CN103608025A - 用于预防或治疗神经退行性疾病的包含草药提取物的组合物 - Google Patents
用于预防或治疗神经退行性疾病的包含草药提取物的组合物 Download PDFInfo
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Abstract
本发明涉及一种用于预防和改善神经退行性疾病的药物组合物和保健功能性食品，其包含重量比为3.5:1(w/w)的山药(Dioscorea Rhizoma)和穿龙薯蓣(Dioscorea nipponica)的混合草药提取物。所述以3.5:1的重量比混合的山药和穿龙薯蓣的草药提取物具有增加体内神经生长因子的量，提高神经细胞增殖、促进神经炎(neuritis)形成以及提高认知能力的协同效果。因此，本发明的草药提取物可用于预防或治疗神经退行性疾病的药物组合物和保健功能性食品。
Description
技术领域
本发明涉及一种用于预防或治疗神经退行性疾病的包含草药提取物的组合物，其中该组合物包含以3.5:1(w/w)的重量比混合的山药(Dioscorea Rhizoma)和穿龙薯蓣(Dioscorea nipponica)。
致谢
该项工作得到了韩国知识经济部所资助的策略研发计划(OSP)办公室的全球领先技术项目的支持(No.10039303)。
背景技术
神经退行性疾病意味着神经细胞(神经元)结构和功能上的逐渐丧失。它们通常影响神经系统中的特定部分，伴随有例如痴呆、锥体外系疾病、小脑失常、感觉迟钝或运动障碍的症状。当同时影响多个部分时会显示为复杂的症状。虽然可通过患者的临床表现给出诊断，但是在此种情况下却难以作出诊断，这是因为患者显示出多种症状，且不同疾病有着相同的临床表现(Soc.Sci.Med.Vol.40.No.6,pp.847-585,1995)。
神经退行性疾病发生的迹象显示为逐渐地且大部分与衰老共同出现。一旦爆发，神经退行性疾病可延续数年或数十年直至死亡。已知根据家族史，遗传的作用是很重要的。依据临床症状可将神经退行性疾病划分为：麻痹性痴呆(阿尔茨海默症等)，神经系统病变(皮克病等)，姿势和运动异常(帕金森病等)，进行性共济失调，肌肉萎缩和虚弱，以及感觉和行动障碍(International Journal ofEngineering and Technology,Vol.2,No.4,2010年8月,Classification ofNeurodegenerative Disorders Based on Major Risk Factors Employing MachineLearning Techniques)。
在20世纪80年代，提出了神经营养因子具有治疗神经退行性疾病的潜能，如阿尔茨海默病的实验(Nature.1987年9月3-9日；329(6134):65-8.Ameliorationof cholinergic neuron atrophy and spatial memory impairment in aged rats by nervegrowth factor)。可通过向大脑侧脑室施用神经生长因子(NGF)而恢复如在阿尔茨海默病中所知晓的衰老导致的基底前脑神经元的丧失。由于报道了实验动物的记忆得到了改善，因此，通过使用神经营养因子实施治疗神经退行性疾病的研究。作为后续研究，其取得了良好结果：在研究中，通过切割面部神经和坐骨神经而损伤运动神经元功能后，通过作为神经营养因子家族的脑源性神经营养因子(BDNF)、神经营养素3(NT-3)、神经营养素4(NT-4)和睫状神经营养因子(CNTF)修复了损伤的运动神经元的功能(Nature.1992年12月24-31日;360(6406):757-9.Brain-derived Neurotrophic Factor Prevents the Death of MotorNeurons in Newborn Rats After Nerves Section)。在使用患有运动神经元及其功能逐渐丧失的基因重组小鼠(wobbler)的实验中，通过施用BDNF和CNTF增加运动神经元的数量而增进了其功能(Science.1994年8月19日;265(5175):1107-10.Arrest of Motor Neuron Disease in Wobbler Mice Cotreated with CNTF andBDNF)。除所述实验外，神经营养因子在运动神经元和各种感官的病理学模型中增加了神经元数量及其功能，因此，其在实验动物中显示出对记忆、知觉和行为相关失常的改善效果。
