玄参和黄连的化学成分分离及其生物活性研究
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摘要
玄参为玄参科植物玄参Scrophularia ningpoensis Hemsl.的根。重庆市南川区目前已成为全国最大的玄参种植基地,是全国玄参的重点产区。黄连属毛莨科黄连Coptis chinensis Franch.的根。黄连为重庆石柱县的地道中药材。
为了更好的开发利用玄参和黄连的药用价值,发展当地中药产业经济,本文对玄参和黄连进行了化学成份和生物活性研究。本研究内容包括：
1.提取分离实验
1.1玄参化学成分的分离
取玄参根,粉碎,用70%的乙醇渗漉提取,再经D101大孔树脂分离洗脱为30%,60%和90%乙醇的三部分。此三部分利用硅胶柱层析、HSCCC色谱等手段从玄参中分离出9个化合物,经波谱数据鉴定结构确定为哈巴苷、桃叶珊瑚苷、类叶升麻苷、升麻素苷、蔗糖、肉桂酸、哈巴俄苷、安格洛苷C和二十七烷。其中60%乙醇部分,用高速逆流色谱(HSCCC)技术在氯仿-正丁醇-甲醇-水(4：1：3：2)体系中分离,首次同时分离出高纯度哈巴俄苷(98%)和安格洛苷C(98.5%),此为这两化合物分离提供了一条新的简单容易分离手段。
1.2黄连化学成分的分离
本实验采用HSCCC法,在CHCl3-MeOH-0.2M HC1(4:1.5:2)体系中分离黄连浸膏,直接一步分离出小檗碱(纯度为80.56%)、黄连碱(纯度为82%)、药根碱(纯度为82%)、巴马汀(纯度为78%)及表小檗碱(纯度为85.65%),各单一斑点的流分再分别过Sephadex LH-20柱纯化,以氯仿／甲醇系统洗脱,可分别得到纯度较高的5个生物碱(98%)。
2.细胞实验
2.1体外的降糖活性初步研究
本实验对玄参和黄连化学成分的降糖活性初步研究,选择用HepG2细胞。从玄参中分离得到的各浸膏组分和化合物均能在不同程度上促进HepG2细胞中葡萄糖消耗。过大孔树脂分离的60%乙醇组分为玄参降糖活性的主要活性部位。在0.1μg/ml-2.5gg/ml浓度范围内,筛选玄参和黄连中的各个化合物的降糖活性,以小檗碱的葡萄糖消耗能力最高,对促进HepG2细胞中葡萄糖消耗具有一定的剂量依赖关系；哈巴俄苷和黄连碱对促进HepG2细胞中葡萄糖消耗相对较好。
2.2HepG2细胞内活性氧清除实验
采用高糖刺激的方法来建立ROS模型,用荧光法测定,依据药物的荧光强度值和抑制率的结果可知,玄参和黄连中化合物对细胞内活性氧都有抑制作用,只是抑制的程度不同。在1-10μg/ml的药物浓度时,与高糖组相比,化合物中的小檗碱和黄连碱有较好的抗氧化活性,其在一定浓度下能够较好的抑制高糖刺激的活性氧升高,且呈现剂量依赖关系；同时,黄连中分离的生物碱比玄参中的化合物的抗氧化能力基本上要强。
2.3玄参化学成分对血管紧张素转化酶(ACE)的抑制作用
血管紧张素转化酶(angiotensin converting enzyme, ACE)在肾素-血管紧张素系统中具有调控血压的作用。本实验采用高效液相色谱(HPLC)的方法测定ACE-HHL-ACEI反应体系产物Hip,计算抑制率,验证玄参的降压机制是否与抑制ACE活力相关。实验中,考察玄参中各化合物在同一浓度(2mg/ml)下,加入不同体积(体积X为30、60和120μl)对ACE活性的抑制作用。结果表明各化合物在同一浓度加入不同体积对ACE活性的抑制作用有剂量关系,加入体积越大,抑制效果越好,但与卡托普利的抑制作用相比,玄参中各化合物在此浓度下的ACE活力的抑制率明显较低(P<0.01),说明玄参中各化合物降压效果一般。
