CN116617277A - 具有抗阿尔茨海默症活性的锁阳精制组分制备方法及应用 - Google Patents
具有抗阿尔茨海默症活性的锁阳精制组分制备方法及应用 Download PDFInfo
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- CN116617277A CN116617277A CN202310617755.5A CN202310617755A CN116617277A CN 116617277 A CN116617277 A CN 116617277A CN 202310617755 A CN202310617755 A CN 202310617755A CN 116617277 A CN116617277 A CN 116617277A
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Abstract
本发明一种具有抗阿尔茨海默症活性的锁阳精制组分制备方法及应用，属于中药研制领域；锁阳对抗阿尔茨海默症精制组分的制备方法，主要为对含乙醇水溶液的锁阳粗粉进行提取，并收集滤液，将滤液蒸干，所得固体纯水溶解后进行膜分离得到锁阳中药对抗阿尔兹海默症的精制组分。本发明是首次应用膜分离从锁阳药对中分离出能够抗阿尔茨海默症的精制组分，制备方法明确，抗阿尔茨海默症作用较为明显，保证了中药效用的可靠性，为中药有效组分的提取分离奠定了基础。有望开发为以锁阳为原料的具有广泛治疗效果和商业开发价值的食品或保健品，对中药组分新药开发具有积极作用。
Description
技术领域
本发明属于中药研制领域，尤其涉及锁阳药对抗阿尔茨海默症的精制组分的制备方法及其应用。
背景技术
阿尔兹海默病是一种常见的中枢神经系统退行性疾病，主要发病于65岁以上的老年人群，通常又被称为原发性老年痴呆症。临床早期多表现为记忆障碍，以近期记忆力受损为主，随着病情的进展，病人可出现失语、失写、焦虑、淡漠、攻击行为以及日常生活不能自理等表现，严重影响病人的生活质量，给病人造成深重的痛苦，给家庭和社会带来沉重的负担。
目前，对AD发病机制的报道不仅包括先天遗传和物理损伤，还包括多种主要的病理机制，如氧化机能的损伤、胆碱能损伤、β-淀粉样蛋白(β-amyloid protein，Aβ)沉积和神经细胞损伤等，进而造成大脑皮质褶皱改变、神经元丢失及神经递质传递异常等现象。氧化应激被认为是促使衰老和多种神经退行性疾病发展的主要诱导因素。氧产量的增加可导致线粒体功能的丧失，改变金属稳态和抗氧化防御的减少则直接影响神经元的突触活动和神经递质传到，进而导致认知功能障碍的发生。此外，受氧自由基影响的分子靶点包括线粒体、DNA、脂质、蛋白、钙稳态、细胞结构、受体转运、内吞作用以及能量稳态。胆碱能损伤是最早提出的AD发病机制，在AD发病学说中占有重要地位。胆碱能损伤，简单来说即为胆碱能系统缺陷。乙酰胆碱是重要的神经中枢兴奋递质，与学习和记忆等高级行为相关，由于ACh可被乙酰胆碱酯酶(AChE)快速水解而导致含量下降，胆碱酯酶抑制剂(AChEIs)通过抑制AChE水解ACh，进而达到促进胆碱能传递。此外，AChE和丁基胆碱酯酶(BChE)在老年斑形成早期的Aβ聚集中起着重要的作用。因此，AChE和BCHE已被认为是治疗AD的关键靶点，通过增加脑区乙酰胆碱的可用性并减少Aβ沉积进而缓解AD的发展。
锁阳锁阳(Cynomorium songaricum Rupr)别名不老药、黄骨狼，为桃金娘目锁阳科锁阳属多年生肉质寄生植物。分布于新疆、青海、甘肃、宁夏、内蒙古、陕西等地。锁阳的主要化学成分包括胡萝卜苷、熊果酸、儿茶素、原儿茶酸、没食子酸、β-谷甾醇等成分，还存在黄酮类、糖类以及15种游离氨基酸等多种成分。近年来有学者就锁阳对痴呆大鼠学习记忆能力以及相关脑区突触体超微结构变化的影响作用进行了探讨，结果显示给药锁阳的小鼠比不给药的的模型组通过迷宫的时间明显缩短，同时突触后膜致密物质的厚度明显增加，提示了锁阳能够明显改善包括AD在内的神经退行性病变。但是锁阳中治疗AD的有效成分和相关分子机制多数不明确。有病理学研究表明，胆碱能机制是AD主要发病原因，AD患者脑内胆碱能活性降低会导致认知记忆功能障碍，提高脑内乙酰胆碱(ACh)水平可以改善AD患者的症状。因此，有必要对锁阳中的AChEI进行系统筛选，以期得到高效无毒的AChEI，为开发抗AD的组分中药新药奠定基础。