基于临床前实验结果，在20世纪90年代，有试验使用神经营养因子治疗洛盖赫里格病(Lou Gehrig’s Disease)。洛盖赫里格病是退行性神经疾病，其中只有运动神经元选择性消亡，从而使得人由于呼吸器官功能障碍和全身麻痹而死亡。BDNF通过皮下或蛛网膜下腔给药，但显示出注射部位疼痛和对消化系统的副作用。因此，在别无选择的情况下，只能以低于临床前实验的BDNF剂量给药。结果，运动神经元及其功能的再生和改善效果甚微(Exp Neurol.1993年11月;124(1):64-72.Review.Experimental rationale for the Therapeutic Use ofNeurotrophins in Amyotrophic Lateral Sclerosis)。类似地，当对患有洛盖赫里格病的病人注射CNTF时也出现了例如发烧、注射部位疼痛或食欲减退的症状，这是比施用BDNF情况下更为严重的副反应，因此，CNTF的给药剂量有限。结果，运动神经元及其功能的再生和改善效果并不明显(Neurobio Aging.1994年3-4月;15(2):249-51.Review Neurotrophic Growth Factors and NeurodegerenativeDiseases:Therapeutic Potential of the Neurotrophins and Ciliary NeurotrophicFactor)。通过体内注射，将例如BDNF，CNTF等神经营养因子以重组蛋白的形式到达中枢和外周神经系统的方法具有有限的蛋白注射量。在试图使用NGF治疗患有阿尔茨海默病的病人的实验中，由于存在副作用，注射剂量、药物递送方式和药效动力学不确定性的限制，也未能显示显著的效果。
尽管临床实验中的结果令人失望，但也存在着许多使用神经营养因子治疗神经退行性疾病可能性的实验证据。典型地，在以行动异常、人格改变、认知能力降低和由亨廷顿蛋白中poly Q增加所导致的早亡为症状的亨廷顿氏病中，许多研究注意到BDNF是异常亨廷顿蛋白的主要靶标。该理论得到了患有亨廷顿氏病的病理学实验动物和病人的纹状体中BDNF的量减少的支持(Science.2001年7月20日;293(5529):493-8.Epub2001年6月4日.Loss of Huntington-mediated BDNF Gene Transcription in Huntington's Disease)。
仍需指出，当选用与已有方法一样的经由皮下或蛛网膜下腔在体内施用重组蛋白形式的神经营养因子的方法治疗退行性疾病时，由于副作用，降低给药剂量以及降低治疗效果仍会重现。因此，在21世纪初，研究了以间接方式提高神经营养因子本身在体内的生物合成量的神经营养因子促进剂(Hum.Gene Ther.1999年12月10日；10(18):2987-97.Brain-derived neurotrophic factor-mediatedprotection of striatal neurons in an excitotoxic rat model of Huntington's disease,asdemonstrated by adenoviral gene transfer)。
山药，是属于薯蓣科的植物，该术语是指脚板薯(Dioscorea batatas Decaisne)或日本薯蓣(Dioscorea japonica Thunberg)的没有周皮的新鲜根状茎，或草药中将新鲜根状茎蒸熟和干燥后的获得物。其广泛分布于韩国、中国和日本，且被当作药物使用。其在滋补营养、消化功能紊乱、糖尿病、咳嗽、肺部疾病、强化肾功能等方面有治疗作用，且通常不产生毒副作用。此外，穿龙薯蓣是薯蓣科多年生攀缘植物，穿龙薯蓣(Dioscorea nipponica Makino)的根状茎。其广泛分布于韩国、中国和日本，且被当作药物使用。其在改善血液循环、放松肌肉、去除消化不良、保持小便畅通、化痰以及预防疟疾方面具有作用，且通常不产生毒副作用。
韩国专利No.854621提供了用于预防和治疗外周神经病的组合物，其包含选自穿龙薯蓣、菊叶山药(Dioscorea quinqueoloba)、脚板薯、日本薯蓣和粉萆薢(Dioscorea tokora)的植物的提取物，并公开了该组合物诱导神经突生长以及增加内源性神经生长因子的分泌，从而有效预防和治疗外周神经病。
