CN114712351B - 钩藤碱在制备治疗炎症性肠炎药物中的应用 - Google Patents
钩藤碱在制备治疗炎症性肠炎药物中的应用 Download PDFInfo
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Abstract
本发明钩藤碱在制备治疗炎症性肠炎药物中的应用。本发明首先发现钩藤碱对炎症性肠炎导致的损伤具有修复作用;研究发现,钩藤碱可以显著降低结肠中炎症因子浓度、保护结肠组织、修复肠屏障通透性,以及激活AhR,从而可以减轻肠道炎症、修复肠屏障通透性。本发明提出钩藤碱在制备治疗炎症性肠炎药物中的应用前景。
Description
技术领域
本发明属于药物应用的技术领域,具体涉及钩藤碱在制备治疗炎症性肠炎药物中的应用。
背景技术
近20年来,我国炎症性肠炎(Inflammatory Bowel Disease,IBD)病例数迅猛增加,患病率0.24-0.34%,年死亡率为0.019-0.023%。预计到2025年,中国的IBD患者将达到150万人。IBD病程冗长,症状反复发作,患者的发病年龄多在30岁以下,长期疾病导致患者情绪焦虑、抑郁、不能正常睡眠及娱乐。由于长期反复的炎症,促使IBD演化成结肠癌。据统计IBD发生结肠癌的风险是正常人群2-4倍。
目前IBD的药物治疗多集中在肠道局部抗炎、全身免疫抑制和新型生物制剂(如:英夫利昔单抗)等。柳氮磺胺吡啶曾作为IBD治疗的一线药物,但导致过敏反应、肝肾功能损害等不良反应使其在临床应用中逐渐受到限制。氨基水杨酸、糖皮质激素、免疫抑制剂和生物制剂虽然可以缓解IBD的症状,但IBD病情呈动态变化,漫长的用药过程中不可避免出现药物过敏、药物依赖、药物抵抗,甚至药物无效等情况,使得IBD治疗领域仍有诸多问题亟待解决。
钩藤是茜草科钩藤属藤本植物,以带钩的茎枝作为中药材,古方记载有清热平肝,息风定惊等疗效。钩藤中的化学成分主要包括生物碱类、萜类、黄酮类和有机酸类等。随着国内外对钩藤的药理学研究不断深入,确定了钩藤碱(Rhynchophylline,Rhy)是其发挥药理作用的重要物质基础,具有舒张血管及降血压、抑制血管平滑肌细胞增殖、抑制血管紧张素Ⅱ(AngiotensinⅡ,AngⅡ)诱导的心肌细胞肥大、保护脑缺血损伤、抗心律失常、抗惊厥、镇痛等作用。
本发明建立DSS诱导的小鼠IBD模型,通过小鼠灌胃钩藤碱溶液,观察小鼠体重改变,结肠长度及重量、结肠形态学改变、肠黏膜通透性,评估小鼠肠道炎症损伤情况,为治疗炎症性肠炎的药物研发奠定基础。
发明内容
本发明的目的在于提供钩藤碱的新用途,在制备治疗炎症性肠炎药物中的应用,可以促进肠屏障完整性,为中药钩藤的深度开发和钩藤碱作为功能性成分的应用提供参考。
为了实现上述目的,所采用的技术方案为:
钩藤碱在制备治疗炎症性肠炎药物中的应用。
进一步的,所述的钩藤碱在制备减轻肠道炎症药物中的应用。
再进一步的,所述的钩藤碱在制备减少结肠中炎症因子的药物中的应用。
再进一步的,所述的钩藤碱在制备激活AhR的药物中的应用。
进一步的,所述的钩藤碱在制备修复肠屏障功能的药物中的应用。
再进一步的,所述的钩藤碱在制备修复肠屏障通透性的药物中的应用。
再进一步的,所述的钩藤碱在制备修复结肠组织损伤的药物中的应用。
进一步的,所述的钩藤碱在制备减小炎症性肠炎导致的体重下降的药物中的应用。
进一步的,所述的钩藤碱在制备避免炎症性肠炎导致的结肠长度变短、重量减轻的药物中的应用。
与现有技术相比,本发明的有益效果在于:
本发明建立葡聚糖硫酸钠诱导的小鼠IBD模型,灌胃钩藤碱后可缓解IBD小鼠结肠炎症状,降低肠黏膜通透性。与模型比较,钩藤碱组AhR表达显著升高。从而提出钩藤碱在制备治疗炎症性肠炎药物,特别是促进肠屏障完整性发明的药物,为中药钩藤的深度开发和钩藤碱作为功能性成分的应用提供参考。
附图说明