3.动物实验
3.1黄连的化合物对实验性胃溃疡保护作用的研究
本实验考察了黄连中的5个生物碱和8-烷基小檗碱衍生物(8-BBR-Cn,n=4,8,12和16)对大鼠胃溃疡保护作用的可能机制。
在无水乙醇致胃黏膜损伤性模型中,与模型对照组相比,大鼠胃黏膜损伤指数和抑制率的考察结果可知,表小檗碱、巴马汀和药根碱(25、50、100mg/kg)均无明显的抑制乙醇诱导的大鼠急性胃黏膜损伤。而西咪替丁(50mg/kg,阳性对照组),黄连碱、小檗碱和8-烷基小檗碱衍生物(25、50、100mg/kg)均能显著的抑制乙醇诱导的大鼠急性胃黏膜损伤(P<0.001)。对胃黏膜的前列腺素E2(PGE2)和一氧化氮合酶(NOS)检测实验中,黄连碱、小檗碱和8-烷基小檗碱衍生物对乙醇诱导的大鼠急性胃黏膜损伤的保护作用可能是通过PGE2和NOS的通路来调节改善,而8-十六烷基小檗碱可明显抑制乙醇诱导的大鼠急性胃黏膜损伤(P<0.001),其抑制效果最好。
幽门结扎法复制大鼠胃溃疡模型中,与模型对照组相比,黄连碱、小檗碱和8-烷基小檗碱衍生物(25、50、100mg/kg)能显著减少其胃液量、降低胃液总酸度和胃蛋白酶活性(P<0.001),且呈现剂量依赖关系。灌胃给药100mg/kg的黄连碱、小檗碱和8-烷基小檗碱衍生物也可显著抑制H+K+-ATP酶活力(P<0.05,P<0.01),其结果是抑制由于幽门结扎手术引起的胃酸分泌过多,从而使药物对胃溃疡有保护作用。在影响NO上,各给药组(25、50、100mg/kg)均显著促进NO生成(P<0.05,P<0.01)。在影响MDA上,黄连的化合物中仅有黄连碱对幽门结扎型消化性溃疡大鼠MDA的抑制有显著的作用(P<0.01)。
3.2大鼠长期食用黄连中的巴马汀对其体重调节和性别偏好的影响
在实验90天考察中,各组大鼠每10天称体重1次,根据体重调节给药量。与空白雌性大鼠对照组的体重相比,食用巴马汀(100mg/Kg)的雌性大鼠在50天后体重明显增加(P<0.05)；在60-90天内,食用巴马汀的雌性大鼠的体重显著增加(P<0.01)。与空白雄性大鼠对照组的体重相比,食用巴马汀(100mg/Kg)的雄性大鼠体重在40-70天内明显减少(P<0.05),而80-90天大鼠体重显著降低(P<0.01)。所以,巴马汀在大鼠体重有性别选择的调节作用。通过检查血液学的参数,雌激素水平和分析肾组织中UCP2表达(免疫印迹法)的方法来验证巴马汀对大鼠体重调节和性别偏好影响的可能机制。
Xuanshen is the root of Scrophularia ningpoensis Hemsley, family Scrophulariaceae. Nanchuan district of Chongqing has become the largest national planting base, which is the focus areas of S. ningpoensis(Scrophularia ningpoensis). Huanglian is the root of Coptis chinensis Franch., family Ranunculaceae. Huanglian is Chinese herbs from Shizhu county of Chongqing.
