| 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 minks30minks 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 minks30minks 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 minks30minks 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 minksApomorphine 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 minksLoperamide 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 minksThe 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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