图1为钩藤碱化学结构;
图2为各实验组小鼠结肠长度、结肠重量图;其中,a为小鼠结肠长度,b为结肠重量;*P<0.05,**P<0.01,***P<0.001;
图3为各实验组小鼠结肠图片,从左往右依次为对照组、模型组、钩藤碱组、阳性药组;
图4为小鼠结肠组织病理切片(HE染色×100);其中,图a为对照组,图b为模型组,图c为钩藤碱组,图d为阳性组;
图5为小鼠结肠组织学评分;*P<0.05,**P<0.01,***P<0.001;
图6为各组小鼠结肠中炎症因子浓度;其中,图a为血浆中TNF-α浓度,图b为血浆中IL-1β浓度,图c为血浆中CXCL1浓度,图d为血浆中MPO浓度;*P<0.05,**P<0.01,***P<0.001;
图7为各实验组小鼠血清中FITC-Dex浓度;*P<0.05,**P<0.01,***P<0.001;
图8为各实验组小鼠结肠CYP1A1的表达;其中,图a为各实验组小鼠结肠CYP1A1的表达条带,图b为各实验组小鼠结肠CYP1A1的灰度值,*P<0.05,**P<0.01,***P<0.001。
具体实施方式
为了进一步阐述本发明钩藤碱在制备治疗炎症性肠炎药物中的应用,达到预期发明目的,以下结合较佳实施例,对依据本发明提出的钩藤碱在制备治疗炎症性肠炎药物中的应用,其具体实施方式、结构、特征及其功效,详细说明如后。在下述说明中,不同的“一实施例”或“实施例”指的不一定是同一实施例。此外,一或多个实施例中的特定特征、结构或特点可由任何合适形式组合。
下面将结合具体的实施例,对本发明钩藤碱在制备治疗炎症性肠炎药物中的应用做进一步的详细介绍:
本发明前期建立DSS诱导的小鼠IBD模型,通过小鼠灌胃钩藤碱溶液,观察小鼠体重改变,结肠长度及重量、结肠形态学改变、肠黏膜通透性,评估小鼠肠道炎症损伤情况。结果发现,IBD模型组小鼠体重明显降低,结肠长度明显缩短、结肠重量减轻,肠黏膜正常形态改变,表现为炎症细胞浸润、上皮细胞融合脱落等,且肠黏膜通透性增加。而灌胃钩藤碱组小鼠体重下降幅度减小,死亡率降低,结肠长度和重量明显增加,肠黏膜形态有所恢复,且炎性细胞浸润有所改观,肠黏膜通透性降低。说明钩藤碱可以缓解IBD小鼠的结肠炎症状。
本发明采用蛋白免疫印迹法(Western Blottingting)检测CYP1A1蛋白表达评估AhR的活性变化,结果发现,与对照组相比,IBD组CYP1A1表达明显下降,而钩藤碱组CYP1A1表达显著增加,提示钩藤碱能够显著激活AhR,可以缓解结肠炎炎症。具体见以下实施例:
实施例1.
(1)动物分组及给药
将60只鼠龄6-7周,体重18-22g C57/BL6j小鼠分为对照组、阳性药组、模型组、钩藤碱(低、中、高)剂量组,每组10只。对照组小鼠每日正常饮食饮水,不做处理。模型组、钩藤碱(低、中、高)组、阳性药组小鼠每日自由饮用2%DSS(葡聚糖硫酸钠)溶液代替饮水,自由进食。对照组与模型组小鼠每天以0.1ml/10g体重灌胃灭菌水,钩藤碱(低、中、高)组分别灌胃钩藤碱水溶液(低剂量组2mg/kg,中剂量组4mg/kg、高剂量组8mg/kg)每日1次,连续灌胃7天。阳性药组以地塞米松0.0004mg/g腹腔注射,每日1次,连续注射7天。
钩藤碱的结构式如图1所示。
(2)钩藤碱对IBD小鼠DAI评分及体重的影响
每日根据Hamamoto N等制定的标准每日对小鼠DAI进行评估,DAI评分见表1,DAI=(体重下降分数+大便性状分数+便血分数)/3;体重下降分数分为5级,0分:无下降,1分:下降1-5%,2分:下降6-10%,3分:下降11-15%,4分:下降大于15%;大便性状正常为干而小粒状,记0分,半稀便为糊状但不粘肛门,记2分。稀便为液状而且粘肛门,记4分。大便隐血用联苯胺法检测。便血阴性为0分,隐血阳性为2分,肉眼血便为4分。
表1DAI评分标准
各实验组小鼠10天后的DAI评分和体重见表2-3。
