CN106074668A - 用于神经退行性疾病或神经再生的中药制剂 - Google Patents
用于神经退行性疾病或神经再生的中药制剂 Download PDFInfo
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- CN106074668A CN106074668A CN201610629861.5A CN201610629861A CN106074668A CN 106074668 A CN106074668 A CN 106074668A CN 201610629861 A CN201610629861 A CN 201610629861A CN 106074668 A CN106074668 A CN 106074668A
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/41—Crassulaceae (Stonecrop family)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
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- Mycology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
本发明涉及一种可用于治疗神经退行性疾病或神经再生的中药制剂，属于中药领域。其由中药组合物和辅料组成，所述中药组合物由红景天总黄酮和尿石素组成，所述辅料为微晶纤维素和硬脂酸镁。
Description
技术领域
本发明涉及一种可用于治疗神经退行性疾病或神经再生的中药制剂，属于中药领域。
背景技术
带有蛋白质沉淀的神经退行性疾病包含大量的临床症状。其特征为蛋白质或蛋白质片段(肽)的病理性异常、全身或局部浓缩，从而导致沉淀或积聚，并可能通过预聚合或低聚作用成为有序排列的结构(例如：原纤维)，甚至可能会形成蛋白质晶体结构(例如：阿兹海默病脑内斑块的β淀粉样蛋白)。
在这些病理性病状后还隐藏着一些疾病，例如阿尔茨海默病(Alzheimer’sdisease，AD)阿尔茨海默病的发病随年龄的增长而增加。目前，世界上阿尔茨海默病的发病率男性为3.05％，女性为4.82％，美国85岁以上痴呆发病率达4.72％。在西方国家里，阿尔茨海默病正逐渐取代卒中，位居神经科疾病之首。我国阿尔茨海默病的病人总数已占世界第一位，预期到2050年，我国65岁以上和80岁以上的老年人和高龄老人将占总人口的35％和22％，届时，AD患者可达到2500万。现在我国60岁以上人口已超过10％。目前已经上市治疗老年痴呆症的药物主要以乙酰胆碱酯酶抑制剂和N-甲基-D-天门冬氨酸受体拮抗剂(NMDA)为主，这些药物能在一定程度上改善患者的痴呆症状，但不能从根本上阻止病情的恶化、逆转病情，因此寻找抗老年痴呆症药物的研制已经引起全世界的重视，并已建立许多相关的生物活性筛选和评价体系。
另外，神经损伤不可避免地给患者带来极大的经济及精神负担，与神经退行性疾病相似的是损伤区会存在明显神经细胞的凋亡现象，并且这种现象是不可逆的。因此周围神经缺损的修复与重建是当前周围神经损伤领域的一大难题。目前在临床治疗过程中解决神经缺损的手段依然以自体神经移植为标准手术，但由于自体神经来源有限且造成供区较多的并发症。
红景天属于景天科(Crassulaceae)红景天属(Rhodiola L)植物，世界上有90多种，中国有70多种。要分布于喜马拉雅山地区，亚洲西北部和北美洲，我国主产于东北、华北和西南。红景天属植物民间多以全草入药，有活血止血、清肺止咳的功效，用于治疗咳血、咯血、肺炎咳嗽、妇女白带等症，古代亦用作滋补强壮药。红景天最早作为药用见记载于公元1200年的藏医《四部医典》中，记为“神药－－苏罗玛葆”，即现在的宽果红景天(R.eurycarpa S.H.FU)。现代的医药书籍根据红景天植物学特征分成多种，作为药用的见记载有《中华人民共和国药典》(1985版)和《四川省中成药标准》(1993版)记载的大花红景天(R.crenulataH.Ohba)和狭叶红景天(R.kirilowii Maxim)。
