CN115590935B - 脑灵丹的制备、组成及其在预防和干预阿尔茨海默病药物中的应用 - Google Patents
脑灵丹的制备、组成及其在预防和干预阿尔茨海默病药物中的应用 Download PDFInfo
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Abstract
本发明属于医药健康技术领域,具体为使用天然中草药提取物组合物制备有效预防干预阿尔茨海默病的脑灵丹。该脑灵丹能显著改善阿尔茨海默症模型鼠学习记忆能力,消减大脑慢性炎症,阻止老年痴呆症病情发展,显著提高免疫功能。因此,该脑灵丹在预防干预和治疗阿尔茨海默病特异食品或药物方面有广阔的应用前景。
Description
技术领域
本发明属于医药健康技术领域,具体为使用天然中草药提取物组合物制备有效预防干预阿尔茨海默病的脑灵丹。该脑灵丹能显著改善阿尔茨海默症模型鼠学习记忆能力,消减大脑慢性炎症,阻止老年痴呆症病情发展,显著提高免疫功能。
背景技术
阿尔茨海默症(Alzheimer’s Disease,AD),俗称老年痴呆症,目前已成为世界最重大的疾病之一,美国FDA和中国CFDA批准的抗阿尔茨海默病药物很少,药物治标不治本,疗效不显著。65岁及以上的AD患病率达到4.8%,年龄每增加5岁,患病率增长一倍,85岁以上老人AD患病率达到28.9%。2000年,约400万美国人AD患病,护理费多达1000亿美元/年。美国、日本等8个主要国家阿尔茨海默症治疗的市场规模达到100亿美元以上,而且该药物市场逐年增加。
阿尔茨海默症是由德国学者Alosi Alzheimer于1907年首次报道。这是一种常发于老年人群中的中枢神经系统原发性退行性疾病,目前全世界有超过五千多万例AD患者,其临床表现为不同程度的记忆力丧失,语言困难,定向力障碍,认知能力降低,人格及行为和感情活动异常,进行性智力障碍,以至于生活不能自理,完全呆傻,最后全身衰竭,并发感染而亡。目前AD已经成为继心脏病、肿瘤和中风之后的第四位死亡原因。AD最典型的病理特征为:大脑皮层和海马组织内出现大量的老年斑(senile plaques,SP)、神经纤维缠结(neurofibrillary tangles,NFTs)、神经慢性炎症、脑血管损伤、神经元数量减少和颗粒空泡变性。AD的发病机理十分复杂,可能是多种因素相互作用的结果。迄今为止,其确切的发病机理还是一个未解之谜,但在近三十年的研究证据表明,淀粉样多肽(amyloid-betapeptide,Aβ)、淀粉样前体蛋白(amyloid precursor protein,APP)、大脑内稳态调节蛋白及其相关的的金属离子内稳态平衡与AD的发生、发展有着密切的联系。
另外,大脑消耗人体20%的氧气,而且抗氧化剂和相关酶的浓度相对较低又富含不饱和脂肪酸,易受氧化损伤。正常情况下,细胞可以通过调节内稳态平衡对抗氧化攻击,但随着年龄增长,细胞保持平衡的能力减低,导致自由基积累,线粒体功能失调,神经元损伤。氧化损伤诱发信号传导通路,操纵细胞对压力的反应,这个反应的表现就是ROS的增加。当ROS的数量超过了神经元细胞对抗的能力时就会发生氧化胁迫,进而导致线粒体机能障碍以及神经元细胞损伤。线粒体中缺乏组蛋白以及线粒体中DNA修复功能的减弱都是造成线粒体易产生氧化胁迫的原因。铁、铜离子被认为是AD中氧化胁迫发生的重要原因。在AD病中,氧化损伤的增加不是最终的结果,而是具有起始作用。AD的初期,神经细胞尽管氧化损伤增加,但实际上仍然是处于内稳态平衡的。随着AD病的发展及相应的ROS水平的增加,Aβ-金属化合物和过度磷酸化的tau蛋白将不能有效的被去除,导致淀粉样斑块和神经纤维缠结的不可控地增加,而这又会导致反应活性物质的进一步增多,这种恶化的反馈机制最终造成神经元功能丧失。