目前国内外医药学者从中药中寻找抗AD有效成分的不断研究，但目前未见锁阳药对用于治疗AD的研究报道，且现有上市的改善记忆功能的产品在临床上的效果仍然不够理想。因此，研发一种锁阳药对抗阿尔茨海默症的精制组分的制备方法具有社会价值和经济价值。
发明内容
本发明提出了一种具有抗阿尔茨海默症活性的锁阳药对精制组分的制备方法，用于克服目前临床缺乏药物资源丰富、毒副作用小的治疗阿尔茨海默症药物不足的技术问题。主要为对含乙醇水溶液的锁阳粗粉进行提取，并收集滤液，蒸干，纯水溶解后将滤液进行膜分离得到锁阳药对抗阿尔兹海默症的精制组分。本发明是首次从锁阳药对中分离出能够抗阿尔茨海默症的精制组分，制备方法明确，抗阿尔茨海默症作用明显，保证了中药效用的可靠性，为中药有效组分的提取分离奠定了基础。
为实现上述目的，本发明的具有抗阿尔茨海默症活性的锁阳精制组分制备方法及应用的具体技术方案如下：
一种具有抗阿尔茨海默症活性的锁阳精制组分制备方法，包括以下步骤，且以下步骤顺次进行：
步骤一、制备粗粉
取干燥洁净的锁阳饮片若干个，将其全部粉碎，过10～30目筛，粗粉备用
步骤二、制备锁阳醇提物
选取锁阳干燥粉碎体1份，以锁阳干燥粉碎体总质量5～50倍的50％～70％乙醇为提取溶剂，采用超声提取法对锁阳干燥粉碎体进行提取，每次提取50～70min，共提取2次，过滤提取液，合并滤液；
步骤三、制备精制组分：
取步骤二中滤液，将滤液蒸干，除去残留有机溶剂，将所得干燥固体一份溶解于纯水中，将所得溶液以截留分子量为1kd～10kd的超滤膜包进行膜分离，浓缩得精制组分。
进一步，所述步骤一中，将锁阳粉碎至粒径为20目。
进一步，所述步骤二中，提取溶剂为锁阳干燥粉碎体总质量10倍的50％乙醇，提取时间为60min，提取次数为2次。
进一步，所述步骤三中，使用截留分子量为3kd的超滤膜包进行膜分离。
本发明还提供了一种具有抗阿尔茨海默症活性的锁阳精制组分的应用，所制备的锁阳精制组分作为抑制乙酰胆碱酯酶的活性成分的应用。
进一步，所制备的锁阳精制组分作为抑制乙酰胆碱酯酶的活性成分在制备抗老年痴呆药物方面的应用。
本发明的具有抗阿尔茨海默症活性的锁阳精制组分制备方法及应用具有以下优点：本发明中锁阳药对的精制组分对改善阿尔茨海默症具有一定的作用，具体表现为对乙酰胆碱酯酶具有明显的抑制作用。本发明是首次从锁阳药对中分离出能够抗阿尔茨海默症的精制组分，制备方法明确，抗阿尔茨海默症作用明显，保证了中药效用的可靠性，为中药有效组分的提取分离奠定了基础。有望开发为以锁阳为原料的具有广泛治疗效果和商业开发价值的食品或保健品，对推动传统中药药品发展具有积极作用；
本发明具有创新型，锁阳研究较为广泛，但锁阳药对在抗阿尔茨海默症方面的研究涉及较少；普遍性，中药由于成分复杂，质量标准不明确，作用机制尚不清楚，很难广泛生产，本实验制作方法明确，保证了中药效用可靠；广泛性，该发明具有外延性，在一定的程度上给其他中药的研究生产提供一条新的思路和质量标准研究；简便性，该研究方法简单、方便、快速、经济，适合于市场和一般个体应用。
附图说明
图1为实施例1制备得到的锁阳药对精制组分锁阳RRLC色谱图。
具体实施方式
为了更好地了解本发明的目的、结构及功能，下面结合附图，对本发明一种具有抗阿尔茨海默症活性的锁阳精制组分制备方法及应用做进一步详细的描述。