鞣花鞣质(Ellagitannin)是在某些水果、浆果和坚果(诸如石榴、悬钩子、草莓、黑悬钩子、胡桃和杏仁)中富含的单体多酚、低聚多酚和聚合多酚。水果和浆果被广泛地在新鲜时消费，并作为饮料(诸如果汁)，并且已经报道它们会促进健康。
尿石素是鞣花酸、安石榴苷(PA)、石榴皮鞣质(punicalin)(PB)、新唢呐素(tellimagrandin)(TL)和其它鞣花鞣质的代谢物。目前临床及科研研究表明其具有抗炎、抗氧化及抗癌活性。
发明内容
本发明的一个目的是提供一种可用于治疗神经退行性疾病及神经再生的中药制剂，其由中药组合物和辅料组成，所述中药组合物由红景天总黄酮和尿石素组成，所述辅料为微晶纤维素和硬脂酸镁。
在一个实施方案中，所述红景天总黄酮和尿石素的重量比为10∶0.1-3；优选为10∶0.7。
在另一个实施方案中，所述红景天总黄酮是指黄酮类成分高于90％的红景天提取物，所述尿石素为尿石素A。
在本发明进一步实施方案中，所述中药组合物由红景天总黄酮、玉竹总皂苷、黄连总生物碱和尿石素组成，红景天总黄酮、玉竹总皂苷、黄连总生物碱和尿石素的重量比为10∶2-5∶1-4∶0.1-3；优选为10∶3∶2∶0.7。
在又一个实施方案中，所述中药组合物、微晶纤维素和硬脂酸镁的比例为10∶2∶0.1。
本发明的另一个目的是提供所述中药制剂在制备治疗神经退行性疾病或神经再生药物中的应用。
在一个实施方案中，所述神经退行性疾病优选为阿尔茨海默症，所述神经再生是指神经神经损伤后的神经细胞再生或促进骨髓干细胞归巢而导致的神经再生。所述干细胞归巢是指在脑、心脏和肝脏等多种组织或器官损伤后发现干细胞归巢现象，干细胞归巢对组织或器官损伤修复发挥重要作用。神经系统损伤后同样存在干细胞归巢现象。
在本发明中，所述红景天总黄酮、玉竹总皂苷及黄连总生物碱可直接通过商业渠道获得，当然也可以通过本领域已知的相关制备方法进行制备。
具体实施方式
还可进一步通过实施例来理解本发明，其中所述实施例说明了一些制备或使用方法。然而，要理解的是，这些实施例不限制本发明。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和以下要求保护的本发明范围之内。
实施例1中药组合物对Aβ42淀粉样蛋白聚集的影响
红景天总黄酮制备：将红景天药材粉碎过筛，以10倍量的水回流提取三次，每次1小时，过滤，滤液浓缩得浸膏，将浸膏上大孔树脂LSA-10，先以正己烷以三倍柱体积洗脱，然后以75％乙醇进行洗脱，收集75％乙醇洗脱液，浓缩干燥即得红景天总黄酮。
玉竹总皂苷制备：将玉竹药材粉碎过筛，以15倍量80％乙醇60℃提取三次，过滤，滤液浓缩得浸膏，用正丁醇1∶1萃取5次，合并正丁醇萃取液，浓缩后上大孔树脂AB-8，以80％乙醇洗脱，合并洗脱液，浓缩干燥即得玉竹总皂苷。
黄连总生物碱制备：将黄连药材粉碎过筛，以12倍量0.1％硫酸溶液浸泡1小时后，然后加热回流提取1小时，反复提取三次，过滤，向滤液加入药材重量0.5％的大孔树脂AB-8进行吸附，浓缩滤液至原滤液体积的10％；向浓缩滤液中加入氯化钠至15％(重量)并加入氯化铁至5％(重量)，结晶48小时，滤过沉淀，水洗干燥后即得黄连总生物碱。
0.1mgAβ42蛋白冻干粉溶于10μLDMSO和543.78μL磷酸缓冲液体系中配置成终浓度为40μM的Aβ42蛋白储备溶液。12.5μL待检测样品溶液、25μLAβ42蛋白储备溶液及12.5μLThT储备液(浓度为80μM)加于96孔板板孔中，混合并置96孔板振荡仪以90rpm振荡15min后于37℃二氧化碳培养箱静置孵育16h。16h后，利用英国TTP Labtech公司的高速细胞分析仪(Acumene X3型)405通道测定其荧光强度。
