CN109350615A - 盐酸水苏碱在预防和治疗缺血性脑血管疾病的新用途 - Google Patents
盐酸水苏碱在预防和治疗缺血性脑血管疾病的新用途 Download PDFInfo
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Abstract
本发明涉及盐酸水苏碱的新用途。具体涉及盐酸水苏碱在制备预防和治疗缺血性脑血管疾病的药物、食品或保健品中的应用。本发明经大鼠局部脑缺血模型的药理试验，结果证实，本发明的盐酸水苏碱能显著降低大鼠线栓法致局部脑缺血引起的脑损伤面积百分率，并显著改善大鼠缺血后的神经行为，增加血清中SOD的含量，降低MDA的含量。盐酸水苏碱脑保护作用强，而且由于分子量小，具有显著的脑通透性优势。在预防和治疗缺血性脑血管病中具有良好的应用效果。
Description
技术领域
本发明涉及医药领域，特别是涉及盐酸水苏碱在预防和治疗缺血性脑血管疾病的新用途。
背景技术
盐酸水苏碱(stachydrine)是唇形科植物益母草中的主要生物碱成分，化学式C7H13NO2·HCl分子量为179.5，CAS号471-87-4。分子结构式如式(Ⅰ)所示
有研究表明，盐酸水苏碱具有活血调经，利尿消肿，收缩子宫的作用。对肾上腺素所引 起心肌缺血有提高冠状动脉和心肌营养性血流量、减少心肌细胞坏死率、降低血黏度、降低 血管阻力、改善微循环、减慢心率、减少心输出量及抗血小板凝聚等作用；还有改善和增加 肾脏的血流量，使肾小球和肾小管得到修复、改善肾功能的作用。对子宫具有引起节律性收 缩和兴奋子宫的作用。也也报道认为其具有抗炎作用。
缺血性脑血管病(ischemic brain disease)又称为缺血性脑卒中，是世界上发病率、死亡 率、致残率最高的疾病之一，极大威胁着人类、特别是老年人的健康和生活质量，已经成为 全球社会健康资源的巨大负担。临床上，缺血性脑卒中死亡率和致残率已在神经系统疾病中 占首位。目前国内外应用于治疗缺血性脑血管病的有效药物很少。因此，深入开展缺血性脑 血管病的药物防治研究具有重要意义。近些年来的研究发现，缺血后有部分血管能够自然再 通或者通过溶栓治疗恢复再通，但是随之而来的是进一步的脑损伤和功能障碍，即缺血再灌 注损伤(ischemia reperfusion injury)。因此减轻缺血再灌注损伤是治疗缺血性脑血管病的关 键环节。
目前，尚没有文献报道盐酸水苏碱用于缺血性脑血管病。
发明内容
本发明的目的在于提供盐酸水苏碱在预防和治疗缺血性脑血管疾病的新用途。
本发明第一方面提供了盐酸水苏碱作为预防和治疗缺血性脑血管疾病的有效成分，在制 备预防和治疗缺血性脑血管疾病药物、食品或保健品中的用途。
进一步地，所述药品、食品或保健品中，盐酸水苏碱作为作用于缺血性脑血管疾病的唯 一有效成分。所述盐酸水苏碱也可以作为具有治疗缺血性脑血管疾病功能的有效成分之一。
本发明第二方面提供一种预防和治疗缺血性脑血管疾病的药物，所述药物中，预防和治 疗缺血性脑血管疾病的有效成分包括盐酸水苏碱。
进一步地，所述药物以盐酸水苏碱作为预防和治疗缺血性脑血管疾病的唯一有效成分。
所述预防和治疗缺血性脑血管疾病的药物中还包含药学上可接受的载体。
药学上可接受的载体为各种药学上常用的辅料和/或赋形剂，包括(但不限于)糖类(如 乳糖、葡萄糖和蔗糖)，淀粉(如玉米淀粉和土豆淀粉)，纤维素及其衍生物(如羧甲基纤维 素钠、乙基纤维素和甲基纤维素)，黄蓍胶粉末，麦芽，明胶，滑石，固体润滑剂(如硬脂酸 和硬脂酸镁)，硫酸钙，植物油，如花生油、棉籽油、芝麻油、橄榄油、玉米油和可可油，多元醇(如丙二醇、甘油、山梨糖醇、甘露糖醇和聚乙二醇)，海藻酸，乳化剂(如Tween、聚 氧乙烯蓖麻油)，润湿剂(如月桂基硫酸钠)，着色剂，调味剂，压片剂、稳定剂，抗氧化剂， 防腐剂，无热原水，等渗盐溶液和磷酸盐缓冲液等；该载体可根据需要提高配方的稳定性、 活性及生物有效性等。
所述预防和治疗缺血性脑血管疾病的药物为注射用药物或口服药物。
