CN107106624B - 预防、改善或治疗退行性神经***疾病的含桑葚和茯苓皮的混合提取物的组合物 - Google Patents
预防、改善或治疗退行性神经***疾病的含桑葚和茯苓皮的混合提取物的组合物 Download PDFInfo
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Abstract
本发明涉及用于预防、改善或治疗退行性神经***疾病的、含桑葚和茯苓皮的混合提取物作为活性成分的组合物,及其应用。本发明组合物中所含的作为活性成分的桑葚和茯苓皮的混合提取物通过抑制β淀粉样肽的形成、抑制tau蛋白磷酸化并且促进NGF生成而具有保护神经元的功能,并且通过保护神经元和抑制乙酰胆碱酯酶而具有提高记忆力的功能,从而能用于预防或治疗退行性神经***疾病的药物组合物,或用于相同目的的功能性食品中。
Description
技术领域
本发明涉及一种用于预防、改善或治疗退行性神经***疾病的、含桑葚和茯苓皮的混合提取物的组合物。
背景技术
退行性神经***疾病是其中心智功能由于神经细胞(神经元)逐渐发生结构和功能性的丢失而恶化的疾病。由于神经***特定区域中的神经细胞发生退行性变性,退行性神经***疾病可能伴随诸如痴呆、锥体外系异常、小脑异常、感觉障碍和运动障碍等症状。此外,由于同时发生多种异常而可能出现复杂的症状。按照患者的临床表现对疾病进行诊断。但是症状差异很大,不同的疾病常常具有相同的临床症状,这使得诊断很困难(Soc.Sci.Med.Vol.40.No.6,pp.847-858,1995)。
在退行性神经***疾病中,疾病的症状是慢慢发展的,而且该疾病常常是由衰老引起的。一旦疾病已经显现出来,就会持续进行数年或数十年,直至死亡,并且根本治疗很困难,因此增加了社会负担。已知遗传影响,诸如家族史,很可能是疾病的病因,但获得性因素也起到重要作用。按照其临床症状,可对退行性神经***疾病进行分类,例如进行性痴呆(阿尔茨海默氏病等)、神经***障碍(例如皮克病)、姿势和运动障碍(例如帕金森氏病)、进行性共济失调、肌肉萎缩和无力,以及感知和运动障碍等(International Journal ofEngineering and Technology,Vol.2,No.4,August 2010Classification ofNeurodegenerative Disorders Based on Major Risk Factors Employing MachineLearning Techniques)。
Aβ斑块和过磷酸化tau蛋白缠结的细胞毒性作为阿尔茨海默氏痴呆(一种典型的退行性脑病)的直接病因正在得到关注。
Aβ是从前体APP,通过诸如β-分泌酶和γ-分泌酶等酶的作用而生成,分布在神经细胞外部。当Aβ浓度低时,它处于溶解状态,但当高于一定水平时,Aβ蛋白之间结合而形成不溶的老年斑(senile plaque)。该物质可通过导致炎症和神经毒性,而破坏周围的神经细胞。例如,已知在阿尔茨海默氏病患者中观察到的神经元死亡和小神经胶质细胞增生与老年斑相关。体外测试示出Aβ能诱导小神经胶质细胞活化(脑巨噬细胞)。这支持了在阿尔茨海默氏病患者脑部中发现的小神经胶质细胞增生和脑部炎症是Aβ诱导的阿尔茨海默氏病的主要病因的假说。迄今为止,还没有被广泛接受的预期一旦形成老年斑就可显著溶解Aβ,或预防沉积物形成的疗法或治疗药物。
tau蛋白由四部分组成:N末端突出部,脯氨酸聚集结构域、微管结合结构域和C-末端(Mandelkow et al.,Acta.Neuropathol.,103,26-35,1996)。它起到连接微管的作用,其中微管形成神经细胞的物理结构。已知在中枢神经***的神经细胞中的tau蛋白经异常过磷酸化或修饰,会导致退行性脑病,例如tau蛋白病变(tauopathy)。阿尔茨海默氏病(Alzheimer's disease)、皮克病(Picks disease)、17号染色体相关的额颞痴呆合并帕金森症(FTDP-17)等是典型的tau蛋白病变(Lee et al.,Annu.Rev.Neurosci.,24,1121-1159,2001;Bergeron et al.,J.Neuropathol.Exp.Neurol.,56,726-734,1997;Bugianiet al.,J.Neuropathol.Exp.Neurol.,58,667-677,1999;Delacourte et al.,Ann.Neurol.,43,193-204,1998;Ittner and Gotz,Nat.Rev.Neurosci.,12,65-72,2011)。