活性物质的抗Aβ42蛋白聚集活性的计算：Vi＝[(F0-Fi)/F0]×100。其中，Vi为相对抑制率，Fi为加入待测样品后的Aβ42聚集物的荧光强度，F0为未加入待测样品时的Aβ42聚集物的荧光强度。
具体结果如下：
实施例2中药组合物提高老年痴呆果蝇学习记忆活性测试
(1)老年痴呆果蝇的培育
w1118(isoCJ1)作为实验的对照组背景果蝇。成功转入致病性Aβ42蛋白的果蝇为(UAS-Aβ42)。该品系果蝇通过与全脑表达Gal4启动子果蝇进行杂交，获得携带elav-GAL4c155(P35)与Aβ42的果蝇品系。
(2)老年痴呆果蝇的给药
试验设置健康果蝇无药对照、疾病果蝇无药对照和疾病果蝇给药的三种组别。
所有测试果蝇的亲本均在恒温24℃，恒湿42％RH(Relative humidity)的蝇房饲养和繁殖。果蝇羽化后的第一天将对照组果蝇及疾病组果蝇和待喂药组果蝇通过二氧化碳麻醉之后，挑选正确性状的果蝇在含有食物的玻璃管中。在给药阶段，所有测试果蝇在28℃恒温和42％恒湿的保温箱内饲养，以保证果蝇吃药的效率。每日果蝇喂药4小时，从挑出果蝇的第二天一直喂药到第8天。
所喂药物在挑蝇第二天配制并与配制当天给果蝇喂药。另外，对照组果蝇喂含有1％DMSO的糖水。对于每个行为指数(Performance Index)，需要有2管果蝇组，每管中含有约100只果蝇。
1)在训练阶段，将大约100只左右的果蝇装入安置有铜网交叉电极的训练管，先后通入辛醇(OCT)和甲基环己醇(MCH)两种气味各60s，中间间隔45s的新鲜空气。在通入第一种气味(CS+)的同时给予果蝇60V的脉冲电击刺激(US，脉冲时长1.5s，间隔3.5s)。通入第二种气味(CS-)时不给予电击。如此完成一个训练周期。
2)在瞬时记忆(学习)能力测试中，完成一个训练周期的果蝇被立即转移到T-Maze的选择点，同时从相对的两个方向通入CS+和CS-。经过2min的选择后两侧的果蝇被分别收集，麻醉或处死后进行计数。行为指数(Performance index，PI)的计算公式如下：
PI＝[(CS-)-(CS+)]/[(CS-)+(CS+)]×100。
分别使用OCT和MCH作为CS+进行训练和测试，得到的两个PI的平均值作为一次实验的PI使用。PI＝0表示测试中果蝇对于两种气味的选择为50∶50，即没有形成记忆；PI＝100表示测试中果蝇全部逃避伴随电击的气味，即完美记忆。进行活性测试时，同时进行不喂药的同遗传背景健康蝇(2U*H29.3)、不喂药的老年痴呆疾病蝇(P35*H29.3)、喂测试药的老年痴呆疾病蝇的嗅觉短期记忆缺陷测试，分别计算它们的总学习记忆行为指数(PI)。将喂测试药的老年痴呆疾病蝇学习记忆行为指数与不喂药的同遗传背景健康蝇(2U*H29.3)行为指数、不喂药的老年痴呆疾病蝇(P35*H29.3)行为指数相比较，评价测试药物抗老年痴呆的作用。喂食测试物的老年痴呆疾病蝇学习记忆行为指数相对越高则说明测试物抗老年痴呆作用越强。采用T检验比较，喂食测试物的老年痴呆疾病蝇学习记忆行为指数和不喂药(仅给不含药样品的溶剂)的老年痴呆疾病蝇学习记忆行为指数，P＜0.05为有明显差别，P＜0.01为有显著差别，P＜0.001为有极显著差别。
数据分析和图形展示通过使用GraphPad Prism 5.03进行处理
实施例3中药组合物对小鼠Aβ模型的影响
雄性昆明小鼠，麻醉后在前囟处皮肤开一小口，暴露出颅骨，将老化的Aβ25-354nmol注入侧脑室，对照组注入生理盐水。次日起给药组灌服药物，10天后进行Morris水迷宫测定，一天两次，连续7天。数据采集和处理均由图象自动监视和处理系统完成。