所述预防和治疗缺血性脑血管疾病的药物的形式选自片剂、胶囊剂、颗粒剂、混悬剂、 乳剂、溶液剂、糖浆剂或注射剂。
本发明第三方面提供盐酸水苏碱作为脑缺血保护或降低脑梗死面积的有效成分，在制备 药物、制剂、食品或保健品中的用途。
本发明第四方面一种食品或保健品，含有盐酸水苏碱作为该食品中用于预防和治疗缺血 性脑血管疾病的有效成分。
进一步地，所述食品或保健品以盐酸水苏碱作为预防和治疗缺血性脑血管疾病的唯一有 效成分。
如上所述，本发明的盐酸水苏碱在预防和治疗缺血性脑血管疾病的新用途，具有以下有 益效果：本发明的盐酸水苏碱对脑损伤具有抑制作用，明显的脑缺血保护作用。在预防和治 疗缺血性脑血管病中具有良好的应用效果。
附图说明
图1显示为盐酸水苏碱对大鼠神经功能缺损评分的影响(**P<0.01，模型组vs.假手术 组；#P<0.05，##P<0.01，模型组vs.给药组(n＝10))。
图2显示为盐酸水苏碱对大鼠脑缺血再灌注损伤脑梗死面积百分比的影响(**P<0.01， 模型组vs.假手术组；#P<0.05，##P<0.01，模型组vs.给药组(n＝10))。
图3显示为盐酸水苏碱对脑缺血再灌注损伤大鼠血清中SOD和MDA的影响(A.实验各组血清中SOD含量；B.实验各组血清中MDA含量。**P<0.01，模型组vs.假手术组；#P<0.05，##P<0.01，模型组vs.给药组(n＝4))。
具体实施方式
以下通过特定的具体实例说明本发明的实施方式，本领域技术人员可由本说明书所揭露 的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加 以实施或应用，本说明书中的各项细节也可以基于不同观点与应用，在没有背离本发明的精 神下进行各种修饰或改变。
实施例1.盐酸水苏碱用于治疗缺血性脑血管病的动物实验
大鼠线栓法制作局部脑缺血再灌注损伤模型的药理实验是验证药物具有防治缺血性脑血 管病作用常用的动物实验，因此用其验证盐酸水苏碱对实验性动物脑缺血的保护作用。
1.1动物
健康雄性SD大鼠，体重240～280g。购于上海斯莱克实验动物有限责任公司，质量合格 证号(动物合格证号：SCXK(沪)2013-0016)。饲养于清洁级动物房。
1.2药物
将实验大鼠进行分组：
假手术组：给予与药物实验组等量的生理盐水，不进行脑缺血手术
模型组：给予与药物实验组等量的生理盐水进行脑缺血手术。
给药组：给予盐酸水苏碱5mg/kg和30.0mg/kg。
1.3实验方法
实验大鼠用2％戊巴比妥钠腹腔注射麻醉，颈正中切口，分离并结扎右侧颈总动脉近心段、 颈外动脉及其分支血管。分离右侧颈内动脉，沿着颈内动脉向下分离翼颚动脉，根部结扎该 分支。在颈内动脉近端备线、远端放置动脉夹，颈总动脉分叉处切口，按照体重选择栓线扎 入，栓线进入颈内动脉，入颅至大脑前动脉，阻断大脑中动脉所有血流来源。撤去动脉夹， 扎紧备线，缝合皮肤，术后回笼饲养，照暖灯保持大鼠体温。以上过程均在室温恒定情况下 进行，以利于评价脑缺血程度。缺血15分钟后尾静脉给药一次，缺血2小时后拔出尼龙线进 行再灌注。
术后24小时进行行为学评分，评分采用单盲法，评分参考Zea Longa的5分制评分标准， 标准为：0分，大鼠正常，无神经损伤症状；1分，不能完全伸展对侧前爪；2分，向外侧转 圈；3分，向对侧倾倒；4分，不能自发行走，意识丧失。
评分后，麻醉后取血，断头取脑，将大脑平均冠状分为6片，放于1％的TTC溶液中，37℃温育10～15min染色。梗死区不着色，正常脑组织染成红色。用Image-Pro Plus图像分析软件测出各区面积，计算梗死区面积占全脑面积的百分比。
1.3统计学处理
所有的数据实验数据均以均数±标准差(mean±SD)表示，各组间数据比较用SPSS17.0 软件包，采用单因素方差分析(ANOVA)进行显著性分析。
1.4实验结果
1.4.1药物对大鼠脑缺血模型行为学评分的影响
