sc) was administered30minutes after treatment with the antiemetic agent or its vehicle, except to the blank control group. Following administration of apomorphine, animals were observed continuously for2hours for the emetic responses and the number of both retching and vomiting.
Animals were sacrificed at2hours after administration of apomorphine. Tissues of the area postrema were removed. The distribution of substance P and c-fos in the area postrema were measured by immunohistochemistry.The levels of NK1receptor expression in the area postrema were measured by western-blot.
2. Antiemetic effect of ginerols on loperamide-induced emesis in minks
30minks were randomly divided into the following five groups (n=6):the blank control group, the loperamide group, and three ginerols groups. The blank control group were pretreated with sterile saline, the loperamide group were preadministered with vehicle (1%tragacanth,5ml·kg-1, ig), the ginerols groups were preadminstered with ginerols (50mg·kg-1,100mg·kg-1or200mg·kg-1, ig), which was dissolved in1%tragacanth. Loperamide (0.5mg·kg-1, sc) was administered30minutes after treatment with the antiemetic agent or its vehicle, except to the blank control group. Following administration of loperamide, animals were observed continuously for2hours for the emetic responses and the number of both retching and vomiting.
Animals were sacrificed at2hours after administration of loperamide. Tissues of the area postrema were removed. The distribution of substance P and c-fos in the area postrema were measured by immunohistochemistry.The levels of NK1receptor expression in the area postrema were measured by western-blot.
3. Antiemetic effect of ginerols on copper sulfate-induced emesis in minks
30minks were randomly divided into the following five groups (n=6):the blank control group, the copper sulfate group, and three ginerols groups. The blank control group were pretreated with sterile saline, the copper sulfate group were preadministered with vehicle (1%tragacanth,5ml·kg-1, i.g), the ginerols groups were preadminstered with ginerols (50mg·kg-1,100mg·kg-1or200mg·kg-1, ig), which was dissolved in1%tragacanth. Copper sulfate (40mg·kg-1, ig) was administered30minutes after treatment with the antiemetic agent or its vehicle, except to the blank control group. Following administration of copper sulfate, animals were observed continuously for2hours for the emetic responses and the number of both retching and vomiting.
Animals were sacrificed at2hours after administration of copper sulfate. Tissues of the area postrema as well as the ileum were removed. The distribution of substance P and c-fos in the area postrema and ileum were measured by immunohistochemistry.The levels of NK] receptor expression in the area postrema and ileum were measured by western-blot. The levels of cGMP、cAMP、IP3、DAG/DG were measured by ELISA.
Results:
1. Antiemetic effect of ginerols on apomorphine-induced emesis in minks
Apomorphine evoked a profound emetic response in minks, pretreatment with gingerols reduced the number of retches and vomits induced by apomorphine in a dose-dependent manner during the2h observation period (26.5±2.1b,15.2±4.3b,9.2±11.7bvs31.7±12.5;3.7±0.5c,3.0±0.6b,2.0±0.9b vs4.7±0.8, bP<0.01, cP<0.05).
Apomorphine produced a significant increase in SP and c-fos levels in the area postrema of minks (4.2±0.9a vs0.7±0.5;4.5±1.2a vs1.7±0.7, aP<0.01), and this increase was significantly inhibited by gingerols (2.8±0.8b,2.3±0.5c,1.5±0.6c vs4.2±0.9;3.8±1.7,2.8±0.7b,2.0±0.9c vs4.5±1.2, b P<0.05,c P<0.01).
The expression of NK1receptor was analyzed by western-blot respectively, the expression levels of NK1receptor significantly increased after treatment with apomorphine (0.70±0.08a vs0.20±0.03, a P<0.01), the elevated expression was inhibited by the pretreatment of gingerols in the area postrema (0.46±0.04b,0.39±0.05b0.27±0.03bvs0.70±0.08, bP<0.01).
2. Antiemetic effect of ginerols on loperamide-induced emesis in minks
Loperamide evoked a profound emetic response in minks, pretreatment with gingerols reduced the number of retches and vomits induced by loperamide in a dose-dependent manner during the2h observation period (30.5±4.3b,25.3±3.0b20.0±2.5bvs51.7±13.2;4.5±1.0,3.7±0.5c,2.8±0.7b vs5.3±1.0, bP<0.01,cP<0.05).