具体结果如下：
实施例4中药组合物促进神经导管材料的体外BMSC募集
使用Transwell共培养体系将支架和BMSC隔开，具体分组为：
空白组Transwell上室添加100μlBMSC细胞悬液(1×106个/ml)，下室添加500μl无血清培养基；
对照组Transwell上室添加100μl BMSC细胞悬液(1×106个/ml)，下室添加500μl浸泡神经导管(Neurolac)的无血清培养基；
给药组Transwell上室添加100μl BMSC细胞悬液(1×106个/ml)，下室添加500μl浸泡神经导管(Neurolac)的无血清培养基；所述培养基中添加100μg/L的药物。
37℃孵育24小时，PBS洗3次，4％多聚甲醛固定10min，用棉签擦去上室未迁移过膜的细胞，DAPI染色30min，PBS洗3次，荧光显微镜下随机选择5个视野，拍照计数。相同实验重复3次，具体结果如下：
实施例5中药组合物体外诱导BMSC定向分化神经细胞的研究
分别将不同药物组添加到不同的培养皿中(终浓度100μg/L)，加入1ml包含1×106个/ml BMSC的培养基(10％FBS/DMEM)，对照组中不添加任何药物，37℃孵育8小时后进行免疫细胞化学检测，分别采用nestin和GFAP抗体作为一抗，FITC标记的羊抗小鼠IgG为二抗，计算各组细胞表达阳性率，每组平行试验3次，具体结果如下：
实施例6中药制剂
精密称取10g红景天总黄酮、3g玉竹总皂苷、2g黄连总生物碱以及0.7g尿石素A，搅拌混匀后添加3.1g微晶纤维素，60％乙醇制粒，添加0.16g硬脂酸镁，压片，即得(片重300mg/片)
本发明内容仅仅举例说明了要求保护的一些具体实施方案，其中一个或更多个技术方案中所记载的技术特征可以与任意的一个或多个技术方案相组合，这些经组合而得到的技术方案也在本申请保护范围内，就像这些经组合而得到的技术方案已经在本发明公开内容中具体记载一样。
Claims (8)
1.一种可用于治疗神经退行性疾病及神经再生的中药制剂，其由中药组合物和辅料组成，所述中药组合物由红景天总黄酮和尿石素组成，所述辅料为微晶纤维素和硬脂酸镁。
2.根据权利要求1所述的中药制剂，其特征在于，所述红景天总黄酮和尿石素的重量比为10∶0.1-3；优选为10∶0.7。
3.根据权利要求1所述的中药制剂，其特征在于，所述红景天总黄酮是指黄酮类成分高于90％的红景天提取物，所述尿石素为尿石素A。
4.根据权利要求1所述的中药制剂，其特征在于，所述中药组合物由红景天总黄酮、玉竹总皂苷、黄连总生物碱和尿石素组成。
5.根据权利要求4所述的中药制剂，其特征在于，红景天总黄酮、玉竹总皂苷、黄连总生物碱和尿石素的重量比为10∶2-5∶1-4∶0.1-3；优选为10∶3∶2∶0.7。
6.根据权利要求1所述的中药制剂，其特征在于，所述中药组合物、微晶纤维素和硬脂酸镁的比例为10∶2∶0.1。
7.权利要求1-6任一项所述中药制剂在制备治疗神经退行性疾病或神经再生药物中的应用。
8.根据权利要求7所述的应用，所述神经退行性疾病优选为阿尔茨海默症，所述神经再生是指神经神经损伤后的神经细胞再生或促进骨髓干细胞归巢而导致的神经再生。
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| CN115252893A (zh) * | 2022-08-26 | 2022-11-01 | 上海市第十人民医院 | 一种抗炎抗氧化性神经导管的制备 |
| CN115252893B (zh) * | 2022-08-26 | 2023-04-25 | 上海市第十人民医院 | 一种抗炎抗氧化性神经导管的制备 |
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