在二十世纪八十年代对阿尔茨海默氏病的研究中,暗示神经营养因子具有对退行性神经***疾病的治疗潜力(Nature.1987Sep 3-9;329(6134):65-8.Amelioration ofcholinergic neuron atrophy and spatial memory impairment in aged rats bynerve growth factor)。研究示出了通过向侧脑室给予神经生长因子(NGF)恢复了基底前脑中的胆碱能神经元,从而使实验动物的记忆力得到改善,其中胆碱能神经元由于衰老而丢失,并已知是阿尔茨海默氏病的病因之一。因此,对使用神经营养因子来治疗退行性神经***疾病进行了持续研究。在后来的研究中,通过将脑源性神经营养因子(BDNF)、神经营养蛋白-3(NT-3)、神经营养蛋白-4(NT-4)和睫状神经营养因子(CNTF)(这些是神经营养因子家族)注射到由于面神经和坐骨神经结节而运动神经功能受损的实验动物中,进行了恢复运动神经功能的研究,并且获得了阳性结果(Nature.1992Dec24-31;360(6406):757-9.Brain-derived neurotrophic factor prevents the death of motoneurons innewborn rats after nerve section)。进一步地,在使用患运动神经元的数量和功能随着年龄增长而逐渐丧失的疾病的重组小鼠(wobbler)的实验中,通过给予小鼠BDNF和CNTF,使运动神经元的数量增加,并且改善了功能(Science.1994Aug 19;265(5175):1107-10.Arrest of motor neuron disease in wobbler mice co-treated with CNTF andBDNF)。除了上述研究之外,还报道了神经营养因子通过增加多种感知和运动神经病变模型中的神经元的数量和功能,改善了实验动物的记忆、认知和行为障碍。
桑葚的学名是Morus alba(桑椹子),当落叶桑树的果实呈洋红色时,采摘果实并进行干燥,用作草药。在东方医学中,已知桑葚用于治疗头晕,耳鸣,口渴和糖尿病等。在日本,桑葚具有治疗养血祛风和风热,并且已知用于治疗例如滋补、止痛、失眠、耳鸣、头晕、背痛和便秘等(Namba,T.,The Encyclopedia of Wakan-Yaku with Color PicturesVol.1Hoikusha,Osaka,Japan,1993)。在《东医宝鉴》中,桑葚治疗口渴并且有益于五脏,桑葚具有桑树的生命力(精)(Donguibogam korean translation committee,Donguibogam,Namsandang,Seoul,Korea,2000)。在中国的药典(CP)里,也将桑葚描述为用于治疗头晕、耳鸣、失眠和口渴等的药物。
桑葚具有作为主要组分的花青素、酚酸和黄酮类等,并且已经报道了分离的单一组分和它的提取物具有降低血糖、MAO(单胺氧化酶)抑制活性、抗氧化效果和神经元细胞保护效果。
茯苓(茯)的学名是Poria cocos。茯苓在分类上属于真担子菌纲、层菌亚纲,非褶菌目,多孔菌科的真菌。茯苓是一类属于杆菌的真菌,是褐腐菌,是在松树中的一类腐生生物,但也寄生于活的松树的根部。菌丝体生长,同时长出白色分枝,并且菌丝开始长在一起。当适当的环境条件,诸如温度和湿度持续存在时,形成菌核硬块,这被称为茯苓。根据内部的颜色,白色的是白茯苓,淡红色的是赤茯苓。茯苓的外皮被称为茯苓皮。
茯苓的主要成分是茯苓酸(C33H52O5)、松苓酸(C30H18O3)、松苓新酸(3β羟基-7,9(11),24-羊毛甾三烯-21-酸(3β-Hyderoxy-lanosta-7.9(11),24-Trien-21-oic acid)、土莫酸(C31H50O)和齿孔酸(C31H50O3)等。还含有破坏敏酸齿孔酸、聚亚苯基酸A和C和三萜系化合物等。并且,还含有麦角甾醇、卵磷脂、腺嘌呤、胆碱、葡萄糖、果糖和蛋白质,以及大量的无机物质。
茯苓味甘性暖,味道和性质均轻,故为良性的药物物质。在过去的文献中,记载了茯苓可缓解口渴、便于排尿、去湿气、适当地调整身体状态,通过协调消化***的功能而增加能量,并且通过舒缓腰部来改善腹部淤血的血液循环。茯苓皮主要用于与记忆力相关的药方。在最近的文献中,报道了茯苓具有抗糖尿病和抗癌效果(Ling Hui,Evaluation ofthe chemotherapeutic and chemopreventive potential of triterpenoids fromPoria cocos,Ling Hui,doctoral thesis of department of pharmacy,NationalUniversity of Singapore,2010)。
茯苓皮是属于多孔菌科的茯苓菌核的外皮。已知作为药用物质,具有利水消肿的效果。它尤其含有丰富的羊毛甾烷类三萜茯苓新酸,并且《东医宝鉴》中记载了茯苓皮用于水肿药方的五皮散(橘皮、大腹皮、茯苓皮、生姜皮、桑白皮)的成分。在最近的研究中,报道了茯苓皮具有如利尿、促进排尿、消除水肿等治疗效果(Triterpenes from the surfacelayer of Poria cocos,Takaaki tai,Phytochem,39,5,1995;Urinary metabonomicstudy of the surface layer of Poria cocos as an effective treatment forchronic renal injury in rats,ying yong zhao et al,Journal ofEthnopharmacology,148,2,2013)。
在这一背景下,本发明人进行了研究,以开发用于有效预防、改善和治疗退行性神经***疾病的药物组合物和食品组合物的材料。结果,在研究桑葚和茯苓皮的神经心理活性过程中,本发明的发明人证明了这些草药提取物在由多种脑损伤或记忆抑制药物所诱导的脑神经病变模型中,显示出显著的记忆恢复活性。此外,这些草药提取物示出抑制导致脑中神经细胞死亡的物质的生成,并且通过促进促神经细胞再生和分化的蛋白的表达来保护神经细胞。本发明人通过证明与单一组分的草药提取物相比,当桑葚和茯苓皮的草药提取物以一定比例混合时,显示出最大效果,从而完成了本发明。