国内外已对AD的神经病理机制进行了大量的研究。70年代中期以来,大量药理学研究集中于提高突触裂隙中的乙酰胆碱水平,发现了一系列乙酰胆碱酯酶的抑制剂类药物。然而,这种治疗仅是缓解症状的治标疗法。80年代中期以来,许多研究围绕Aβ的形成、聚集以及清除机制,或Aβ的神经毒性机制进行。以Aβ为靶标治疗AD病的药物有Aβ前体蛋白APP分泌酶的抑制剂、抗Aβ聚集的金属离子螯合剂和Aβ的抗体等。然而,2008年Lancet报道,Aβ疫苗能有效地清除脑内 Aβ斑,但并不能阻止痴呆症状的发展。这一报道对围绕Aβ斑的治疗研究提出了疑问。这些结果说明,Aβ斑本身并不是细胞毒性的主要根源,可能的机制是,Aβ斑在形成过程中产生的ROS对神经细胞造成毒性。
德国波恩大学的一项突破性研究发现:阿尔茨海默症是由脑部免疫细胞的炎症所引起。此前人类对于阿尔兹海默症的致病原因及发病机制一直未能完全确定,这一发现无疑是超级重磅。科学家预言,这项新发现为药物研发提供了新思路,人类或可能在未来五年内治愈甚至预防阿尔兹海默症。该研究结果已发表在世界顶级科学类杂志《自然》上。德国波恩大学MichaelHeneka教授和他的同事认为,有炎症参与阿兹海默症过程,β—淀粉样蛋白斑块是由炎症引起的。他们发现,破坏脑中的小胶质细胞,可以减少阿尔茨海默症形成的β—淀粉样蛋白斑块。因此,他们的研究直接针对引起炎症的小胶质细胞,而不是β—淀粉样蛋白。研究人员发现,当炎症发生时,小胶质细胞会释放出ASC微粒蛋白,活化β—淀粉样蛋白,促进淀粉样斑块产生。德国波恩大学的Heneka 教授说,这个病理过程可能发生在阿尔茨海默氏症的早期阶段。
近年来,大规模外显子测序研究发现,很多小胶质细胞基因上的突变与AD 发病风险相关,提示大脑免疫功能紊乱可能与AD的病理进程相关。其中最具代表性的发现是,发现了髓样细胞触发性受体-2(TREM2)是多个神经退行性疾病的共有风险基因,其编码区R47H突变增加近3倍罹患AD的风险,同时也显著增加额颞叶痴呆、肌萎缩侧索硬化病和帕金森病等的发病风险。TREM2在大脑内的小胶质细胞中特异表达,其突变与AD风险的增加高度关联。但是,关于 TREM2如何参与并影响AD病理进程尚不十分清楚。
本研究使用天然中草药提取物组合物制备有效预防干预阿尔茨海默病的脑灵丹。探索该脑灵丹对改善阿尔茨海默症模型鼠学习记忆能力、消减大脑慢性炎症、阻止老年痴呆症病情发展以及提高免疫功能方面的重要影响情况。
发明内容
本发明的主要内容主要包括使用天然中草药提取物组合物制备有效预防干预阿尔茨海默病的脑灵丹的制备方法、工艺过程及脑灵丹在预防和干预阿尔茨海默病特医食品或药物中的应用。本发明实验研究表明,该脑灵丹能显著改善阿尔茨海默症模型鼠学习记忆能力,消减大脑慢性炎症,阻止老年痴呆症病情发展,显著提高免疫功能。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中,以下所述的实施例是为了更好地阐述本发明,并不是用来限制本发明的范围。
实施例1:脑灵丹的制备
1、原材料:
远志、益智、灵芝、石菖蒲、何首乌、西洋参、葛根、枸杞子、卵磷脂、VE、 VB、红枣、薄荷。
2、制备工艺方法:
原料优选组合配比如下(按总100克):远志(20g)、益智(20g)、灵芝(15g)、石菖蒲(10g)、何首乌(5g)、西洋参(10g)、葛根(5g)、枸杞子(10g)、红枣(3g)、薄荷(2g)。