In order to develop and utilize the medicinal value of Xuanshen and Huanglian, and develop economy of local herbal industry, we studied chemical constituments and biological activities of two drugs. This paper has seven major parts:
1. Extraction and separation experiments
1.1Study on chemical constituents from S. ningpoensis
A sample of air-dried root of S. ningpoensis was chopped and diacolated with70%ethanol at room temperature. The crude extract was redissolved in water and was loaded on a glass column containing D101macroporous resin, and washed with water, then eluted using a gradient mehtod with30%,60%and90%ethanol fractions. Three fractions were separated by silica gel column and HSCCC to obtain nine compounds. The structures of compounds were identified by1H and13C-NMR spectroscopic data. Compounds were identified as Harpagide、Aucubin、Acteoside、Prim-O-glucosyl-cimifugin、D-(+)-sucrose、Cinnamic acid、Harpagoside、Angroside C and Twenty-seven alkane. The60%ethanol fraction was used for subsequent HSCCC isolation. HSCCC is liquid-liquid distribution chromatography technology. S. ningpoensis was isolated in chloroform-n-butanol-methanol-water (4:1:3:2, v/v/v/v) solvent system by HSCCC. The crude extract was loaded onto a HSCCC column and yielded harpagoside and angroside C with the purity of higher than98%and98.5%resepctively. It is feasible to isolate active compounds harpagoside and angroside C from Scrophularia ningpoensis using HSCCC.
1.2Study on chemical constituents from Rhizoma Coptidis
Extracts of Rhizoma Coptidis were isolated in CHCl3-MeOH-0.2MHCl (4:1.5:2) solvent system by HSCCC with one step of separation, which were berberine palmatine, coptisine, epiberberine and jatrorrhizine with the purity of80.56%、78%、82%、82%and85.65%resepctively. Each part with single spot respectively from HSCCC separation by Sephadex LH-20column chromatography with eluting in chloroform/methanol system, could obtain5alkaloids with the purity of higher than98%.
2. Cell experiments
2.1Antihyperglycemic effect of constituents in vitro
In this experiment, we studied antihyperglycemic activity of the chemical constituents of S. ningpoensis and Rhizoma Coptidis by glucose consumption in HepG2cells. The extracts and compounds can promote glucose consumption of HepG2cells in different extent from S. ningpoensis. The60%ethanol fraction was the main active parts of S. ningpoensis in antihyperglycemic activity. Antihyperglycemic activity of each compounds in0.1-2.5μg/ml concentration range was selected, and glucose consumption ability of berberine was highest, and had dose-dependent relationship within test concentration in glucose consumption ability of HepG2cell. The glucose consumption ability of harpagoside and coptisine were higher.
2.2Inhibition the level of reactive oxygen in HepG2cell
This experiment established reactive oxygen species model by using the method of glucose stimulation and measured by fluorescence method. According to the results of the fluorescence intensity and inhibition rate of S. ningpoensis and Rhizoma Coptidis, compounds had different degree of suppression. Compared with glucose group, berberine and coptisine (1～10μg/ml) had good antioxidant activity, which could inhibit the level of reactive oxygen by glucose stimulation and had dose-dependent relationship within test concentration. At the same time, compared to the compounds from S. ningpoensis, the antioxidant ability of the alkaloids in Rhizoma coptidis was basically better.
2.3The effect of inhibition on ACE activity to chemical constituents of S. ningpoensis
Angiotensin converting enzyme (ACE) in the renin-angiotensin system is the role of regulating blood pressure. We measured the content of hippuric acid by HPLC in ACE-HHL-ACEI system and calculated the inhibition rate of ACE activity. In this experiment, we investigated the effect of inhibition on ACE activity of each compound at the same concentration (2mg/ml), with different volume (volume X is30,60and120μl). These results showed that compounds had the effect of inhibition on ACE activity in the same concentration with increasing volume. But compared to the inhibitory effect of captopril, inhibition of ACE activity of each compound of S. ningpoensis was significantly lower at this concentration (P<0.01), which indicated that the effects of compounds in lowering blood pressure were not well.
3. Animal experiments
3.1Gastroprotective effect of compounds from Rhizoma Coptidis on experimented gastric ulcer in rats
This paper studied the possible mechanisms underlying the gastroprotective effect of5alkaloids from Rhizoma Coptidis and8-Alkylberberine (8-BBR-Cn) derivatives with a long aliphatic chain (n=4,8,12and16) against gastric mucosal injury in rats.