发明内容
【技术问题】
本发明的目的是提供用于预防和治疗退行性神经***疾病的药物组合物,和用于预防和改善退行性神经***疾病的健康功能性食品,所述药物组合物和所述健康功能性食品包含作为活性成分的桑葚和茯苓(学名:Poria cocos)皮的混合提取物。
【技术方案】
为了实现上述目的,本发明提供了用于预防和治疗退行性神经***疾病的药物组合物,和用于预防和改善退行性神经***疾病的健康功能性食品,所述药物组合物和所述健康功能性食品包含桑葚和茯苓皮的混合提取物。
【有益效果】
根据本发明,桑葚和茯苓皮的混合提取物抑制可通过诱导神经元死亡而导致退行性脑病的β-淀粉样肽(Aβ)的生成和tau蛋白的磷酸化,通过促进NGF(促神经细胞存活和分化的因子)生成而显示出保护神经细胞的效果。此外,它还显示出以下效果:抑制乙酰胆碱酯酶(AChE),从而提高神经传导且介导记忆增强作用。因此,桑葚和茯苓皮的混合提取物可有效用于开发预防和治疗退行性神经***疾病(包括痴呆)的药物组合物,或用于开发预防和改善退行性神经***疾病的健康食品。
附图说明
图1示出了在使用β-淀粉样肽诱导神经毒性的模型中,通过注射草药混合提取物、单一提取物和对照药物,并且使用神经细胞标记物NeuN染色所获得的结果。
图2示出了向使用β-淀粉样肽诱导神经毒性的模型,给予混合提取物、单一提取物和对照药物,并且使用细胞死亡标记物FJB染色所获得的结果。
具体实施方式
下面,将详细描述本发明。
本发明涉及用于预防或治疗退行性神经***疾病的药物组合物,所述药物组合物包含作为活性成分的桑葚(Mulberry)和茯苓(学名:Poria cocos)皮的混合提取物。
本发明的混合提取物可按照制备草药提取物的常规方法来提供,但具体指使用水、醇,或水和醇的混合物获得的粗提取物。为提取溶剂之一的醇可以是,但并不限于具有1至4个碳原子的低级醇,优选是甲醇、乙醇、丁醇或酒精,更优选是乙醇。在此,“酒精”指通过发酵淀粉原料或糖原料,并且进行蒸馏所产生的乙醇。进一步地,水和醇的混合溶剂不受特别限制,可以以任意期望的比例进行混合。
在本发明的一个实施方式中,桑葚和茯苓皮的混合提取物可以使用60%(v/v)~80%(v/v)的乙醇,65(v/v)%~75(v/v)%的乙醇或70(v/v)%的乙醇来提取,但并不限于此。
在本发明的另一实施方式中,桑葚和茯苓皮的重量比可以是4至7:1,4至6:1,或5:1,但并不限于此。
本发明的混合提取物包括所有形式的通过提取桑葚和茯苓混合物所获得的提取物,和通过分别提取桑葚和茯苓,然后混合各提取物所获得的提取物。具体地,以一定的重量比混合桑葚和茯苓皮并进行提取,或者通过适当的方法分别提取桑葚和茯苓皮,然后以一定的重量比混合各提取物。
更具体地,可以通过如下过程获得本发明的混合提取物。首先,分别洗涤并干燥桑葚和茯苓皮,然后切制干燥的草药以获得切制的草药。基于茯苓皮重量,以0.1至10倍的重量比,将干燥切制的桑葚与干燥切制的茯苓皮混合,优选地,以桑葚:茯苓皮=4至7:1的重量比混合来制备混合物。以混合物重量的1~20(v/w)倍或优选5~10(v/w)倍的量,将水、具有1至4个碳原子的低级醇或水和低级醇优选70(v/v)%乙醇的混合物,添加到桑葚和茯苓的混合物中。然后,在10℃至100℃的温度下,优选在室温下进行1至72小时的提取,优选通过以下方式进行48小时的提取:冷水提取,热水提取,超声提取,回流冷却提取,加热提取,超临界提取。优选地,所述提取可通过冷水提取进行一次,在减压下进行浓缩以产生桑葚和茯苓皮的混合提取物。
本发明的含桑葚和茯苓皮的混合提取物作为活性成分的组合物可用于治疗退行性神经***疾病。相应地,本发明提供了含桑葚和茯苓皮的混合提取物作为活性成分的、用于预防和治疗退行性神经***疾病的药物组合物,桑葚和茯苓皮的混合提取物在制备退行性神经***疾病的治疗剂中的应用,和治疗退行性神经***疾病的方法,该方法包括向个体给予治疗有效量的桑葚和茯苓皮的混合提取物。
如上所述,本发明的退行性神经***疾病指,由神经细胞(神经元)逐渐发生结构和功能性丢失所引起的心智功能退行性疾病。具体地,它包括选自由阿尔茨海默氏病、克雅二氏病、亨廷顿氏舞蹈病、多发性硬化症、格林-巴利综合征、帕金森氏病、卢伽雷氏病、进行性共济失调和由神经元逐渐死亡所引起的进行性痴呆等所组成的组中的疾病。
在本发明的一个实施方式中,用于预防和治疗退行性神经***疾病的药物组合物基于100重量份的全部药物组合物,可包含作为活性成分的0.01至90重量份、0.1至90重量份、1至90重量份、或10至90重量份的桑葚和茯苓皮的混合提取物,但并不限于此,可依据疾病的状态、类型和进展的不同而不同。
在本发明的另一实施方式中,含桑葚和茯苓皮的混合提取物作为活性成分的、用于预防和治疗退行性神经***疾病的药物组合物可被配制成用于预防和治疗退行性神经***疾病的药物制剂,该药物制剂包括药学上可接受的载剂、稀释剂或赋形剂。
载剂、赋形剂和稀释剂的实例包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、***胶、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、羟苯甲酯、羟苯丙酯、滑石、硬脂酸镁和矿物油。