小鼠于饮用2%DSS溶液后第3天出现懒动、厌食、体质量下降、粪便隐血阳性,进食和饮水量减少。随时间延长,IBD模型组小鼠症状逐渐加重,DAI评分逐渐升高,第5-7天出现不同程度的肉眼血便。与对照组比较,IBD模型组小鼠DAI评分明显升高(P<0.01),表明DSS诱导IBD模型成功;与IBD模型组比较,低、中、高剂量钩藤碱干预后的小鼠DAI评分都显著降低(P<0.01),表明钩藤碱可以明显降低IBD小鼠DAI评分;与IBD模型组比较,阳性药组地塞米松干预后的小鼠DAI评分都显著降低(P<0.01),表明地塞米松可以明显降低IBD小鼠DAI评分。
表2各实验组小鼠DAI评分
注:与空白对照组比较*P<0.05,**P<0.01;与模型组比较#P<0.05,##P<0.01
与对照组比较,IBD模型组小鼠体重明显降低(P<0.01),表明DSS诱导IBD模型成功;与IBD模型组比较,低、中、高剂量钩藤碱干预后的小鼠体重都显著升高(P<0.01),表明钩藤碱可以明显减小IBD小鼠体重下降幅度;与IBD模型组比较,阳性药组地塞米松干预后的小鼠DAI评分都显著升高(P<0.01),表明地塞米松可以明显减小IBD小鼠体重下降幅度。
表3各实验组小鼠体重
注:与空白对照组比较*P<0.05,**P<0.01;与模型组比较#P<0.05,##P<0.01
(3)钩藤碱对IBD小鼠结肠长度及重量的影响
结果如图2-3所示。与对照组比较,IBD模型组小鼠结肠明显缩短(P<0.01)、结肠重量明显减轻(P<0.01);与IBD模型组比较,低、中、高剂量钩藤碱干预后的小鼠结肠缩短幅度明显减小(P<0.01)、结肠重量减轻幅度显著减小(P<0.01);与IBD模型组比较,阳性药组地塞米松干预后的小鼠结肠缩短幅度明显减小(P<0.01)、结肠重量减轻幅度显著减小(P<0.01)。
(4)染色镜下观察
对小鼠结肠组织进行病理切片,结果如图4所示,其中,图a为对照组,图b为模型组,图c为钩藤碱组,图d为阳性组。
对照组:小鼠结肠黏膜完整、连续,腺体排列规则、结构清楚,无炎症细胞浸润及溃疡。
IBD模型组:小鼠结肠炎症主要累及黏膜和黏膜下层,结肠黏膜不完整,大部分腺体被破坏,腺体正常结构丧失,排列紊乱,腺腔消失;可见密集炎性细胞浸润,以中性粒细胞、淋巴细胞为主,伴有少量单核细胞。
钩藤碱组、阳性药组小鼠结肠腺体破坏较轻,结构基本恢复正常,炎性细胞浸润深度较模型组浅,炎性细胞数量也显著减少,炎症程度明显减轻。
(5)钩藤碱对小鼠结肠组织学损伤评分的影响
对小鼠结肠组织学进行损伤评分,组织学评分标准见表4,结果见图5。
由图5可知,模型组的组织学评分明显高于钩藤碱组的评分,差异有统计学意义(P<0.001),也明显高于阳性药组的评分,差异有统计学意义(P<0.01)。
表4组织学评分标准
(6)ELISA检测各组小鼠结肠中炎症因子浓度
采用ELISA检测各组小鼠结肠中炎症因子浓度,结果见图6;其中图a为血浆中TNF-α浓度,图b为血浆中IL-1β浓度,图c为血浆中CXCL1浓度,图d为血浆中MPO浓度。
结肠匀浆炎症因子的含量:模型组TNF-α、IL-1β、CXCL1、MPO浓度明显高于对照组,钩藤碱干预后,TNF-α、IL-1β、CXCL1、MPO浓度明显下降,差异有统计学意义(P<0.01)。阳性药地塞米松干预后,TNF-α、IL-1β、CXCL1、MPO浓度明显下降,差异有统计学意义(P<0.01)。
(7)钩藤碱对小鼠结肠通透性影响
在处死动物前4h前禁食和禁水,使用异硫氰酸荧光素标记的右旋葡聚糖(fluorescein isothiocyanate dextran,FITC-Dex)60mg/100g灌胃,收集血清,采用荧光分光光度计测量每个样本的荧光密度,并检测血清中FITC-Dex浓度。结果见图7。