Gastric mucosal injury in rats was induced by ethanol. The ulcer index and percentage inhibition were evaluated. Compared with model control group, the ulcer index of epiberberine, palmatine and jatrorrhizin (25、50、100mg/kg) was not decreased significantly. Additionally, the ulcer index of cimetidine, berberine, coptisine and8-alkyl berberine derivatives was decreased significantly in rats (P<0.001). In this experiment, to test PGE2and NOS, we found the fact that berberine, coptisine and8-BBR-Cn (n=4,8,12and16) had protective effect on gastric mucous membrane, which was related to prostaglandin E2and nitric oxide synthase pathways.8-BBR-C16displayed stronger gastroprotective effect (P<0.001).
Coptisine, berberine and8-alkylberberine derivatives (25,50,100mg/kg, ig) could significantly reduce the volume of gastric juice and the total gastric acidity, and decrease activity of pepsin (P<0.001) in gastric mucosal ulcer model by pylorus-ligature, which showed dose-dependent relationship. Coptisine, berberine and8-alkylberberine derivatives Coptisine, berberine and8-alkylberberine derivatives (25,50,100mg/kg, ig) also could significantly inhibit H+K+-ATP enzyme activity (P<0.05, P<0.01), these results indicated that drugs could inhibit excessive secretion of gastric acid by pylorus-ligature operation and had protective effect on gastric ulcer. To NO, each drug was significantly increased NO level (P<0.05, P<0.01). To MDA, coptisine could significantly inhibit MDA level in chemical constituents from Rhizoma Coptidis (P<0.05,P<0.01).
3.2Weight regulation and gender preference effects by palmatine in long-term treatment in rat
Body weight of both genders was measured at10-day intervals for three months. A significant increase in the female body weight and a decrease in the male body weight were observed in rats after treatment with palmatine for90days. Comparing to the female control group, body weight of female rats by palmatine treatment (100mg/Kg) increased from50day (P<0.05), and body weight of female rats increased significantly from60day to90day (P<0.01). Body weight of male rats relative to the male control group rats decreased from40day to70day (P<0.05) and decreased significantly from80day to90day (P<0.01). So, palmatine had the regulation effect of gender selection in rat weight. This experiment provides evidence that the changes in hematological parameters, estrogen level and uncoupling protein2(UCP2) expression are involved in the effect of the body weight regulated by palmatine.
为了更好的开发利用玄参和黄连的药用价值,发展当地中药产业经济,本文对玄参和黄连进行了化学成份和生物活性研究。本研究内容包括：
1.提取分离实验
1.1玄参化学成分的分离