为了将其制备成药剂形式,可按照常规方法将本发明的组合物配制成如下形式:口服制剂,例如粉剂,颗粒剂,片剂,胶囊,混悬剂,乳剂,糖浆剂和气雾剂;外用制剂,栓剂或无菌注射液。通常来讲,在配制的情况中,可通过使用常用的稀释剂如填充剂、增量剂、粘结剂、润湿剂、崩解剂、表面活性剂或赋形剂进行制备。口服给药的固体形式的制剂包括片剂、丸剂、粉剂、颗粒剂、胶囊等,可包含至少一种赋形剂,例如淀粉、碳酸钙、蔗糖、乳糖、明胶等。除了简单的赋形剂之外,还可使用润滑剂,例如硬脂酸镁和滑石。口服用液体制剂包括混悬剂、溶液、乳剂和糖浆剂。除了常用的简单稀释剂如水和液体石蜡之外,还可包括各种赋形剂,例如润湿剂、甜味剂、芳香剂、防腐剂等。肠胃外给药的制剂包括无菌水溶液、非水溶液、混悬剂、乳剂、冻干制剂和栓剂。悬浮剂的实例包括丙二醇,聚乙二醇,植物油如橄榄油,可注射性酯如油酸乙酯,等等。栓剂基质的实例包括外特坡松(witepsol)、聚乙二醇、吐温(tween)61、可可油脂、月桂酯和甘油明胶等等。
本发明提供了一种治疗退行性神经***疾病的方法,该方法包括向哺乳动物,包括人,给予治疗有效量的含桑葚和茯苓皮的混合提取物作为活性成分的药物组合物。
本发明的含桑葚和茯苓皮的混合提取物作为活性成分的、用于预防和治疗退行性神经***疾病的药物组合物的剂量可依据患者的年龄、性别和体重的不同而不同。通常,0.1至100mg/kg,优选1至30mg/kg的量可一天给药一次至几次。剂量也可依据给药途径、疾病程度、性别、体重、年龄、健康状态、饮食、给药时间、给药方法、***率等增加或减小。相应地,上述用量不是要以任何方式限制本发明的范围。
本发明的含桑葚和茯苓皮的混合提取物的药物组合物可以各种途径给予哺乳动物,例如大鼠、小鼠、牲畜和人。所有的给药方式均可预期,例如口服给药、直肠或静脉内给药、肌内给药、皮下给药、子宫内硬膜给药或大脑内注射给药。
本发明的桑葚和茯苓皮的混合提取物的毒副作用小,因此可用于预防目的而安全地长期使用。
本发明还提供了含桑葚和茯苓皮的混合提取物的食品组合物。桑葚和茯苓皮的混合提取物抑制导致脑中神经细胞死亡的物质的生成,促进促神经细胞再生和分化的蛋白的表达来保护神经细胞,从而可有效用于生产健康功能性食品和普通食品,该健康功能性食品和普通食品尤其可显示出预防和改善神经退行性疾病的效果。
具体地,本发明所限定的健康功能性食品被定义为:最近通过“2002年对于健康功能性食品的规定”所定义的,“韩国食品药品管理局的通知2004-12中规定的、已充分确立了在人体内的功能性和安全性的、健康功能性食品成分识别列表上的健康食品”。
本发明的含桑葚和茯苓皮的混合提取物的食品组合物可用于各种食品中以缓解退行性神经***疾病症状。可向其中添加本发明的草药提取物的食品是各种食品,例如饮料、口香糖、茶、维生素复合物、健康功能性食品和健康功能性饮料,并且可以丸剂、粉剂、颗粒剂、浸剂、片剂、胶囊或饮料的形式来使用。
在本发明的食品中,桑葚和茯苓皮的混合提取物的量通常为0.1wt%至15wt%,优选0.2wt%至10wt%,而在健康功能性饮料组合物的情况中,基于100mL饮料组合物,可包含0.1g至30g,优选0.2g至5g的桑葚和茯苓皮的混合提取物。
当本发明的食品组合物制备为饮料形式时,除了以所示比例含所述草药提取物作为必要成分的那些之外,对于液体成分没有特别限制。此外,如普通饮料那样,可添加各种调味剂或天然碳水化合物作为额外的成分。
上述天然碳水化合物的实例包括单糖,例如葡萄糖和果糖;双糖,例如麦芽糖、蔗糖等;多糖,如糊精、环糊精等;或糖醇,例如木糖醇、山梨糖醇和赤藓糖醇等。除了上面提到的天然调味料之外,可有利地使用天然调味剂(甘味料、甜菊提取物(如莱苞迪甙A、甘草甜素等))和合成的调味料(糖精、阿斯巴甜等)。天然碳水化合物的比例通常为每100ml本发明的总组合物约1g至20g,优选约5g至12g。
除了上面的描述之外,本发明的食品组合物可进一步包括各种添加剂,例如各种营养物、维生素、矿物质(电解质),调味剂例如合成的调味料和天然的调味料,色素和增稠剂,果胶酸及其盐,褐藻酸及其盐,有机酸,保护胶体增稠剂,pH调节剂,稳定剂,防腐剂,甘油,醇,碳酸饮料中使用的碳酸化剂等。此外,本发明的组合物可包括天然果汁和果肉,用于生产果汁饮品和植物饮品。这些成分可独立使用或组合使用。这些添加剂的比例不受特别的限制,但通常选自每100重量份的本发明的总食品组合物的0至约20重量份的范围内。
在另一实施方式中,本发明是用于预防、改善或治疗退行性神经***疾病的方法,所述方法包括给予含桑葚和茯苓皮的混合提取物的组合作为活性成分的组合物。或者,本发明提供了桑葚和茯苓皮的混合提取物在预防、改善或治疗退行性神经***疾病中的应用。用于所述方法或应用的所述含桑葚和茯苓皮的混合提取物的组合物的用量、剂型、给药方法等如上所述。
【本发明的实施方式】
将参考下面的实施例和实验,对本发明进行详细的解释。但是,下面的实施例和实验仅是用于示例本发明,本发明的范围并不限于此。
<实施例1>本发明的茯苓皮提取物的制备
在京东(Kyungdong)市场的草药店购买干燥的桑葚(Mulberry)和茯苓(Poriacocos)皮,去除污染物,将完全干燥的草药用于实验。经切割机切制的桑葚和茯苓皮以5:1的重量比混合300g的量。并且将3L 70(v/v)%的乙醇水溶液添加到草药混合物中,将混合物在室温冷却48小时。过滤后,在减压下浓缩混合物,然后进行冻干以获得实施例1的草药粗提物(粗提物)(参见表1)。