本发明人验证了如韩国专利No.854621所公开的：选自穿龙薯蓣、菊叶山药、脚板薯、日本薯蓣和粉萆薢的植物的提取物的功能是诱导神经突显著生长和增加内源性NGF分泌。基于上述内容，尽管当研究通过增加实验动物体内神经生长因子含量而具有神经细胞增殖的效果、促进神经炎(neuritis)形成且提高认知能力的草药提取物时，所述草药中的每一种或其混合草药提取物都令人惊讶地诱导了几乎相同的神经突的生长以及增加内源性神经生长因子分泌，但是本发明是在确定了选择性地特定比例的山药和穿龙薯蓣显示出非常显著的协同作用后完成的。
发明内容
技术问题
因此，本发明的目的在于，从韩国专利No.854621所公开的草药之中，提供可选的草药组合物，其通过在刺激神经生长因子的产生和分泌后提高神经细胞增殖并促进神经炎(neuritis)形成，促进神经元再生和阻止神经元凋亡，从而在提高认知能力方面显示出协同作用。
本发明的另一目的在于提供用于预防和治疗神经退行性疾病的药物组合物和保健功能性食品，其包含作为活性成分的所述草药组合物。
技术方案
与本发明的一个方面相应，本文提供了用于预防和治疗神经退行性疾病的药物组合物和保健功能性食品，其包含重量比为3.5:1(w/w)的山药和穿龙薯蓣的混合提取物。
本发明将在下文中给予详细说明。
本发明涉及用于预防和治疗神经退行性疾病的药物，其包含重量比为3.5:1(w/w)的山药和穿龙薯蓣的混合提取物。
与总重量相比，所述重量比为3.5:1(w/w)的山药和穿龙薯蓣的混合提取物是粗提物，其优选是以50%乙醇提取的。
所述山药和和穿龙薯蓣的提取物可通过以下方法获得。首先，将山药和穿龙薯蓣分别清洗和干燥后，通过切割干燥的草药制备所述草药。然后，可以在使用比所述切割草药总重量多5倍的50%乙醇在室温下冷提取48小时一次后，通过减压浓缩获得重量比为3.5:1(w/w)的山药和穿龙薯蓣的混合草药提取物。
本发明提供了以重量比3.5:1(w/w)混合的山药和穿龙薯蓣的草药提取物用于制备预防或治疗神经退行性疾病的药物组合物的用途。
本发明中神经退行性疾病的实例包括阿尔茨海默病、克-雅氏病、亨廷顿氏病、多发性硬化、格林-巴利综合征、帕金森病、洛盖赫里格病、由逐渐的神经细胞死亡导致的麻痹性痴呆和进行性失调(progressive incotinentia)所引起的疾病。
根据本发明，可通过将药学上可接受的载体、稀释液(diluent)或稀释剂(diluting agent)加入到重量比为3.5:1(w/w)的山药和穿龙薯蓣的混合草药提取物中而配制所述用于预防和治疗神经退行性疾病的药物制品。
配制本发明药物制剂所需的草药提取物包括与总重量相比，0.01-80%，优选1-50%重量的所述提取物。
可包括于本发明组合物中的载体、稀释液或稀释剂可以是乳糖、右旋葡萄糖、蔗糖、山梨醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯(prophylhydroxybenzoate)、滑石、硬脂酸镁或矿物油。
此外，可以根据常规方法，以口服剂(例如散剂，颗粒剂，片剂，胶囊剂，悬浮液，乳剂，糖浆或气雾剂)、外用制剂、栓剂或无菌注射溶液的形式配制和使用本发明的组合物。
特别地，所述药物制品可以采用稀释液或稀释剂制备，例如常用的过滤料(filter)，膨胀剂，粘合剂，湿润剂，崩解剂或表面活性剂。用于口服给药的固态药物制剂包括片剂、丸剂、散剂、颗粒剂和胶囊剂。所述固态药物制剂可通过将至少一种或多种稀释剂加入到所述草药复合物中而配制，此类稀释剂例如淀粉、碳酸钙、蔗糖、乳糖或明胶。此外，除所述的稀释剂外，还可有例如硬脂酸镁或滑石的润滑剂。液态药物制剂包括悬液、用于内服的药液、乳剂或糖浆。除经常使用的简单稀释液(如水和液体石蜡)外，还可以包括各种稀释剂，如湿润剂、甜味剂、清新剂(air freshener)或防腐剂。用于肠胃外施用的药物制剂包括无菌溶液、非水溶剂、悬液、乳剂、冻干剂或栓剂。丙二醇(prophyl glycol)、聚乙二醇、植物油(例如橄榄油)或可注射酯(例如油酸乙酯)可被用作非水溶剂或悬液。对于栓剂，可采用witepsol、聚乙二醇、吐温61、可可脂、laurinum或甘油明胶。
根据本发明的另一方面，本文提供了用于治疗神经退行性疾病的方法，其中向包括人在内的哺乳动物施用药学活性量的药物组合物，所述药物组合物包含作为活性成分的以3.5:1的重量比混合的山药和穿龙薯蓣的草药提取物。
所述包含以3.5:1的重量比混合的山药和穿龙薯蓣的草药提取物的药物组合物的剂量依赖于患者的年龄、性别和体重，但也可以施用0.01到10g/kg，优选1到5g/kg的量，该剂量可以一天一次或一天分多次地施用。此外，所述剂量可依据注射途径、疾病程度、性别、体重、年龄、健康状况、饮食、注射时间、注射方法或排出率而增加或降低。因此，所述剂量无意于以任何方式限制本发明的范围。