取玄参根,粉碎,用70%的乙醇渗漉提取,再经D101大孔树脂分离洗脱为30%,60%和90%乙醇的三部分。此三部分利用硅胶柱层析、HSCCC色谱等手段从玄参中分离出9个化合物,经波谱数据鉴定结构确定为哈巴苷、桃叶珊瑚苷、类叶升麻苷、升麻素苷、蔗糖、肉桂酸、哈巴俄苷、安格洛苷C和二十七烷。其中60%乙醇部分,用高速逆流色谱(HSCCC)技术在氯仿-正丁醇-甲醇-水(4：1：3：2)体系中分离,首次同时分离出高纯度哈巴俄苷(98%)和安格洛苷C(98.5%),此为这两化合物分离提供了一条新的简单容易分离手段。
1.2黄连化学成分的分离
本实验采用HSCCC法,在CHCl3-MeOH-0.2M HC1(4:1.5:2)体系中分离黄连浸膏,直接一步分离出小檗碱(纯度为80.56%)、黄连碱(纯度为82%)、药根碱(纯度为82%)、巴马汀(纯度为78%)及表小檗碱(纯度为85.65%),各单一斑点的流分再分别过Sephadex LH-20柱纯化,以氯仿／甲醇系统洗脱,可分别得到纯度较高的5个生物碱(98%)。
2.细胞实验
2.1体外的降糖活性初步研究
本实验对玄参和黄连化学成分的降糖活性初步研究,选择用HepG2细胞。从玄参中分离得到的各浸膏组分和化合物均能在不同程度上促进HepG2细胞中葡萄糖消耗。过大孔树脂分离的60%乙醇组分为玄参降糖活性的主要活性部位。在0.1μg/ml-2.5gg/ml浓度范围内,筛选玄参和黄连中的各个化合物的降糖活性,以小檗碱的葡萄糖消耗能力最高,对促进HepG2细胞中葡萄糖消耗具有一定的剂量依赖关系；哈巴俄苷和黄连碱对促进HepG2细胞中葡萄糖消耗相对较好。
2.2HepG2细胞内活性氧清除实验
采用高糖刺激的方法来建立ROS模型,用荧光法测定,依据药物的荧光强度值和抑制率的结果可知,玄参和黄连中化合物对细胞内活性氧都有抑制作用,只是抑制的程度不同。在1-10μg/ml的药物浓度时,与高糖组相比,化合物中的小檗碱和黄连碱有较好的抗氧化活性,其在一定浓度下能够较好的抑制高糖刺激的活性氧升高,且呈现剂量依赖关系；同时,黄连中分离的生物碱比玄参中的化合物的抗氧化能力基本上要强。
2.3玄参化学成分对血管紧张素转化酶(ACE)的抑制作用
血管紧张素转化酶(angiotensin converting enzyme, ACE)在肾素-血管紧张素系统中具有调控血压的作用。本实验采用高效液相色谱(HPLC)的方法测定ACE-HHL-ACEI反应体系产物Hip,计算抑制率,验证玄参的降压机制是否与抑制ACE活力相关。实验中,考察玄参中各化合物在同一浓度(2mg/ml)下,加入不同体积(体积X为30、60和120μl)对ACE活性的抑制作用。结果表明各化合物在同一浓度加入不同体积对ACE活性的抑制作用有剂量关系,加入体积越大,抑制效果越好,但与卡托普利的抑制作用相比,玄参中各化合物在此浓度下的ACE活力的抑制率明显较低(P<0.01),说明玄参中各化合物降压效果一般。
3.动物实验
3.1黄连的化合物对实验性胃溃疡保护作用的研究
本实验考察了黄连中的5个生物碱和8-烷基小檗碱衍生物(8-BBR-Cn,n=4,8,12和16)对大鼠胃溃疡保护作用的可能机制。
在无水乙醇致胃黏膜损伤性模型中,与模型对照组相比,大鼠胃黏膜损伤指数和抑制率的考察结果可知,表小檗碱、巴马汀和药根碱(25、50、100mg/kg)均无明显的抑制乙醇诱导的大鼠急性胃黏膜损伤。而西咪替丁(50mg/kg,阳性对照组),黄连碱、小檗碱和8-烷基小檗碱衍生物(25、50、100mg/kg)均能显著的抑制乙醇诱导的大鼠急性胃黏膜损伤(P<0.001)。对胃黏膜的前列腺素E2(PGE2)和一氧化氮合酶(NOS)检测实验中,黄连碱、小檗碱和8-烷基小檗碱衍生物对乙醇诱导的大鼠急性胃黏膜损伤的保护作用可能是通过PGE2和NOS的通路来调节改善,而8-十六烷基小檗碱可明显抑制乙醇诱导的大鼠急性胃黏膜损伤(P<0.001),其抑制效果最好。
幽门结扎法复制大鼠胃溃疡模型中,与模型对照组相比,黄连碱、小檗碱和8-烷基小檗碱衍生物(25、50、100mg/kg)能显著减少其胃液量、降低胃液总酸度和胃蛋白酶活性(P<0.001),且呈现剂量依赖关系。灌胃给药100mg/kg的黄连碱、小檗碱和8-烷基小檗碱衍生物也可显著抑制H+K+-ATP酶活力(P<0.05,P<0.01),其结果是抑制由于幽门结扎手术引起的胃酸分泌过多,从而使药物对胃溃疡有保护作用。在影响NO上,各给药组(25、50、100mg/kg)均显著促进NO生成(P<0.05,P<0.01)。在影响MDA上,黄连的化合物中仅有黄连碱对幽门结扎型消化性溃疡大鼠MDA的抑制有显著的作用(P<0.01)。
3.2大鼠长期食用黄连中的巴马汀对其体重调节和性别偏好的影响
在实验90天考察中,各组大鼠每10天称体重1次,根据体重调节给药量。与空白雌性大鼠对照组的体重相比,食用巴马汀(100mg/Kg)的雌性大鼠在50天后体重明显增加(P<0.05)；在60-90天内,食用巴马汀的雌性大鼠的体重显著增加(P<0.01)。与空白雄性大鼠对照组的体重相比,食用巴马汀(100mg/Kg)的雄性大鼠体重在40-70天内明显减少(P<0.05),而80-90天大鼠体重显著降低(P<0.01)。所以,巴马汀在大鼠体重有性别选择的调节作用。通过检查血液学的参数,雌激素水平和分析肾组织中UCP2表达(免疫印迹法)的方法来验证巴马汀对大鼠体重调节和性别偏好影响的可能机制。
Xuanshen is the root of Scrophularia ningpoensis Hemsley, family Scrophulariaceae. Nanchuan district of Chongqing has become the largest national planting base, which is the focus areas of S. ningpoensis(Scrophularia ningpoensis). Huanglian is the root of Coptis chinensis Franch., family Ranunculaceae. Huanglian is Chinese herbs from Shizhu county of Chongqing.