结果显示，盐酸水苏碱5mg/kg和30.0mg/kg尾静脉注射给药均能改善局部性脑缺血大鼠 行为学评分；(p<0.01，与模型组相比)。见图1。
1.4.2药物对大鼠脑缺血模型脑梗死面积百分比的影响
结果显示，盐酸水苏碱5mg/kg和30.0mg/kg静脉注射给药对局部性脑缺血模型大鼠的脑 梗死百分率有非常显著的降低作用(p<0.01，与模型组相比)。见图2。
1.4.3盐酸水苏碱提高大鼠血清中SOD的含量降低MDA的含量
再灌注24h后取血，室温静置后离心取血清，按照说明书进行操作。盐酸水苏碱给药后 对脑缺血再灌注大鼠的损伤有改善，比较前期的实验结果我们选择30mg/kg组检测大鼠血清 中SOD的含量，结果如图所示，显示假手术组血清中SOD含量为(22.44±0.23U/mL)与模 型组(14.91±1.6U/mL)相比差异具有意义(P<0.01)，盐酸水苏碱30mg/kg给药组为(19.07 ±0.83U/mL)与模型组相比SOD水平上升且差异具有意义(P<0.01)。对血清中MDA的含 量也进行了测定，检测结果显示，假手术组为(3.24±0.34nmol/mL)与模型组(10.11±2.34nmol/mL)相比，模型组血清中MDA含量上升(P<0.05)；盐酸水苏碱给药组(30mg/kg) 为(4.89±0.77nmol/mL)与模型组相比下降，差异具有统计意义(P<0.05)。结果见图3。
上述实验结果表明，盐酸水苏碱(0.25mg/kg和0.5mg/kg)对大鼠线栓法致局脑缺血有明 显治疗作用，能改善大鼠的行为学缺陷，降低脑梗死面积百分比。因此，盐酸水苏碱可用于 预防和治疗缺血性脑血管疾病方面的应用。
综上所述，本发明经大鼠局部脑缺血模型的药理试验，结果表明，本发明的盐酸水苏碱 能显著降低大鼠线栓法致局部脑缺血引起的脑损伤面积百分率，并显著改善大鼠缺血后的神 经行为，增加血清中SOD的含量，降低MDA的含量。盐酸水苏碱脑保护作用强，而且由于 分子量小，具有显著的脑通透性优势。所以，本发明具高度产业利用价值。
上述实施例仅例示性说明本发明的原理及其功效，而非用于限制本发明。任何熟悉此技 术的人士皆可在不违背本发明的精神及范畴下，对上述实施例进行修饰或改变。因此，举凡 所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等 效修饰或改变，仍应由本发明的权利要求所涵盖。
Claims (10)
1.盐酸水苏碱作为预防和治疗缺血性脑血管疾病的有效成分，在制备预防和治疗缺血性脑血管疾病药物、食品或保健品中的用途。
2.如权利要求1所述盐酸水苏碱的用途，其特征在于，所述药品、食品或保健品中，盐酸水苏碱作为作用于缺血性脑血管疾病的唯一有效成分。
3.一种预防和治疗缺血性脑血管疾病的药物，所述药物中，预防和治疗缺血性脑血管疾病的有效成分包括盐酸水苏碱。
4.如权利要求3所述的预防和治疗缺血性脑血管疾病的药物，其特征在于，所述药物以盐酸水苏碱作为预防和治疗缺血性脑血管疾病的唯一有效成分。
5.如权利要求3所述的预防和治疗缺血性脑血管疾病的药物，其特征在于，所述预防和治疗缺血性脑血管疾病的药物中还包含药学上可接受的载体。
6.如权利要求3所述的预防和治疗缺血性脑血管疾病的药物，其特征在于，所述预防和治疗缺血性脑血管疾病的药物为注射用药物或口服药物。
7.如权利要求3所述的预防和治疗缺血性脑血管疾病的药物，其特征在于，所述预防和治疗缺血性脑血管疾病的药物的形式选自片剂、胶囊剂、颗粒剂、混悬剂、乳剂、溶液剂、糖浆剂或注射剂。
8.盐酸水苏碱作为脑缺血保护或降低脑梗死面积的有效成分，在制备药物、制剂、食品或保健品中的用途。
9.一种食品或保健品，含有盐酸水苏碱作为该食品中用于预防和治疗缺血性脑血管疾病的有效成分。
10.如权利要求9所述的食品或保健品，其特征在于，所述食品或保健品以盐酸水苏碱作为预防和治疗缺血性脑血管疾病的唯一有效成分。
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