【表1】
本发明的茯苓皮和桑椹组合提取物的制备
<对比例1>桑葚提取物的制备
以与实施例1相同的方法,制备200g与实施例1相同的桑葚的植物性原料,以获得桑葚的粗提物用作对比例1(参见表2)。
<对比例2>茯苓皮提取物的制备
以与实施例1相同的方法,制备200g与实施例1相同的茯苓皮的植物性原料,以获得茯苓皮的粗提物用作对比例2(参见表2)。
【表2】
桑葚和茯苓皮的单一提取物的产量
<对比例3~8>桑葚和茯苓皮的混合粗提物的制备
将与实施例1中使用的桑葚和茯苓皮相同的植物性原料用于本实验。经切割机切制桑葚和茯苓皮,将桑葚和茯苓皮如表3中所示进行混合,然后将草药混合物10倍体积的70%的乙醇水溶液添加到草药混合物中,在室温对混合物进行冷提取48小时。在减压下浓缩之后,冻干混合物以获得草药粗提物(粗提物),用作对比例3~8。
【表3】
桑葚和茯苓皮的混合草药提取物的产量
<实验例1>对混合的草药提取物的记忆改善和神经细胞保护效果的测试
<1-1>实验动物的准备
东莨菪碱诱导的记忆受损(Scopolamine induced memory impairment)模型
六周龄ICR小鼠用于实验,并且每一实验组均由8只动物组成。在口服给予实施药物(实施例)、对比药物(对比例)和对照药物多奈哌齐(Donepezil)30分钟之后,腹腔内(i.p)给予1mg/kg东莨菪碱。向正常动物注射相同量的生理盐水。
在给予东莨菪碱30分钟之后,进行行为研究。
Aβ灌注模型
六周龄的ICR小鼠用于本实验。麻醉动物,固定在立体***(Stoelting)中,使用Hamilton微量注射器(配备有26号针头)注射3μL溶媒(vehicle)(人造CSF)或Aβ42 6分钟。
将经Aβ42处理的动物随机分成实验组。从给予Aβ422天后开始,每天给予一次实验药物和阳性对照药物持续给药11天。
将冻干的药物,对比药物和对照药物悬浮在3%HPMC水溶液中,所有药物均在实验当天制备。
测量脑中的蛋白
为了检验混合的草药提取物对神经细胞死亡诱导物或参与细胞保护的物质生成的效力,持续5天给予六周龄ICR小鼠实施药物、对比药物和对照药物。在第五天,给药后4小时,处死实验动物并且分离出脑。将除了小脑和延髓之外的部位用于本实验。
<1-2>被动回避测试(Passive avoidance task)
在两个独立分开的明亮方盒和黑暗方盒中进行被动回避实验。使用50W白炽灯对明亮区域(20×20×20cm)进行照明。明亮区域和黑暗区域(20×20×20cm)相隔1cm,并且安装了2mm不锈钢杆。
在习惯期期间,两个部分通过闸门(5×5cm)分隔开,将实验动物放置在明亮部分中30秒之后,打开闸门。允许动物自由通过。当它们抵达黑暗区域时,关闭闸门,3秒之后拿出动物。
24小时后进行获得实验(acquisition trial)。在给药30分钟后,腹腔内给予1mg/kg东莨菪碱,并且在30分钟之后进行行为实验。实验小鼠最初放置在明亮区域中,30秒之后打开区域之间的门。当实验小鼠进入黑暗区域中时,关闭闸门,通过不锈钢杆立即施加持续2秒,强度为0.5mA的电击(electrical foot shock),10秒之后取出动物。我们测量了动物进入黑暗区域的时间。
在进行获得试验并且给予了24小时休息时间之后,将实验动物放置在明亮区域中以进行保留试验(retention trial),测量直至进入黑暗区域的时间。获得试验和保留试验都测定小鼠的四只爪子全部从明亮房间进入黑暗房间所花费的时间。
结果如下面的表4和表5所示,证实了在东莨菪碱诱导的记忆丧失模型和Aβ42诱导的阿尔茨海默氏痴呆模型中,均具有改善记忆的效果。与桑葚和茯苓皮单一提取物的对比例1和对比例2,以及桑葚和茯苓皮混合提取物的对比例3~8相比,桑葚与茯苓皮的5:1混合物示出显著提高空间记忆的效果。实施例1的混合提取物示出与1mg/kg已知的乙酰胆碱酯酶抑制剂多奈哌齐(DPZ)相当或更高的效力。
【表4】
东莨菪碱模型-在被动回避实验中的记忆提高效力
【表5】
给予Aβ42的模型-在被动回避实验中的记忆提高效力
<1-3>Y-迷宫测试
进行Y-迷宫实验,来研究短期记忆效果。将动物放置在Y-迷宫的一个臂上,允许动物自由移动8分钟。测量自发交替(spontaneous alternation)和总进入次数。当动物相继进入三个臂时,它们被定义为交替(alternation)进入,通过下面的等式1计算比率。
[等式1]
自发交替率(%)=[(变换次数)/(总进臂数-2)]×100
结果如表6和表7所示,我们证实了在东莨菪碱诱导的记忆衰退模型和Aβ42诱导的阿尔茨海默氏痴呆模型中,均具有改善记忆的效果。具体地,与桑葚和茯苓皮单一提取物的对比例1和对比例2,以及桑葚和茯苓皮混合提取物的对比例3~8相比,实施例1的桑葚与茯苓皮的5:1混合物示出显著提高识别和记忆的效果。实施例1的混合提取物尤其示出比1mg/kg已知的乙酰胆碱酯酶抑制剂多奈哌齐(DPZ)好的效力。
【表6】
东莨菪碱模型-在Y-迷宫实验中的记忆提高效力
【表7】
给予Aβ42的模型-在Y-迷宫实验中的记忆提高效力
<1-4>新物体识别(NOR)测试