In order to develop and utilize the medicinal value of Xuanshen and Huanglian, and develop economy of local herbal industry, we studied chemical constituments and biological activities of two drugs. This paper has seven major parts:
1. Extraction and separation experiments
1.1Study on chemical constituents from S. ningpoensis
A sample of air-dried root of S. ningpoensis was chopped and diacolated with70%ethanol at room temperature. The crude extract was redissolved in water and was loaded on a glass column containing D101macroporous resin, and washed with water, then eluted using a gradient mehtod with30%,60%and90%ethanol fractions. Three fractions were separated by silica gel column and HSCCC to obtain nine compounds. The structures of compounds were identified by1H and13C-NMR spectroscopic data. Compounds were identified as Harpagide、Aucubin、Acteoside、Prim-O-glucosyl-cimifugin、D-(+)-sucrose、Cinnamic acid、Harpagoside、Angroside C and Twenty-seven alkane. The60%ethanol fraction was used for subsequent HSCCC isolation. HSCCC is liquid-liquid distribution chromatography technology. S. ningpoensis was isolated in chloroform-n-butanol-methanol-water (4:1:3:2, v/v/v/v) solvent system by HSCCC. The crude extract was loaded onto a HSCCC column and yielded harpagoside and angroside C with the purity of higher than98%and98.5%resepctively. It is feasible to isolate active compounds harpagoside and angroside C from Scrophularia ningpoensis using HSCCC.
1.2Study on chemical constituents from Rhizoma Coptidis
Extracts of Rhizoma Coptidis were isolated in CHCl3-MeOH-0.2MHCl (4:1.5:2) solvent system by HSCCC with one step of separation, which were berberine palmatine, coptisine, epiberberine and jatrorrhizine with the purity of80.56%、78%、82%、82%and85.65%resepctively. Each part with single spot respectively from HSCCC separation by Sephadex LH-20column chromatography with eluting in chloroform/methanol system, could obtain5alkaloids with the purity of higher than98%.
2. Cell experiments
2.1Antihyperglycemic effect of constituents in vitro
In this experiment, we studied antihyperglycemic activity of the chemical constituents of S. ningpoensis and Rhizoma Coptidis by glucose consumption in HepG2cells. The extracts and compounds can promote glucose consumption of HepG2cells in different extent from S. ningpoensis. The60%ethanol fraction was the main active parts of S. ningpoensis in antihyperglycemic activity. Antihyperglycemic activity of each compounds in0.1-2.5μg/ml concentration range was selected, and glucose consumption ability of berberine was highest, and had dose-dependent relationship within test concentration in glucose consumption ability of HepG2cell. The glucose consumption ability of harpagoside and coptisine were higher.