包含本发明的以3.5:1(w/w)的重量比混合的山药和穿龙薯蓣的草药提取物的药物组合物可通过各种途径施用给哺乳动物，例如大鼠、小鼠、牛或人。所有的施用方式均可预期，例如，口腔、直肠或静脉、肌肉、皮下、子宫内膜或脑室内注射。
本发明的以3.5:1的重量比混合的山药和穿龙薯蓣的草药提取物几乎从未显示过毒性或副作用，因此，出于预防的目的而长期用药是安全的。
本发明人采用所述以3.5:1的重量比混合的山药和穿龙薯蓣的草药提取物研究了在实验动物中对神经细胞增殖、促进神经突形成和通过增加神经生长因子的量以提高认知能力的效果。随后，通过对实验动物模型或细胞的试验，发现与山药和穿龙薯蓣的单独提取物相比，以及与两者的其他比例相比的显著协同作用。
此外，本发明提供了用于预防或改善神经退行性疾病的保健功能性食品。
本文所使用的术语“保健功能性食品”，意在包括那些在“2002年保健功能型食品法”(“2002Law for health functional foods”)中所定义的那些，例如根据韩国食品药品管理局的KFDA通告No.2004-12号，在规定了经证实对人具有功能性且安全的保健功能性食品材料或原料的名单中的保健食品。
更具体地，本发明提供了用于预防或改善神经退行性疾病的保健功能性食品，其包含以3.5:1的重量比混合的山药和穿龙薯蓣的草药提取物以及营养学上可接受的食物添加剂。
所述包含以3.5:1的重量比混合的山药和穿龙薯蓣草药提取物的组合物可应用于药物、食品或饮品以缓解神经退行性疾病的症状。例如，可加入本发明草药提取物的食品包括饮料、口香糖、茶、复合维生素和辅食。对于在药物中应用，药草提取物可以是丸剂，散剂，颗粒剂，片剂，胶囊剂或液体的形式。
当应用于固态食品时，本发明的草药提取物以基于所述食品总重量的0.1到15重量%的食品量使用，并且优选0.2到10重量%的量。在液态形式的保健品中，本发明的草药提取物的量可以在每100mL液体0.1到30g的范围，优选0.2到5g。
除必需草药成分的给定的特定比例外，对于液态保健组合物没有特别的限制。如典型的饮料一样，该液态保健组合物可进一步包含各种风味剂，天然碳水化合物，或其他添加剂。
天然碳水化合物的优选实例包括单糖，如葡萄糖，果糖等；二糖，如麦芽糖，蔗糖等；多糖，如糊精，环糊精等；和糖醇，如木糖醇，山梨糖醇，赤藓糖醇等。可用于本本发明的风味剂可以是天然的(索马甜(thaumatin)，甜叶菊提取物(例如，莱鲍迪甙A，甘草甜素)，或合成的(糖精，阿斯巴甜)。天然碳水化合物的用量可以为每100毫升液态保健组合物，大约1到20g，且优选为大约5到12g的量。
另外，本发明的组合物可含有各种营养素、维生素、矿物质(电解质)、合成的和/或天然的风味剂、着色剂、填料(奶酪，巧克力等)、果胶酸及其盐、海藻酸及其盐、有机酸、保护性的胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、醇类，以及碳酸饮料的碳酸化剂。在用于天然果汁、果汁饮料或蔬菜汁饮料时，本发明的组合物可进一步含有果肉。这些添加剂可单独或组合使用。典型但并不重要地，所述添加剂的量为每100重量份的组合物，约0到20重量份。
本发明的有益效果
该以3.5:1的重量比混合的山药和穿龙薯蓣的草药提取物对于增加体内神经生长因子(NGF)的量，增加神经细胞增殖、促进神经突形成，以及提高认知能力具有协同效果。因此，本发明的草药提取物可用于预防或改善神经退行性疾病的药物组合物和保健食品。
附图说明
图1是脑组织海马区的照片，其说明了根据实施例1采用NGF免疫组化方法对神经生长因子分泌效果进行评价的结果。
具体实施方式
现将以实施例的方式对本发明作进一步详细地说明。对于本领域技术人员而言显而易见的是，这些实施例的目的在于更具体地阐明，而本发明的保护范围由后附的权利要求所限定，并不限于或受限于这些实施例。
<实施例1>山药和穿龙薯蓣混合草药提取物的制备
山药和穿龙薯蓣均为干燥状态，购自从韩国Kyoungdong市场的中草药商店。将草药去除杂质后以切刀剁碎，并按山药：穿龙薯蓣为3.5:1的重量比混合。对于2kg混合物添加10L50%的乙醇溶液，随后，在室温下搅拌保温48小时。通过过滤移除草药混合物，并将滤液真空浓缩并冷冻干燥以获得混合的草药提取物(粗提物)(见表1)
表1：混合草药提取物的产率
<比较例1和2>草药粗提物的制备
1.山药粗提物的制备