在45cm宽、45cm长和50cm高的黑暗盒子内,放置相同尺寸但不同形状的两个塑料物体。允许实验动物自用移动8分钟,测量在每一物体上花费的时间(训练过程)。24小时后,将实验动物放置在具有一个来自训练过程的熟悉物体和一个新物体的盒子中,测量在每一物体上花费的时间(测试过程)。使用下面的等式(2)计算记录的值,表示为新物体的识别结果。
[等式2]
新物体的识别率(%)=在新物体上花费的时间/(在新物体上花费的时间+在有经验的物体上花费的时间)×100
结果如表8和表9所示,我们证实了在东莨菪碱诱导的记忆衰退模型和Aβ42诱导的阿尔茨海默氏痴呆模型中,均具有改善记忆的效果。与桑葚和茯苓皮单一提取物的对比例1和对比例2,以及桑葚和茯苓皮混合提取物的对比例3~8相比,桑葚与茯苓皮的5:1混合物示出显著提高识别和记忆的效果。与1mg/kg已知的乙酰胆碱酯酶抑制剂多奈哌齐(DPZ)相比,实施例1的混合提取物在东莨菪碱诱导的记忆形成被抑制的模型中,示出相当的认知和记忆改善效果,并且在给予Aβ42的模型中显示出相当或更高的认知和记忆改善效果。
【表8】
东莨菪碱模型-在NOR实验中的记忆提高效果
【表9】
给予Aβ42的模型-在NOR实验中的记忆提高效力
<1-5>免疫组化染色
对于免疫组化染色,向如实验例1-1中所述的Aβ灌注动物注入1×PBS(磷酸盐缓冲盐水),经4%多聚甲醛固定,并且摘取脑。将脑在相同的溶液中固定一天,并且保存在30%蔗糖溶液中,4℃中,每两天换一次溶液,直至进行冷冻切片。之后,在冷冻切片机(cryostat)中通过滴加OCT(优化的切片温度)化合物,在-20℃使脑组织充分冷冻,然后进行30μm厚的切片,并且在防腐液中储存在4℃。使用海马区进行免疫组化染色。经PBS冲洗过的组织用1%H2O2处理15分钟。之后,组织用0.05M PBS、1.5%常规山羊血清、0.5mg/ml牛血清白蛋白、0.3%triton X-100和山羊NeuN一级抗体(1:500)处理,并且在4℃反应24小时,以防止非特异性反应。在去除一级抗体之后,使组织与缀合过氧化物酶的二级抗体(1:200)反应90分钟,将ABC稀释在缓冲液中并在室温反应约1小时。使用PBS冲洗三次之后,使用0.02%DAB和0.01%H2O2对组织进行显影,并且进行乙醇和二甲苯脱水来制备玻片样本。
对于FJB(Fluoro-Jade-B)染色,组织切片经含4%多聚甲醛的PBS固定5分钟,储存在-70℃。第二天,将干燥3小时的玻片在0.06%高锰酸钾硝酸盐溶液中浸没10分钟。经水清洗之后,将玻片在0.1%乙酸和0.0004%FJB溶液(Calbiochem,圣地亚哥,加利福尼亚,USA)中浸泡20分钟。玻片经蒸馏水冲洗三次,并且在55℃干燥10分钟。使用多聚焦显微镜(Olympus,日本)进行成像,并且使用软成像***摄像机采集照片。
结果如图1所示,通过给予植物性原料的混合提取物,神经元细胞标记物NeuN的表达高于对照组。这意味着在给予草药混合提取物的组中,抑制了神经元细胞的降低。桑葚和茯苓皮单独的提取物对神经元具有保护效果,但效力弱于草药混合提取物。对照药物多奈哌齐没有示出神经保护效果。
如图2所示,与对照相比,草药混合提取物减少了凋亡标记物FJB的表达。这一结果暗示图1中所鉴定出的神经细胞数量增加,是通过抑制β淀粉样肽聚集所诱导的神经元细胞死亡介导的。
<1-6>测量脑中的β淀粉样肽的生成
进行ELISA实验来研究草药混合提取物对β淀粉样肽生成的抑制效果,其中β淀粉样肽生成已知是导致阿尔茨海默氏病的主要原因。
摘取实验例<1-1>中的正常动物的脑,分离出海马区,添加Ripa缓冲液并且进行机械均质化。离心后,获取上清液,并且使用β淀粉样肽分析试剂盒(IBL)测量脑中β淀粉样肽的浓度。测量1mg蛋白中的Aβ40的表达量。
结果如下面的表10所示,证实了通过给予草药混合提取物显著减少了β淀粉样肽的生成。与桑葚和茯苓皮单一提取物的对比例1和对比例2,以及桑葚和茯苓皮混合提取物的对比例3~8相比,桑葚与茯苓皮的5:1混合物示出对β淀粉样肽形成具有较高的抑制效果。单一的草药提取物也示出β淀粉样肽降低活性。其中,桑葚提取物示出对β淀粉样肽形成具有较强的抑制效果,当桑葚重量比高时,植物性原料的混合提取物中提高了β淀粉样肽降低活性。
阿尔茨海默氏病中使用的乙酰胆碱酯酶抑制剂多奈哌齐(DPZ)以1mg/kg的药量,对β淀粉样肽的生成没有影响。
【表10】
正常动物模型-Aβ40测量
<1-7>NGF(神经生长因子)水平的测量
进行ELISA实验来证明混合提取物对NGF生成的效力,其中NGF已知具有使神经元再生和分化的活性。摘取实验例<1-1>中的正常动物的脑后,分离出海马区,向其中添加RIPA缓冲液并且进行机械均质化。对于NGF测量,添加对应于每一脑的重量的高盐高去垢剂缓冲液,并且进行机械均质化。在添加了10μL 4N HCl并且静置15分钟之后,使与受体结合的NGF分离,添加4N NaOH,使混合物再静置15分钟。通过离心,取出上清液,并且使用NGF测量试剂盒(Millipore)测量脑中的NGF浓度。1mg蛋白中生成的NGF的量示于表中。
结果如下面的表11所示,证实了通过给予草药混合提取物,显著增加了NGF的生成。与桑葚和茯苓皮单一提取物的对比例1和对比例2,以及桑葚和茯苓皮混合提取物的对比例3~8相比,本发明实施例1中的桑葚与茯苓皮的5:1混合物示出较高的促NGF生成的活性。单一的草药提取物也刺激NGF的生成。其中,茯苓皮提取物示出对NGF生成相对强的促进效果。在植物性原料的混合提取物中,当茯苓皮的重量比高时,促NGF生成的效果大。