2.2Inhibition the level of reactive oxygen in HepG2cell
This experiment established reactive oxygen species model by using the method of glucose stimulation and measured by fluorescence method. According to the results of the fluorescence intensity and inhibition rate of S. ningpoensis and Rhizoma Coptidis, compounds had different degree of suppression. Compared with glucose group, berberine and coptisine (1～10μg/ml) had good antioxidant activity, which could inhibit the level of reactive oxygen by glucose stimulation and had dose-dependent relationship within test concentration. At the same time, compared to the compounds from S. ningpoensis, the antioxidant ability of the alkaloids in Rhizoma coptidis was basically better.
2.3The effect of inhibition on ACE activity to chemical constituents of S. ningpoensis
Angiotensin converting enzyme (ACE) in the renin-angiotensin system is the role of regulating blood pressure. We measured the content of hippuric acid by HPLC in ACE-HHL-ACEI system and calculated the inhibition rate of ACE activity. In this experiment, we investigated the effect of inhibition on ACE activity of each compound at the same concentration (2mg/ml), with different volume (volume X is30,60and120μl). These results showed that compounds had the effect of inhibition on ACE activity in the same concentration with increasing volume. But compared to the inhibitory effect of captopril, inhibition of ACE activity of each compound of S. ningpoensis was significantly lower at this concentration (P<0.01), which indicated that the effects of compounds in lowering blood pressure were not well.
3. Animal experiments
3.1Gastroprotective effect of compounds from Rhizoma Coptidis on experimented gastric ulcer in rats
This paper studied the possible mechanisms underlying the gastroprotective effect of5alkaloids from Rhizoma Coptidis and8-Alkylberberine (8-BBR-Cn) derivatives with a long aliphatic chain (n=4,8,12and16) against gastric mucosal injury in rats.
Gastric mucosal injury in rats was induced by ethanol. The ulcer index and percentage inhibition were evaluated. Compared with model control group, the ulcer index of epiberberine, palmatine and jatrorrhizin (25、50、100mg/kg) was not decreased significantly. Additionally, the ulcer index of cimetidine, berberine, coptisine and8-alkyl berberine derivatives was decreased significantly in rats (P<0.001). In this experiment, to test PGE2and NOS, we found the fact that berberine, coptisine and8-BBR-Cn (n=4,8,12and16) had protective effect on gastric mucous membrane, which was related to prostaglandin E2and nitric oxide synthase pathways.8-BBR-C16displayed stronger gastroprotective effect (P<0.001).
Coptisine, berberine and8-alkylberberine derivatives (25,50,100mg/kg, ig) could significantly reduce the volume of gastric juice and the total gastric acidity, and decrease activity of pepsin (P<0.001) in gastric mucosal ulcer model by pylorus-ligature, which showed dose-dependent relationship. Coptisine, berberine and8-alkylberberine derivatives Coptisine, berberine and8-alkylberberine derivatives (25,50,100mg/kg, ig) also could significantly inhibit H+K+-ATP enzyme activity (P<0.05, P<0.01), these results indicated that drugs could inhibit excessive secretion of gastric acid by pylorus-ligature operation and had protective effect on gastric ulcer. To NO, each drug was significantly increased NO level (P<0.05, P<0.01). To MDA, coptisine could significantly inhibit MDA level in chemical constituents from Rhizoma Coptidis (P<0.05,P<0.01).
3.2Weight regulation and gender preference effects by palmatine in long-term treatment in rat
Body weight of both genders was measured at10-day intervals for three months. A significant increase in the female body weight and a decrease in the male body weight were observed in rats after treatment with palmatine for90days. Comparing to the female control group, body weight of female rats by palmatine treatment (100mg/Kg) increased from50day (P<0.05), and body weight of female rats increased significantly from60day to90day (P<0.01). Body weight of male rats relative to the male control group rats decreased from40day to70day (P<0.05) and decreased significantly from80day to90day (P<0.01). So, palmatine had the regulation effect of gender selection in rat weight. This experiment provides evidence that the changes in hematological parameters, estrogen level and uncoupling protein2(UCP2) expression are involved in the effect of the body weight regulated by palmatine.
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