CN102861033B - Gypensapogenin A在治疗急性痛风药物中的应用 - Google Patents
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Abstract
本发明提供了GypensapogeninA在医学中的新用途，具体地说是GypensapogeninA在制备治疗急性痛风药物中的应用。经实验研究结果表明GypensapogeninA对尿酸盐致人血管内皮细胞损伤的急性痛风模型具有保护作用，并抑制ICAM-1表达，因此，GypensapogeninA可用于制备治疗急性痛风炎症药物。本发明涉及的GypensapogeninA在制备治疗急性痛风药物中的用途属于首次公开，由于骨架类型属于全新的骨架类型，而且其对于急性痛风的防治活性强得意想不到，不存在由其他化合物给出任何启示的可能，具备突出的实质性特点，同时用于急性痛风的防治显然具有显著的进步。
Description
技术领域
本发明涉及Gypensapogenin A在医学中的新用途，具体地说是涉及Gypensapogenin A在制备治疗急性痛风药物中的应用。
背景技术
痛风（gouty），又称痛风性关节炎（gouty arthritis），是体内嘌呤代谢紊乱所致的疾病，表现为血中尿酸过多，易于使尿酸盐（MSU）在关节等组织析出结晶。痛风的急性发作是由于沉积在关节的MSU引起中性粒细胞局部浸润和炎性反应。
西药在痛风急性发作期选用三种药：秋水仙碱、非甾体抗炎药和肾上腺皮质激素。秋水仙碱的作用机制是与中性粒细胞的微管蛋白结合，从而妨碍粒细胞的活动，抑制粒细胞浸润。非甾体抗炎药如吲哚美辛，抑制环氧酶（COX）活性而发挥抗炎作用，以及选择性COX2抑制药。它们虽然消炎止痛作用快，但毒副作用也相当明显，如秋水仙碱的有效剂量与产生腹泻等胃肠道症状的剂量相近，非甾体抗炎药在有活动性消化性溃疡、胃肠道出血情况下绝对禁用，而保泰松用药短至3周也可致严重的粒细胞减少症或再生障碍性贫血。
本发明涉及的化合物Gypensapogenin A是一个2012年发表（Li, N.et al., 2012. Triterpenes possessing an unprecedented skeleton isolated from hydrolyzate of total saponins from Gynostemma pentaphyllum. European Journal of Medicinal Chemistry 50, 173–178.）的新骨架化合物，该化合物拥有全新的骨架类型，目前的用途仅仅涉及人肿瘤细胞株的细胞毒活性（Li, N. et al., 2012. Triterpenes possessing an unprecedented skeleton isolated from hydrolyzate of total saponins from Gynostemma pentaphyllum. European Journal of Medicinal Chemistry 50, 173–178.），对于本发明涉及的Gypensapogenin A在制备治疗急性痛风药物中的用途属于首次公开，由于骨架类型属于全新的骨架类型，而且其对于急性痛风的防治活性强得意想不到，不存在由其他化合物给出任何启示的可能，具备突出的实质性特点，同时用于急性痛风的防治显然具有显著的进步。
发明内容
本发明用MSU致人血管内皮细胞（HUVEC）损伤的急性痛风模型评价显示，对MSU致HUVEC损伤具有保护作用，并抑制ICAM-1表达，可用于制备治疗急性痛风炎症药物。本发明的目的在于提供Gypensapogenin A在医学中的新用途，具体地说是涉及Gypensapogenin A在制备治疗急性痛风药物中的应用。
本发明的目的是通过以下的技术方案来实现的：