2kg实施例1所使用的同样的山药，将搅拌的10L50%的乙醇溶液加入到搅拌的2kg实施例1所使用的同样的山药中，室温处理48小时。在提取、过滤并减压浓缩后，最终通过冷冻干燥获得山药粗提物的提取物(见表2)。
表2：山药提取物的产率
2.穿龙薯蓣粗提物的制备
将10L50%的乙醇溶液加入到2kg实施例1所使用的同样的穿龙薯蓣中，并在室温搅拌48小时。在提取、过滤和减压浓缩后，最终通过冷冻干燥获得穿龙薯蓣的提取物(粗提物)(见表3)。
表3：穿龙薯蓣提取物的产率
<比较例3到10>山药和穿龙薯蓣的混合草药提取物的制备
采用实施例1所使用的同样的山药和穿龙薯蓣草药。将山药和穿龙薯蓣用切刀剁碎，并以表4所列的重量比混合。对于2kg的每种混合物添加10L50%乙醇溶液，随后，在室温下搅拌保温48小时。通过过滤移除草药混合物，并将滤液真空浓缩并冷冻干燥以获得混合的草药提取物(粗提物)。(见表4)
表4：混合草药提取物的产率。
<实验例1>草药提取物对于增加神经生长因子分泌的效果
使用产生NGF的大鼠神经胶质瘤细胞系，C6胶质瘤，鉴定了实施例1对于增加和促进NGF分泌的效果。比较例1到10作为该实验的对照组。
将C6细胞与DMEM(添加5%FBS，2mM L-谷氨酰胺，10mM HEPES,1mM丙酮酸钠，50μg链霉素，100U/ml青霉素)培养基，于37℃，5%CO2条件下培养于24孔细胞培养板中。在调节培养细胞浓度到2×105细胞/孔之后，以100、250和500μg/ml进行实施例1，比较例1到10的处理。在同一培养条件下培养细胞2天，然后采用ELISA测定培养基中的NGF的浓度。(见表5)
表5：增加NGF分泌量的效果
如表5所示，NGF的浓度随着山药和穿龙薯蓣的浓度而增加。此外，还显示出NGF的浓度在山药中(比较例1)比在穿龙薯蓣中(比较例2)增加程度更大，因此前者显示出更显著的效果。
尽管实施例1(山药：穿龙薯蓣=155：45)注射的山药浓度较之比较例1(山药为200)少了25%，但在相同浓度下NGF的含量提高了8.9%到15.5%。
此外，与比较例5(山药：穿龙薯蓣=167:33，5:1)相比，实施例1中NGF的浓度多增加大约4.2%到16.4%；与比较例6(山药：穿龙薯蓣=182:18，10:1)相比，则多增加8.9%到16.4%，其中比较例5中山药的注射量多了7.7%，比较例6中山药的注射量多了17.4%。与比较例4(山药：穿龙薯蓣=133:67，2:1)相比，实施例1中NGF的量多增加大约4.4%到12.9%，其中比较例4中的山药注射量少了14.2%。其显示出比其他比较例显著增加的NGF含量。
因此，发现与其他混合比例相比，包含重量比为3.5:1的山药和穿龙薯蓣混合提取物的本发明疾病的药物组合物能有效地增加NGF浓度。所以，其可被用于治疗或预防神经退行性疾病。
在下文中，根据NGF含量，对山药和穿龙薯蓣的草药提取物在细胞增殖、神经突形成和认知能力方面的促进作用进行了比较实验。由此探讨了其用于预防或治疗神经退行性疾病的有效性。
<实验例2>草药提取物对促进认知能力的作用
将由Daehan Biolink(韩国忠清北道)提供的ICR小鼠(雄性，6周龄，25-28g)在庆熙大学(Kyunghee university)药学院干净的笼子里培养并适应7天后使用。允许其随意取食(Daehan Biolink，韩国忠清北道)和饮水。自动控制温度(22±2℃)，湿度(53±3%)和光暗(12小时)循环。
每组分配10只小鼠。对照组小鼠按每kg体重5mL剂量口服施用生理盐水。将分别溶于生理盐水溶液中的10mg/kg、100mg/kg的实施例1，比较例1到10的物质口服施用给实验组小鼠。口服施用一天一次，并在最后一次口服施用后一小时，按照下述进行被动避暗实验(passive avoidance test)。
在具有大小相等的两个连通(在分隔墙上修建了7×7cm的滑动门)隔室的改进型穿梭器(modified shuttle)中进行被动避暗实验，并且使用不锈钢棒地面。右手侧的隔室(电击隔室)涂成黑色以作为暗室。左手侧的隔室以安装于顶部有机玻璃罩上的灯泡(24V；5W)照明。第一天，将亮室的灯打开而在暗室关闭。让小鼠在亮室停留10秒后，由本发明人打开闸门，并随后测定直到有小鼠进入暗室的时间。当小鼠进入暗室时，关闭闸门，使其受到0.3mA的电刺激3秒。24小时后，以同样的方法再次进行被动避暗实验，并测定停留在亮室的延迟时间。结果显示于表6中。
表6：在被动避暗实验中提高认知能力的作用