阿尔茨海默氏病中以1mg/kg的药量使用的乙酰胆碱酯酶抑制剂多奈哌齐(DPZ),对NGF的生成没有影响。
【表11】
正常动物模型-NGF测量
<实验例2>证明桑葚和茯苓皮的混合提取物的体外(in vitro)神经细胞的保护效果
<2-1>测量神经细胞系中的乙酰胆碱酯酶(AChE)的活性
已经开发并且使用了多种乙酰胆碱酯酶抑制剂,因为这些抑制剂通过增加神经节神经递质中的乙酰胆碱浓度来活化胆碱能神经元,从而增强记忆力并且改善痴呆。测量乙酰胆碱酯酶的活性,来证明草药混合提取物的乙酰胆碱酯酶抑制效果。从KCLB(韩国细胞系库)购买了SH-SY5Y细胞,一种神经细胞系。将SH-SY5Y细胞(1×106细胞/孔)接种在六孔培养板上,并且在含10%胎牛血清的DMEM/F12(杜尔贝科改良伊格尔培养基,Dulbecco'smodified Eagle's medium)培养基中培养48小时。使用含10μM视黄酸和3%FBS的DMEM/F12培养基分化5天之后,处理实施例、对比例(10μg/ml)和对照药物(多奈哌齐10μM)。使用RIPA缓冲液(150mM NaCl、0.5%Triton X-100、50mM Tris-HCl、pH 7.4、25mM NaF、20mM EGTA、1mM DTT、1mM Na3VO4、蛋白酶抑制剂鸡尾酒)裂解细胞,并且使用购自Pierce的BCA试剂对蛋白含量进行定量。按照Ellman法,使用乙酰胆碱作为底物来确定乙酰胆碱酯酶的活性。乙酰胆碱酯酶所产生的硫代胆碱与DTNB反应,通过测量405nm的吸光度变化来确定所产生的5-硫代-2-硝基苯甲酸盐。
结果如下面的表12所示,证实了通过给予草药混合提取物,使因为β淀粉样肽处理增加的乙酰胆碱酯酶的活性正常化。与桑葚和茯苓皮单一提取物的对比例1和对比例2,以及桑葚和茯苓皮混合提取物的对比例3~8相比,本发明实施例1中的桑葚与茯苓皮的5:1混合物示出优异的乙酰胆碱酯酶抑制活性。对比例1和对比例2的单一的草药提取物显示出轻微的乙酰胆碱酯酶抑制活性,但两种单一的草药提取物均示出比草药混合提取物低的效力。草药提取物的抑制效果与10μM多奈哌齐(DPZ)的类似,其中多奈哌齐(DPZ)是乙酰胆碱酯酶抑制剂且用于阿尔茨海默氏病。
【表12】
神经元细胞系模型–乙酰胆碱酯酶活性
<2-2>神经细胞系中的细胞保护效果
在由人造聚集物Aβ42引起对神经细胞系毒性的模型中,使用MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐)测定,来测量草药混合提取物的细胞保护效果。将SH-SY5Y(1×104细胞/孔)接种在96孔培养板中,并且在含10%胎牛血清的DMEM/F12(杜尔贝科改良伊格尔培养基:营养物混合物F-12)培养基中培养48小时。在使用含10μM视黄酸和3%FBS的DMEM/F12培养基分化5天之后,经实施例、对比例和对照药物(多奈哌齐10μM)处理6小时,然后使用Aβ42处理总共48小时,在使用2mg/ml MTT处理4小时之后,将Formazon溶解在DMSO中,并且测量590nm处的吸光度。
结果如下面的表13所示,证实了通过给予草药混合提取物,抑制了β淀粉样肽处理所诱导的细胞毒性。与桑葚和茯苓皮单一提取物的对比例1和对比例2,以及桑葚和茯苓皮混合提取物的对比例3~8相比,桑葚与茯苓皮的5:1混合物示出优异的细胞保护效果。阿尔茨海默氏病中使用的乙酰胆碱酯酶抑制剂多奈哌齐(DPZ)在10μM的药量下示出低水平的细胞保护效果。
【表13】
神经元细胞模型-MTT测量值
<2-3>对神经元细胞系中的磷酸化tau蛋白的测量
测量磷酸化tau蛋白的水平,以证明草药粗提取物对tau蛋白过磷酸化的抑制效果。将SH-SY5Y细胞(1×106细胞/孔)接种在六孔培养板上,并且在含10%FBS(胎牛血清)的DMEM/F12(杜尔贝科改良伊格尔培养基)培养基中培养48小时。在使用含10μM视黄酸和3%FBS的DMEM/F12培养基分化5天后,经实施例、对比例(10μg/ml)和对照药物(多奈哌齐10μM)处理6小时,然后经Aβ42处理并且培养总共48小时。使用RIPA缓冲液裂解细胞之后,使用购自Pierce的BCA试剂对蛋白含量进行定量。使用购自Invitrogen的人Tau[pS199]酶联免疫吸附测试(ELISA)试剂盒,测量磷酸化的tau蛋白。
结果如下面的表14所示,证实了通过给予草药混合提取物,抑制了β淀粉样肽处理所诱导的tau蛋白磷酸化增加。与桑葚和茯苓皮单一提取物的对比例1和对比例2,以及桑葚和茯苓皮混合提取物的对比例3~8相比,实施例1的桑葚与茯苓皮的5:1混合物具有优异的tau蛋白磷酸化抑制效果。具体地,与仅桑葚和仅茯苓皮的提取物相比,混合提取物显著提高了抑制tau蛋白磷酸化的效果。阿尔茨海默氏病中使用的乙酰胆碱酯酶抑制剂多奈哌齐(DPZ)在10μM的药量下没有示出对tau蛋白磷酸化的抑制效果。
【表14】
神经元细胞模型-tau蛋白磷酸化的测量
<2-4>神经细胞系中的NGF(神经生长因子)水平的测量