现代医学病理研究说明，痛风性关节炎是MSU引起中性粒细胞局部浸润和炎性反应，急性痛风产生的本质是中性粒细胞（PMN）-血管内皮细胞（HUVEC）黏连增强（Terkeltaub R，et al. The murine homolog of the interleukin-8 receptorcxcr-2 is essentialfor the occurrence of neutrophilic inflammation inair pouch model of acute urate crystal-induced goutysynovitis.Arthritis Rheum,1998,41(5): 900-909.），HUVEC损伤，其分子生物学基础在于PMN与HUVEC表面黏附分子的相互作用（FujiwaraY,et al.Interleukin-8 stimulates leukocyte migrationacross amonolayer of cultured rabbit NF-α,IL-1β,IL-8,and IL-1 rain Monosodium Urate Crystal induced rabbit arthritis. Labinvest,19998,78(5): 559-569.），其中细胞间黏附分子-1（ICAM-1）与粘附功能关系最密切，是急性痛风炎症的重要指标之一（张春，唐怡，刘军，等. 痛风灵方对尿酸钠致大鼠模型关节软组织ICAM-1表达的影响，重庆医学，2002,31（12）：1211-1213.）。
因此，针对急性痛风MSU致HUVEC损伤，ICAM-1表达增多的病理特征，本发明用MSU致HUVEC损伤的体外急性痛风模型（杨妍华，尹莲，王明艳，等.尿酸钠诱导HUVEC损伤的急性痛风模型研究，中华中医药学刊，2010,28（3）：592-594.），评价Gypensapogenin A抗急性痛风炎症活性。MSU致人血管内皮细胞（HUVEC）损伤的急性痛风模型评价显示，对MSU致HUVEC损伤具有保护作用，并抑制ICAM-1表达。
所述化合物Gypensapogenin A结构如式（Ⅰ）所示：
式（Ⅰ）
有益效果
研究结果表明，用MSU致HUVEC损伤的急性痛风模型评价显示，Gypensapogenin A可保护MSU致HUVEC损伤，减少细胞凋亡，提高细胞活性，抑制ICAM-1表达，具有抗急性痛风炎症的活性，Gypensapogenin A可用于制备治疗急性痛风炎症药物。
本发明涉及的Gypensapogenin A在制备治疗急性痛风药物中的用途属于首次公开，由于骨架类型属于全新的骨架类型，而且其对于急性痛风的防治活性强得意想不到，不存在由其他化合物给出任何启示的可能，具备突出的实质性特点，同时用于急性痛风的防治显然具有显著的进步。
具体实施方式
本发明所涉及化合物Gypensapogenin A的制备方法参见文献（Li,N. et al., 2012. Triterpenes possessing an unprecedented skeleton isolated from hydrolyzate of total saponins from Gynostemma pentaphyllum. European Journal ofMedicinal Chemistry 50, 173–178.和Wei, J.X. etal., 1982. Two new dammaran sapogenins from leaves of Panax notoginseng. Planta Medica, 45(3): 167-171.）。
以下通过实施例对本发明作进一步详细的说明，但本发明的保护范围不受具体实施例的任何限制，而是由权利要求加以限定。
实施例1：本发明所涉及化合物Gypensapogenin A片剂的制备：
取20克化合物Gypensapogenin A，加入制备片剂的常规辅料180克，混匀，常规压片机制成1000片。
实施例2：本发明所涉及化合物Gypensapogenin A胶囊剂的制备：
取20克化合物Gypensapogenin A，加入制备胶囊剂的常规辅料如淀粉180克，混匀，装胶囊制成1000片。
下面通过药效学实验来进一步说明其药物活性。
Gypensapogenin A抗急性痛风炎症实验：
1 溶液配制
5g尿酸加1000ml蒸馏水煮沸，加5%NaOH溶液调PH 7.4，搅拌，冷却析晶制成尿酸钠结晶（MSU）。将制好的MSU 10mg高压灭菌，加不含血清的DMEM培养液10ml，研磨配成1mg/ml的DMEM溶液。实验时，此溶液再加DMEM培养液配成不同浓度DMEM的MSU溶液。