如表6所示，山药给药组的滞留延迟时间比穿龙薯蓣给药组增加；与比较例1(山药为200)相比，实施例1(山药：穿龙薯蓣=155:45)的滞留延迟时间增加8.9%到22.2%，虽然实施例1较之比较例1(山药为200)的山药施用量少了25%。
同样地，与比较例5(山药：穿龙薯蓣=167:33，5:1)相比，实施例1的滞留延迟时间增加了4.2%到19%；与比较例6(山药：穿龙薯蓣=182:18，10:1)相比，则多增加了7.3%到25.6%，其中，比较例5中的山药注射量多了7.7%，比较例6中山药的注射量多了17.4%。与比较例4(山药：穿龙薯蓣=133:67，2:1)相比，实施例1的滞留延迟时间增加了8.9%到19%，其中比较例4中的山药注射量少了14.2%。其显示记忆力比其他比较例显著提高。
因此，发现与其他混合比例相比，包含重量比为3.5:1的山药和穿龙薯蓣的混合提取物的本发明疾病的药物组合物具有改进认知能力的作用。
<实验例3>草药提取物对促进神经元产生的作用
将完成实验例2测试后，从每组小鼠分离海马区。在使用过氧化氢对分离的海马区进行脱水后，以5-溴-2-脱氧尿苷(BrdU，santa cruz，鼠源1:500)作为一抗反应过夜。然后，使用生物素化的抗大鼠(vector，羊源)抗体作为二抗，并且在ABC反应(ABC试剂盒，vector)后，通过使用二氨基联苯胺显色。通过计数海马区齿状回区域中BrdU阳性细胞确定对神经细胞产生的促进作用。结果显示于表7中。
表7：促进细胞产生的作用
如表7所示，在对海马区齿状回区域中的BrdU阳性细胞计数时，山药(实施例1)较之穿龙薯蓣(比较例2)显示出增加的BrdU阳性细胞数量。尽管实施例1注射的山药量较之比较例1少25%，但BrdU阳性细胞的数量多增加了大约25%。
此外，与比较例5和比较例6相比，实施例1中的BrdU阳性细胞数量多增加了大约25%，其中比较例5中的山药注射量比实施例1多了7.7%，比较例6中山药的注射量比实施例1多增加了17.4%。与比较例4相比，实施例1中的BrdU阳性细胞数量多增加大约20%，其中比较例4中的山药注射量比实施例1少了14.2%。其显示出比其他比较例更为显著地增加的BrdU阳性细胞数量。
因此，发现与其他混合比例相比，包含重量比为3.5:1的山药和穿龙薯蓣混合提取物的本发明疾病的药物组合物具有增强海马齿状回区域中的神经细胞产生的作用。
<实验例4>草药提取物对神经细胞分化和促进神经突生长的作用
将完成实验例2测试后，从每组小鼠分离海马区。在使用过氧化氢脱水后，以双皮质素(DCX，santa cruz，羊源1:500)作为一抗反应过夜。然后，以生物素化的抗羊(vector，马源)抗体作为二抗，并且，在ABC反应(ABC试剂盒，vector)后，通过使用二氨基联苯胺显色。通过计数海马区齿状回区域中的DCX阳性细胞确定对细胞分化和促进神经突生长的作用。结果显示于表8中。
表8：对细胞分化和促进神经突生长的作用
如表8所示，在海马区齿状回区域中，山药(实施例1)比穿龙薯蓣(比较例2)显示出增加的DCX-阳性细胞数量以及DCX-阳性神经突长度。尽管实施例1注射的山药量较之比较例1少25%，但是其DCX-阳性细胞数量以及DCX-阳性神经突长度分别多增加了大约25%到40%和1.6%到17.3%。
此外，与比较例5(山药注射量比实施例1多了7.7%)相比，实施例1中的DCX-阳性细胞数量以及DCX-阳性神经突长度分别多增加了大约18%到27%和3.3到9.2%。与比较例6(山药的注射量比实施例1多了17.4%)相比，实施例1中的DCX-阳性细胞数量以及DCX-阳性神经突长度分别多增加了大约22.8%到32.6%和3.3%到10%。与比较例4(山药的注射量比实施例1少14.2%)相比，实施例1的DCX-阳性细胞数量以及DCX-阳性神经突长度分别多增加了大约20%到30%和1%到8%。其显示出比其他比较例更为显著地增加的DCX-阳性细胞数量以及DCX-阳性神经突长度。
因此，发现与其他混合比例相比，包含重量比为3.5:1的山药和穿龙薯蓣混合提取物的本发明疾病的药物组合物，具有对齿状回区域中的神经细胞分化和促进神经突生长的作用。
<实验例5>草药提取物对促进体内NFG分泌的效果
将完成实验例2测试后，从对照组和注射了混合提取物(山药：穿龙薯蓣=3.5:1提取物)的实验组小鼠分离海马区。以抗神经生长因子(NGF，abcam，兔源1:500)作为一抗反应过夜，然后，以生物素化的抗大鼠(vector，羊源)抗体作为二抗。随后，在ABC反应(ABC试剂盒，vector)后，通过使用链霉亲和素进行荧光显色。通过计数海马门区域中的NGF阳性细胞确定对NGF分泌的促进作用。结果显示于图1中。
