CN109125308A - 秋水仙碱在预防和治疗缺血性脑血管疾病的新用途 - Google Patents
秋水仙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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- CN109125308A CN109125308A CN201810939598.9A CN201810939598A CN109125308A CN 109125308 A CN109125308 A CN 109125308A CN 201810939598 A CN201810939598 A CN 201810939598A CN 109125308 A CN109125308 A CN 109125308A
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Abstract
本发明涉及秋水仙碱的新用途。具体涉及秋水仙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，本发明的秋水仙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。本发明经细胞氧糖剥夺（OGD）实验证实，秋水仙碱可以提高OGD刺激后细胞的存活率。秋水仙碱脑保护作用强，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，特别是涉及秋水仙碱在预防和治疗缺血性脑血管疾病的新用途。
背景技术
秋水仙碱(colchicine)是百合科植物秋水仙中提取的主要生物碱成分，故也称为秋水仙素，化学式：C22H25NO6分子量：399.437，CAS号64-86-8。分子结构式如式(Ⅰ)所示
目前临床上秋水仙碱主要用于预防和治疗急性痛风。有研究表明，秋水仙碱通过干扰溶酶体脱颗粒降低中性粒细胞的活性、黏附性及趋化性，抑制粒细胞向炎症区域的游走，从而发挥抗炎作用。另外，它干扰细胞间黏附分子及选择素的表达，从而阻碍T淋巴细胞活化及对内皮细胞的黏附，抑制炎症反应。秋水仙碱还可通过减少E-选择素、L-选择素及内皮素的表达，从而发挥其抗炎作用。秋水仙碱可以降低体温，抑制呼吸中枢、增强拟交感药物的作用，收缩血管、升高血压。秋水仙碱还可通过神经元刺激增强胃肠道功能。由于秋水仙碱有抑制细胞分裂，同时还可以干扰肿瘤细胞的蛋白质代谢，抑制RNA多聚酶活力以及细胞膜类脂质的合成和氨基酸在细胞膜上的转运，从而诱导多种实体肿瘤细胞凋亡。研究发现秋水仙碱在体外对胶质瘤细胞生长有明显的抑制和诱导凋亡作用。
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，尚没有文献报道秋水仙碱用于缺血性脑血管病。
发明内容
本发明的目的在于提供秋水仙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秋水仙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，秋水仙碱作为作用于缺血性脑血管疾病的唯一有效成分。所述秋水仙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秋水仙碱。
进一步地，所述药物以秋水仙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秋水仙碱作为脑缺血保护、降低脑梗死面积或神经细胞损伤保护有效成分，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，含有秋水仙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秋水仙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，本发明的秋水仙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：本发明的秋水仙碱对脑损伤具有抑制作用，明显的脑缺血保护作用，可以降低PC12细胞氧糖剥夺后的凋亡率。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显示为秋水仙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<0.01，模型组vs.给药组(n＝6))。
图2显示为秋水仙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＝6))。
图3显示为MTT检测秋水仙碱对OGD后PC12细胞生存率的影响(***P<0.001，OGD组vs.Con.组，##P<0.01，###P<0.001，OGD组vs.给药组(n≥3))。
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.秋水仙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，因此用其验证秋水仙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：给予秋水仙碱0.25mg/kg和0.5mg/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，秋水仙碱0.25mg/kg和0.5mg/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，秋水仙碱0.25mg/kg和0.5mg/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，与与模型组相比)。见图2。
上述实验结果表明，秋水仙碱(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，秋水仙碱可用于制备防治缺血性脑血管疾病药物。
实施例2.秋水仙碱对氧糖剥夺刺激引起的细胞损伤的保护作用
2.1实验材料
秋水仙碱，购自大连美仑生物技术有限公司
大鼠神经元细胞株(PC12)购自中科院上海细胞库
2.2实验方法
2.2.1MTT法检测秋水仙碱对氧糖剥夺所致细胞损伤的保护作用
实验分为对照组(Con，未氧糖剥夺、未给药)、模型组(OGD，氧糖剥夺、未给药)、给药组(氧糖剥夺、给药)。
取对数生长期的PC12细胞以2.0×105/ml的密度接种于96孔板中，每孔100μL，接种24h后待细胞全部贴壁，对照组不作处理，模型组换成无血清无糖的DMEM培养基，给药组分别加入100μL含有终浓度100μM、10μM、1μM、100nM、10nM、1nM的秋水仙碱的无血清无糖的DMED培养液，平衡孵育2h后，将模型组和给药组放入缺氧小室中缺氧6h。缺氧时间结束后，用MTT法检测细胞存活率。
2.3统计学处理
实验数据均以均数±标准差(mean±SD)表示，各组间数据比较用SPSS 17.0软件包，采用单因素方差分析(ANOVA)进行显著性分析。
2.4实验结果
2.4.1MTT法检测秋水仙碱对氧糖剥夺所致细胞损伤的保护作用
正常组细胞的生存率为100±1.28％，缺氧6h后的OGD组生存率为47.00±2.85％；秋水仙碱1nM给药组细胞生存率为73.44±3.34％，与ODG组相比结果具有统计学差异(P<0.01)结果见图3。
上述实验结果表明，秋水仙碱对缺氧引起的神经细胞损伤有保护作用。
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，本发明的秋水仙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。本发明经细胞氧糖剥夺实验证实，秋水仙碱可以提高OGD刺激后细胞的存活率。秋水仙碱脑保护作用强，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.秋水仙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所述秋水仙碱的用途，其特征在于，所述药品、食品或保健品中，秋水仙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秋水仙碱。
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，所述药物以秋水仙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.秋水仙碱作为脑缺血保护、降低脑梗死面积或神经细胞损伤保护有效成分，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，含有秋水仙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秋水仙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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Application publication date: 20190104 |