Gypensapogenin A 2.5mg，用二甲基亚砜（DMSO）溶解，DMSO终浓度<0.02%，再加无血清的DMEM培养液，配制成浓度2.5ug/ml、25ug/ml、250ug/ml。
阳性药吲哚美辛2.0mg，方法同Gypensapogenin A，配制浓度20ug/ml。
2 血管内皮细胞的体外培养
人脐静脉血管内皮细胞HUVEC株由南京中医药大学基础医学院提供，细胞经支原体检测，无支原体污染，细胞经0.25%胰蛋白酶消化，含10%小牛血清的DMEM培养液中和，离心（1000r/min×6min），去上清液，加含10%小牛血清的DMEM培养液，移入细胞培养瓶中，放37℃、5%CO2培养箱中传代培养。
3 对MSU刺激HUVEC活力的影响
HUVEC在培养瓶中培养，待生长至70%~80%融合时，以0.25%胰蛋白酶消化、离心，10%小牛血清DMEM培养液洗涤3次，用10%小牛血清DMEM培养液调成4×104/ml细胞悬液，植入96孔板（每孔200ul），培养24小时后轻吸出原培养液，进行以下实验，每组各8孔，具体分组及加液如下：对照组（200ulDMEM培养液）、模型组（100ug/ml MSU溶液）、干预A组（100ug/ml MSU溶液+2.5ug/ml Gypensapogenin A）、干预B组（100ug/ml MSU溶液+25ug/ml Gypensapogenin A）、干预C组（100ug/mlMSU溶液+250ug/ml Gypensapogenin A），加液后继续放37℃、5%CO2培养箱中培养24小时，收集上清液，剩余的HUVEC用于测定细胞活性，每孔再加5mg/ml MTT液20ul，继续放37℃、5%CO2培养箱中培养4小时后，弃MTT液，加入二甲基亚砜200ul溶解，震荡，于酶标仪读取吸光度值，波长490nm。
阳性药组加液（100ug/ml MSU溶液+20ug/ml吲哚美辛），其他方法同上。
数据统计学处理，细胞活力（%）=实验组吸光度值/对照组吸光度值×100%，结果见表1。
与对照组相比，模型组细胞活力显著减小（P<0.01，P<0.05），阳性药吲哚美辛及Gypensapogenin A干预后细胞活力显著提高（P<0.01，P<0.05），并强于对照组，其中，Gypensapogenin A各浓度组的细胞活力强于阳性药吲哚美辛。
表1 Gypensapogenin A对MSU刺激的血管内皮细胞活力的影响（
）
注：与模型组相比，**P<0.01；与对照组相比，△△P<0.01，△P<0.05
4 对ICAM-1表达影响
将处于对数生长期的HUVEC用0.25%的胰蛋白酶消化，轻轻吹打，制成细胞悬液，调整细胞密度为5×109/L，接种于细胞培养瓶中。待细胞长满后（约24h），弃去上清液，分为下列组：对照组、模型组（100ug/ml MSU溶液）、Gypensapogenin A组（100ug/ml MSU溶液+25ug/ml Gypensapogenin A），继续培养24小时，PBS收集细胞，离心去上清，加入CD54单克隆抗体，30min后，PBS洗涤，重悬细胞，应用流式细胞仪检测其阳性细胞百分率（n=10000），重复3次，结果见表2。
表2 Gypensapogenin A对MSU刺激的血管内皮细胞ICAM-1表达的影响（
）
注：与模型组相比，**P<0.01；与对照组相比，△△P<0.01，△P<0.05
结果显示，空白组HUVEC几乎无ICAM-1表达，模型组ICAM-1的表达最高，与模型组相比，Gypensapogenin A对ICAM-1的表达有较强的抑制作用。
结论：用MSU致HUVEC损伤的急性痛风模型评价显示，GypensapogeninA可保护MSU致HUVEC损伤，减少细胞凋亡，提高细胞活性，抑制ICAM-1表达，具有抗急性痛风炎症的活性，Gypensapogenin A可用于制备治疗急性痛风炎症药物。
Claims (1)
1.Gypensapogenin A在制备治疗急性痛风药物中的应用，所述化合物Gypensapogenin A结构如式（Ⅰ）所示：
式（Ⅰ）。
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