如图1所示，实施例1的草药提取物对于促进海马区NGF的分泌具有显著作用。
因此，发现与其他混合比例相比，包含重量比为3.5:1的山药和穿龙薯蓣混合提取物的本发明的药物组合物具有协同作用。所以，本发明的药物组合物可被用于预防或治疗神经退行性疾病，包括阿尔茨海默病、克-雅氏病、亨廷顿氏病、多发性硬化、格林-巴利综合征、帕金森病、洛盖赫里格病、由逐渐的神经细胞死亡导致的麻痹性痴呆、进行性失调所引起的疾病、姿势和运动异常、进行性共济失调、肌肉萎缩和虚弱，以及感觉和行动障碍。
现将通过制备例进一步详述实施例1公开的包含草药提取物的组合物。其无意于限制权利要求的保护范围，而仅作以具体地解释。
配制例1：注射剂的制备
向所述组分的混合物添加无菌水以构成2ml的总体积，然后将溶液装入2mL的安剖瓶，灭菌以获得注射剂。
配制例2：片剂的制备
将所述组分混合，采用制片方法压制成片剂。
配制例3：胶囊的制备
将所述成分混合，并按照常规方法装入明胶胶囊中以获得胶囊。
配制例4：液态制剂的制备
加入纯水，形成100mL的总体积
将上述组分混合，装入到100mL棕色瓶中，并灭菌以获得液态制剂。
Claims (5)
1.一种用于预防或治疗神经退行性疾病的药物组合物，其包含作为活性成分的重量比为3.5:1(w/w)的山药(Dioscorea Rhizoma)和穿龙薯蓣(Dioscorea nipponica)的混合草药提取物，以及药物可接受的载体。
2.根据权利要求1的用于预防或治疗神经退行性疾病的药物组合物，其中所述神经退行性疾病选自以下组中：阿尔茨海默病、克-雅氏病、亨廷顿氏病、多发性硬化、格林-巴利综合征、帕金森病、洛盖赫里格病、由逐渐的神经细胞死亡导致的麻痹性痴呆和由进行性失调所引起的疾病。
3.一种用于预防或治疗神经退行性疾病的保健功能性食品组合物，其包含重量比为3.5:1(w/w)的山药和穿龙薯蓣的混合草药提取物。
4.根据权利要求3的保健功能性食品组合物，其中所述草药提取物是以50%乙醇提取的粗提物。
5.根据权利要求3的保健功能性食品组合物，其中所述草药提取物制备成选自以下的形式：散剂、颗粒剂、片剂、胶囊剂、糖浆和饮料。
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| CN101108230A (zh) * | 2006-07-19 | 2008-01-23 | 成都地奥制药集团有限公司 | 地奥心血康缓释制剂及其制备方法和用途 |
| CN101296703A (zh) * | 2005-10-28 | 2008-10-29 | 金善砺 | 薯蓣科提取物及包含此提取物、用于预防或治疗外周神经疾病的组合物 |
| CN101791365A (zh) * | 2010-03-10 | 2010-08-04 | 深圳市药品检验所 | 穿龙薯蓣提取物及其在制备抗自由基、降血脂药物中的应用 |
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| KR20070018570A (ko) * | 2005-08-10 | 2007-02-14 | 대구한의대학교산학협력단 | 육미지황탕을 포함하는 치매 예방 및 치료용 조성물 |
| KR100811683B1 (ko) | 2006-11-21 | 2008-03-11 | 영남대학교 산학협력단 | 마 추출물을 유효성분으로 포함하는 장 기능 개선용 조성물및 이를 함유하는 기능성 건강식품 |
| KR20100002668A (ko) | 2008-06-30 | 2010-01-07 | 강원대학교산학협력단 | 항당뇨 조성물 |
| KR20100084926A (ko) * | 2009-01-19 | 2010-07-28 | 주식회사 유니베라 | 염증, 알러지 질환 또는 성인병의 예방 또는 치료용 산약 추출물 |
| BR112012023139A2 (pt) | 2010-03-24 | 2018-06-26 | Dong A Pharm Co Ltd | composição farmacêutica para a prevenção ou o tratamento de doença do fígado gordo não alcóolico e o método para a prevenção ou tratamento de doença do fígado gordo não alcóolico usando a mesma. |