结果发现,与对照组比较,模型组小鼠血清中FITC-Dex浓度明显增高(P<0.001);经过钩藤碱干预后,钩藤碱组小鼠血清中FITC-Dex浓度与模型组比较明显降低(P<0.5);经过地塞米松干预后,地塞米松组小鼠血清中FITC-Dex浓度与模型组比较明显降低(P<0.01)。
(8)钩藤碱结肠上皮细胞AhR
AhR激活影响下游一系列相关基因的表达,其中对细胞色素P450(CYP1A1)的影响最为明显和直接。所以可以通过CYP1A1的表达来判断灌胃钩藤碱是否激活了小鼠结肠上皮的AhR。结果如图8所示,图a为各实验组小鼠结肠CYP1A1的表达条带,图b为各实验组小鼠结肠CYP1A1的灰度值。
结果发现,模型组小鼠的CYP1A1的蛋白表达低于对照组(P<0.001);给予钩藤碱干预后,CYP1A1的蛋白表达明显上调(P<0.001),说明钩藤碱激活了AhR(AhR活化可减轻肠道炎症)。
IBD的发病原因复杂,现在越来越多的研究者认为肠屏障功能损伤参与了IBD的发病。Giovannic Actis等形象地将IBD描述为“屏障器官性疾病”,可见肠屏障在IBD发病中的关键作用。肠屏障作为人体的第一道防线,可以保护肠道免受肠腔有害物质(如:细菌和毒素)的入侵。正常的肠黏膜屏障由机械屏障、化学屏障、免疫屏障和生物屏障组成,其中,机械屏障包括结肠上皮细胞以及上皮细胞间的连接,这些细胞间连接包括紧密连接、缝隙连接和粘附连接等,它们共同作用,封闭细胞间隙。紧密连接由连接粘附分子(junctionadhesion molecule,JAM)、咬合蛋白(Occludin)、闭合蛋白(Claudin)、闭锁小带(zonulaoccludens,ZO-1)等组成。肠黏膜紧密连接遭到破坏后,会引起肠腔内病原体、内毒素及过敏原的入侵,引起肠道过度的免疫应答和炎症反应。研究发现在患有克罗恩病的病人中,Occludin、Claudin-3,-5,-8和JAM-A等蛋白明显减少且发生重新分布。在溃疡性结肠炎病人中,也发现Occludin、Claudin-1,-4和JAM-A等蛋白的表达下降。IBD患者肠道紧密连接的破坏更加严重,说明紧密连接的破坏会加速IBD患者的疾病进程。因此,修复紧密连接的完整性作为治疗IBD的策略可能有效。由上述的内容(4)、(5)、(7)可知,钩藤碱有利于修复紧密连接,促进肠屏障完整性,减轻肠屏障功能损伤。
综合上述内容可知,本发明在动物水平进行钩藤碱抗炎症性肠炎的药效研究,观察到钩藤碱在体内对IBD小鼠的炎症状态、肠屏障通透性、靶基因表达及主要病变部位存在的影响,可以减轻肠道炎症,从而可以用于制备治疗IBD药物。
以上所述,仅是本发明实施例的较佳实施例而已,并非对本发明实施例作任何形式上的限制,依据本发明实施例的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明实施例技术方案的范围内。
Claims (7)
1.钩藤碱在制备治疗炎症性肠炎药物中的应用,其特征在于,
所述的炎症性肠炎为溃疡性结肠炎;
所述的炎症性肠炎药物为减轻肠道炎症、修复肠屏障功能的药物。
2.根据权利要求1所述的应用,其特征在于,所述的钩藤碱在制备减少结肠中炎症因子的药物中的应用。
3.根据权利要求1所述的应用,其特征在于,所述的钩藤碱在制备激活AhR的药物中的应用。
4.根据权利要求1所述的应用,其特征在于,所述的钩藤碱在制备修复肠屏障通透性的药物中的应用。
5.根据权利要求1所述的应用,其特征在于,所述的钩藤碱在制备修复结肠组织损伤的药物中的应用。
6.根据权利要求1所述的应用,其特征在于,所述的钩藤碱在制备减小炎症性肠炎导致的体重下降的药物中的应用。
7.根据权利要求1所述的应用,其特征在于,所述的钩藤碱在制备避免炎症性肠炎导致的结肠长度变短、重量减轻的药物中的应用。
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