制备工艺流程:用细胞破壁机将以上原料混合物破碎,然后将粉碎粉状物在水/乙醇(1:1)混合溶剂(1000毫升)中回流(60度)浸泡提取24小时,用高速离心法去除残渣,收取上层清液用旋转蒸发机去除溶剂,得到棕色稠状提取物(25克),在-20度冷冻冰箱放置48小时,用粉碎机粉碎提取物固体,混合其他添加成分【卵磷脂(10g)、VE(10g)、VB(5g)】,制成丹丸。该丹丸易溶于水,添加调味剂后,可以用纯净水溶解制成各种口服液。
实施例2:Morris水迷宫验证脑灵丹对阿尔兹海默症小鼠认知能力的影响
1、阿尔茨海默症小鼠模型
动物及其饲养条件:BALB/C普通小鼠,雄性,体重20-22g,6周龄,SPF级,购于上海斯莱克实验动物有限责任公司。APP/PS1转基因小鼠购自北京中科泽晟生物技术有限公司,4月龄,体重22-24g。所有小鼠均自由觅食和饮水,在室温(23±2)℃下饲养。饲料及水均经高压灭菌处理,全部实验饲养过程为SPF 级。
受试药物名称:脑灵丹。性状:棕红色丹丸。溶媒:生理盐水。配制方法:临用前用生理盐水溶液配制成所需浓度的溶液。给药剂量为:100mg/kg。小鼠分三组,A组:AD鼠给生理盐水对照组;B组:AD鼠脑灵丹给药组;C组,正常鼠给生理盐水组。每组小鼠10只。给药方式:灌胃,每次300微升/每只;给药次数:每天1次,连续60天。
2、仪器设备及实验方法
装置:圆形水池,直径1m,高50cm,水深30cm,池底白色,水温保持在23±2℃;池壁上标记四个等距离点N、E、S、W作为试验的起始点,分水池为四个象限,在第三象限中央放置平台(平台与池壁圆心距离相等);没于水下1cm,使平台不可见。水池周围贴有丰富的参照线索(不同颜色三角形、四方形、圆、菱形置于各个象限)且保持不变,供小鼠用来定位平台。
定位航行试验:试验共历时6天,每天定于固定时间段训练4次。训练开始时,将平台置于第一象限,从池壁四个起始点的任一点将小鼠面向池壁放入水池。自由录像记录系统记录小鼠找到平台的时间和游泳路径,4次训练即将小鼠分别从四个不同的起始点(不同象限)放入水中。小鼠找到平台后或90秒内找不到平台(潜伏期记为90秒),则由实验者将其引导到平台,在平台上休息10秒,再进行下一次试验。
空间探索试验:定位航行试验结束24h后,撤除站台。然后将鼠由第三象限放入水中,记录鼠在180s内的游泳路径,记录鼠在目标象限(第三象限)的停留时间和穿越原站台所在位置的次数,观察受试鼠的空间定位能力。数据用x± s表示,利用SPSS10.0软件进行处理,采用单因素方差分析(one-wayANOVA) 检验比较各组瘤重差异的显著性,显著性水平a=0.05。实验结果如表1所示(A 为AD模型鼠对照组,B为AD模型鼠脑灵丹给药组,C组为正常鼠组。
研究结果表明:脑灵丹组小鼠给药后60天能明显改善阿尔茨海默症小鼠认知能力。脑灵丹在改善AD模型鼠认知能力方面有明显进步。
表1.脑灵丹对阿尔兹海默症小鼠认知能力改善作用
实施例3:脑灵丹给药对AD小鼠脑淀粉样蛋白斑块的影响
实施例2中AD模式鼠给药60天后,检测AD鼠大脑淀粉样蛋白斑块削减情况。本实验为硫黄素S染色实验,实验流程为:给药60天后,取小鼠脑组织,固定,石蜡包埋,切片,二甲苯脱蜡,乙醇梯度脱水,TBS洗三次,0.3%硫黄素 S(溶于50%乙醇)滴于组织上,室温孵育10min,50%乙醇洗三次,TBS清洗,阴干,封片,激光共聚焦显微镜(Leica,Germany)检测AD鼠脑淀粉样斑块沉积量的变化。实验结果如表2所示,结果表明:脑灵丹给药后60天能明显减少阿尔茨海默症小鼠脑组织淀粉样蛋白斑块量。脑灵丹有明显抑制AD鼠大脑淀粉样斑块的药效。
表2.脑灵丹抑制阿尔兹海默症小鼠脑淀粉样蛋白斑块影响
实施例4:脑灵丹对AD小鼠脑组织炎症因子的表达影响