| KR101180174B1 (ko) | 2010-04-23 | 2012-09-05 | 동아제약주식회사 | 신규한 벤즈아미드 유도체 |
| WO2012070700A1 (ko) | 2010-11-24 | 2012-05-31 | 동아제약주식회사 | 퀴놀린 유도체 화합물, 이의 제조방법 및 이를 포함하는 약학 조성물 |
| JP5599519B2 (ja) | 2010-11-24 | 2014-10-01 | ドン−ア エスティ カンパニー リミテッド | キノリン誘導体化合物、その製造方法およびそれを含む薬学組成物 |
| KR101341692B1 (ko) | 2011-03-16 | 2013-12-20 | 동아에스티 주식회사 | 복합생약추출물을 함유하는 당뇨병성 말초 신경병증의 치료 및 예방을 위한 조성물 |
| KR101341693B1 (ko) | 2011-03-16 | 2013-12-16 | 동아에스티 주식회사 | 생약추출물을 함유하는 퇴행성 신경질환의 치료 및 예방을 위한 조성물 |
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- 2011-12-29 ES ES11861135.9T patent/ES2583652T3/es active Active
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- 2011-12-29 CN CN201180070066.2A patent/CN103608025B/zh active Active
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1212966A (zh) * | 1997-09-26 | 1999-04-07 | 中国人民解放军军事医学科学院放射医学研究所 | 甾体皂甙防治老年性痴呆的用途及新的甾体皂甙 |
| CN101296703A (zh) * | 2005-10-28 | 2008-10-29 | 金善砺 | 薯蓣科提取物及包含此提取物、用于预防或治疗外周神经疾病的组合物 |
| CN101108230A (zh) * | 2006-07-19 | 2008-01-23 | 成都地奥制药集团有限公司 | 地奥心血康缓释制剂及其制备方法和用途 |
| CN101791365A (zh) * | 2010-03-10 | 2010-08-04 | 深圳市药品检验所 | 穿龙薯蓣提取物及其在制备抗自由基、降血脂药物中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2013146104A (ru) | 2015-04-27 |
| ES2583652T3 (es) | 2016-09-21 |
| CN103608025B (zh) | 2015-12-02 |
| JP5763223B2 (ja) | 2015-08-12 |
| PL2685998T3 (pl) | 2016-11-30 |
| KR20120105859A (ko) | 2012-09-26 |
| EP2685998B1 (en) | 2016-04-20 |
| WO2012124887A2 (en) | 2012-09-20 |
| JP2014509609A (ja) | 2014-04-21 |
| EP2685998A2 (en) | 2014-01-22 |
| US20200397845A1 (en) | 2020-12-24 |
| HUE029956T2 (en) | 2017-04-28 |
| US20170216390A1 (en) | 2017-08-03 |
| EP2685998A4 (en) | 2014-08-20 |
| KR101341693B1 (ko) | 2013-12-16 |
| PT2685998T (pt) | 2016-07-28 |
| US10709752B2 (en) | 2020-07-14 |
| US20140044817A1 (en) | 2014-02-13 |
| WO2012124887A3 (en) | 2012-11-08 |
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