Loperamide produced a significant increase in SP and c-fos levels in the area postrema of minks (3.3±0.5a vs0.7±0.5;3.7±0.5a vs0.3±0.5, a P<0.01), and this increase was significantly inhibited by gingerols (2.3±0.5b,1.7±0.5b,0.8±0.4b vs3.3±0.5,3.2±0.7,2.7±0.5b,1.5±0.6b vs3.7±0.5, b P<0.01)
The expression levels of NK1receptor significantly increased after treatment with loperamide (0.63±0.04a vs0.16±0.04,a P<0.01), the elevated expression was inhibited by the pretreatment of gingerols in the area postrema (0.39±0.03b,0.32±0.05b,0.24±0.06b vs0.63±0.04,b P<0.01).
3. Antiemetic effect of ginerols on copper sulfate-induced emesis in minks
The frequency copper sulfate-induced retching and vomiting was significantly reduced by pretreatment with gingerols during observation periods (22.3±2.1b,18.5±1.4b,7.5±1.5b vs31.5±2.5:4.8±0.7c,4.0±0.6b,2.3±0.8b vs6.3±1.2, bP<0.01, cP<0.05).
The expression of SP were analyzed by immunohistochemistry, the expression levels of SP significantly increased after treatment with copper sulfate (3.0±0.6a vs0.7±0.5;2.5±0.5a vs0.5v0.5, a P<0.01), the elevated expression was inhibited by the pretreatment of gingerols in both the ileum and the area postrema (2.3±0.5,1.5±0.5b,1.3±0.5bvs3.0±0.6;2.2±0.4,1.3±0.5b,0.8±0.4b vs2.5±0.5, bP<0.01).
The expression of c-fos were analyzed by immunohistochemistry, the expression levels of c-fos significantly increased after treatment with copper sulfate (3.1±0.7a vs0.7±0.5;2.8±0.8a vs0.5±0.5, a P<0.01), the elevated expression was inhibited by the pretreatment of gingerols in both the ileum and the area postrema (2.5±0.5,1.7±0.5b,1.4±0.4bvs3.1±0.7;2.4±0.6,1.7±0.8b,1.2±0.4b vs2.8±0.8. b P<0.01)
The expression of NK1was analyzed by Western-blot, the expression levels of NK1significantly increased after treatment with copper sulfate(0.73±0.03a vs0.32±0.040.52±0.03a vs0.29±0.02, a P<0.01), the elevated expression was inhibited by the pretreatment of gingerols in both the ileum and area postrema (0.55±0.03,0.42±0.04b, 0.32±0.04bvs0.73±0.03;0.47±0.03c,0.36±0.05b,0.31±0.05b vs0.52±0.03, bP<0.01, cP<0.05).
The levels of cGMP、cAMP、IP3、DAG/DG were measured by ELISA, the levels of cGMP significantly decreased after treatment with copper sulfate (26.82±5.93a vs42.37±10.84;25.60±7.44a vs40.18±12.03, a P<0.01), the decreased levels were inhibited by the pretreatment of gingerols (35.43±6.26b,37.92±7.23b,40.50±7.25b vs26.82±5.93;32.62±8.55b,35.12±3.76b,39.48±5.93b vs25.60±7.44, b P<0.01). Copper sulfate and gingerols had no significant effect on the level of cAMP、IP3、DAG/DG..
Conclusions:
1. Gingerols has good activity against apomorphine-induced emesis of minks possibly by inhibiting central increase of substance P, c-fos and NK1receptors.
2. Gingerols has good activity against loperamide-induced emesis of minks possibly by inhibiting central increase of substance P, c-fos and NKi receptors.
3. Gingerols could decrease copper sulfate-induced emesis of minks, this may be related to inhibiting central or peripheral increase of SP, c-fos protein and NK1receptors, the decreased levels of cGMP were inhibited by the pretreatment of gingerols.
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