实施例2中AD模式鼠给药60天后,检测AD鼠大脑组织炎性因子情况。ELISA 试剂盒购自CloudClone公司。为了探索以上所述脑灵丹对于AD小鼠脑神经炎症的影响。小鼠脑组织中的炎症因子的含量通过ELISA的方法进行测定。我们分别检测了促炎性因子IL-1β和TNF-α在AD鼠脑组织中的含量。
脑组织样品处理方法:取小鼠新鲜脑组织,称重,选用Cloud Clone ELISA试剂盒测定脑组织中炎症因子IL-1β和TNF-α的含量。如表3所示,相比于AD模型组小鼠脑组织中促炎性因子IL-1β和TNF-α的含量,在脑灵丹给药二个月后,脑组织中的IL-1β和TNF-α水平分别显著下降了。这些结果说明脑灵丹能够显著降低中枢神经系统的促炎性因子。这表明脑灵丹能够消减存在于小鼠AD病程中的慢性神经炎症。
越来越多的证据表明多种促炎因子的高水平表达与APP/PS1二转基因AD小鼠的认知障碍密切相关,说明在AD病程中,一系列的炎症信号通路参与其中最终导致认知能力缺陷。因此,脑灵丹能使促炎症因子下调表达,从而改善AD 小鼠的学习记忆能力,减少脑内Aβ沉积,以上实施例研究结果一致。
表3.脑灵丹对AD鼠脑炎症因子IL-1β和TNF-α表达调控影响
实施例5脑灵丹诱发小鼠免疫功能研究
动物及其饲养条件:BALB/C普通小鼠,雄性,体重20-22g,6周龄,SPF级,购于上海斯莱克实验动物有限责任公司。所有小鼠均自由觅食和饮水,在室温 (23±2)℃下饲养。饲料及水均经高压灭菌处理,全部实验饲养过程为SPF级。
小鼠分组:每10只一组,共2组,分别为,A:给药组(OVA+脑灵丹); B:OVA对照组。
每只小鼠腹腔注射10微克OVA,或10微克OVA和200微克脑灵丹(脑灵丹溶于生理盐水,配制成200微升)。分别在第1,7,14天各免疫一次,在第 21天取血样。用ELISA法测定脑灵丹诱导产生抗体的效价。实验结果见表4.测定结果显示,脑灵丹能有效诱导免疫功能。
表4.脑灵丹诱发免疫效价结果
实施例6脑灵丹对小鼠的急性毒性研究
实验材料
ICR小鼠20只(购于上海斯莱克实验动物有限责任公司,雌雄各半,体重20~22g,动物以颗粒饲料喂养,自由摄食和饮水。
实验方法
ICR小鼠按体重分别灌胃2g/kg的脑灵丹药物(生理盐水配制),观察给药后小鼠14天内的毒性反应及死亡情况。结果发现,小鼠给药后,小鼠活动正常。给药后14天内,小鼠未出现死亡,第15天,全部小鼠处死,解剖,肉眼检查各脏器,均未见明显病变。
上述急性毒性实验结果表明,脑灵丹灌胃给药最大耐受量MTD不低于2 g/Kg,说明脑灵丹的急性毒性低。
Claims (3)
1.一种治疗阿尔茨海默病的脑灵丹,其特征在于,由远志、益智、灵芝、石菖蒲、何首乌、西洋参、葛根、枸杞子、卵磷脂、维生素E、维生素B、红枣、薄荷制成,其中,各原料的用量为:远志20g、益智20g、灵芝15g、石菖蒲10g、何首乌5g、西洋参10g、葛根5g、枸杞子10g、红枣3g、薄荷2g、卵磷脂10g、维生素E 10g、维生素B 5g;其制备工艺为:用细胞破壁机将以上中药原料混合破碎,然后将粉碎物添加水/乙醇(1∶1)混合溶剂1000毫升,60度回流浸泡提取24小时,用高速离心法去除残渣,收取上层清液用旋转蒸发机去除溶剂,得到棕色稠状提取物,在冷冻冰箱放置48小时,用粉碎机粉碎提取物固体,添加卵磷脂、维生素E、维生素B,制成丹丸。
2.权利要求1所述的脑灵丹在制备治疗阿尔茨海默病药物中的应用。
3.权利要求1所述的脑灵丹在制备增强免疫力药物中的应用。
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