测量NGF水平,以确定草药混合提取物的认知改善的机制。将SH-SY5Y细胞(1×106细胞/孔)接种在六孔培养板上,并且在含10%胎牛血清的DMEM/F12(杜尔贝科改良伊格尔培养基)培养基中培养48小时。使用含10μM视黄酸和3%FBS的DMEM/F12培养基分化5天之后,对其使用实施例、对比例(10μg/ml)和对照药物(多奈哌齐10μM)处理。使用RIPA缓冲液裂解细胞,并且使用购自Pierce的BCA试剂对蛋白含量进行定量。使用购自Abcam的β神经生长因子人酶联免疫吸附测定(ELISA)试剂盒,测量NGF水平。
结果如表15所示,证实了草药混合提取物增加了NGF的生成。此时,β淀粉样肽不影响NGF的生成。通过对比单一草药提取物对NGF生成的作用,发现茯苓皮提取物的效力较高。在草药混合提取物中,5:1的组合最有效。
阿尔茨海默氏病中用作乙酰胆碱酯酶抑制剂的多奈哌齐(DPZ)在10μM的药量下没有示出促NGF生成的效果。
【表15】
神经细胞模型-NGF的测量
如上所述,桑葚(是本发明的草药混合提取物的材料)的提取物似乎通过去除β淀粉样肽(其被认为是阿尔茨海默氏病的主要病因),促进了神经元的存活并且激活了其功能。另一材料,茯苓皮提取物,被认为尤其通过促进NGF(已知为神经元保护因子)的生成而具有更好的神经细胞保护效力。此外,各草药提取物在抑制乙酰胆碱酯酶上没有显示出高效力,而抑制乙酰胆碱酯酶是目前阿尔茨海默氏痴呆药物的主要作用机制。但是,当它们混合时,效力增加。这些结果表明桑葚和茯苓皮混合提取物保护神经元,并且通过不同机制协同性地增加了记忆力。尤其认为当它们以5:1的重量比混合时,效力是极好的。
因此,本发明的草药混合提取物通过抑制引起神经元细胞死亡而导致退行性脑病的β淀粉样肽的生成和tau蛋白磷酸化,抑制了疾病的发生或进行,并且通过抑制乙酰胆碱酯酶而提高了记忆力。它还促进了NGF的生成,这促进了对神经元的保护和神经分化。因此,本发明可用于预防、改善和治疗由于神经元逐渐死亡而导致的进行性痴呆,例如阿尔茨海默氏痴呆和克雅二氏病、亨廷顿氏舞蹈病、多发性硬化症、格林-巴利综合征、帕金森氏病和卢伽雷氏病。本发明还可用于预防、改善和治疗退行性神经障碍,包括姿势和运动障碍、进行性共济失调、肌肉萎缩和无力,以及感觉和运动障碍等。
下文中,将描述本发明实施例1中的含药物粗提取物的组合物的制备例。但应理解,这仅是是对本发明的详细描述,本发明并不限于此。
制备例1:注射剂的制备
实施例1的提取物.............................100mg
焦亚硫酸钠..................................3.0mg
对羟基苯甲酸甲酯............................0.8mg
对羟基苯甲酸丙酯............................0.1mg
注射用无菌蒸馏水............................适量
通过常规的注射剂制备方法,混合上述成分制成2ml,之后,将混合物填充到2ml安瓿中并且灭菌,以制备成注射剂。
制备例2:片剂的制备
实施例1的提取物...........................200mg
乳糖......................................100mg
淀粉......................................100mg
硬脂酸镁..................................适量
按照常规的片剂制备方法,混合上述组分并且进行压片来制备片剂。
制备例3:胶囊的制备
实施例1的提取物..........................100mg
乳糖.....................................50mg
淀粉.....................................100mg
滑石.....................................2mg
硬脂酸镁.................................适量
按照常规的胶囊制备方法,混合上述组分并且填充到明胶胶囊中来制备胶囊。
制备例4:液体药剂的制备
实施例1的乙醇提取物............................1000mg
糖.............................................20g
柠檬香.........................................适量
添加了纯化水之后,总液体体积....................100mL
按照生产液体制剂的常规方法混合上述组分,填充在100ml棕色瓶中,灭菌来制备液体制剂。
Claims (3)
1.一种用于预防或治疗阿尔茨海默氏病的药物组合物,所述药物组合物包含作为活性成分的桑葚和茯苓皮的混合提取物,其中所述桑葚与所述茯苓皮的重量比为5:1,其中所述桑葚和茯苓皮的混合物提取物是使用70(v/v)%的乙醇提取的。
2.一种用于改善退行性阿尔茨海默氏病的食品组合物,所述食品组合物包含作为活性成分的桑葚和茯苓皮的混合提取物,其中所述桑葚与所述茯苓皮的重量比为5:1,其中所述桑葚和茯苓皮的混合物提取物是使用70(v/v)%的乙醇提取的。
3.药物组合物在制备用于预防、改善或治疗阿尔茨海默氏病的药物中的应用,其中,所述药物组合物包含作为活性成分的桑葚和茯苓皮的混合提取物,其中所述桑葚与所述茯苓皮的重量比为5:1,其中所述桑葚和茯苓皮的混合物提取物是使用70(v/v)%的乙醇提取的。
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