本发明锁阳药对抗阿尔茨海默症精制组分的制备方法，主要为对含乙醇水溶液的锁阳粗粉进行提取，收集滤液，干燥，纯水溶解所得溶液进行膜分离得到锁阳药对抗阿尔兹海默症的精制组分。虽然步骤简单，但每一步需要掌握其中的要领与技巧，下面就结合具体事例简单介绍一下本发明的运用与实施，有利于普通商人和消费者进一步对该法的理解和渗透，而且多数该方法的应用者或机构可以根据自己的需求，通过领会该技术要领而对该发明进行变通利用，已达到更好的效益。任何不违背该发明宏观思想的改进都属于该发明的领域和范畴。
实施例1：
步骤一、取干取干燥洁净的锁阳饮片若干个，将其全部粉碎过20目筛，粗粉备用；
步骤二、选取锁阳干燥粉碎体1份，以锁阳干燥粉碎体总质量5～50倍的50％～70％乙醇为提取溶剂，采用超声提取法对锁阳干燥粉碎体进行提取，每次提取50～70min，共提取2次，过滤提取液，合并滤液；
步骤三、取步骤二中滤液，将滤液蒸干，除去残留有机溶剂，将所得干燥固体一份溶解于纯水中，将所得溶液以截留分子量为1kd～10kd的超滤膜包进行膜分离，浓缩得精制组分。
锁阳药对精制组分抑制乙酰胆碱酯酶活性试验：
(1)溶液的配制
AChE溶液(0.31U/mL)：5U的AChE被溶解于PBS(0.1M pH7.4)缓冲液中稀释，即得0.31U/mL的酶溶液，现用现配。
多奈哌齐(1mg/mL)：准确称取1mg的多奈哌齐粉末，加1ml纯水制得浓度约为1mg/mL的溶液，现用现配。
DTNB溶液(2mM)：3.96mg DTNB先用500μL的50％甲醇溶解，加1.5mg NaHCO3，再用pH 7.4的PBS定容到5mL，现用现配。
ATCI溶液(15mM)：21.67mg ATCI加蒸馏水溶解并定容至5mL，4℃冰箱保存，现用现配。
用纯水配置样品四种样品，分别为乙醇提取的干燥组分、膜过滤后＜3kd的组分、膜过滤后大于3kd的组分，应用AChE抑制试验测定以上各个浓度在405nm的吸光度值，所有的实验平行测定3次。
(2)操作步骤
采用改良Ellman法测定样品的AChE抑制活性。在96孔板每孔中加入0.1mol/L PBS(pH 7.4)80μL、样品溶液20μL、5U/mL乙酰胆碱酯酶溶液20μL和15mmol/L ATCI 40μL，恒温37℃孵育20min，加入2mmol/L的DTNB 40μL在37℃继续反应20min，405nm处测定吸光度值。通过公式计算酶活性抑制率，乙酰胆碱脂酶抑制率计算公式为：
其中空白对照组为用PBS缓冲液代替酶时的吸光值，完全抑制组为阳性药多奈哌齐加酶时的吸光值减去多奈哌齐不加酶时的吸光值，反应组为样品加酶时的吸光值，反应本底组为样品不加酶时吸光值。
(3)实验结果
应用改良Ellman法对锁阳药对精制组分和阳性药进行AChE抑制活性测定，体外酶活性抑制试验的结果表1。
表1不同部位药物对乙酰胆碱酯酶的抑制率
多奈哌齐作为一种抗阿尔茨海默症的临床药物，其副作用较多，长期服用会对患者的生活健康造成一定的影响。锁阳药对<3kd组分作为一种中药的精制组分，因其副作用小且资源丰富等优势，可在治疗阿尔茨海默症中发挥重要作用。
由表1的AChE抑制实验所得数据可知，锁阳药对精制组分的抑制率虽不及多奈哌齐，但该结果可证明通过提取分离及膜分离技术制备所得的锁阳药对精制组分对乙酰胆碱酯酶具有一定的抑制作用，为锁阳药对精制组分抗阿尔茨海默症的后续研究提供了实验依据
实施例2：锁阳药对精制组分制备方法(同实施例1)
步骤一、取干取干燥洁净的锁阳饮片若干个，将其全部粉碎过20目筛，粗粉备用；
步骤二、选取锁阳干燥粉碎体1份，以锁阳干燥粉碎体总质量10倍的50％乙醇为提取溶剂，采用超声提取法对锁阳干燥粉碎体进行提取，每次提取60min，共提取2次，过滤提取液，合并滤液；
步骤三、取步骤二中滤液，将滤液蒸干，除去残留有机溶剂，将所得干燥固体一份溶解于纯水中，将所得溶液用3kd超滤膜在超滤离心机中对滤液进行超滤，回收滤过超滤膜的溶液，蒸干，得<3kd组分。准确称取锁阳药对精制组分5mg，用50％甲醇溶解，过0.45μm超滤膜，即得。
采用AglientPlus C18色谱柱(4.6×250mm，5μm)，检测波长为210nm，柱温30℃，进样量20μL，流速0.6mL/min。流动相A为乙腈，流动相B为0.1％甲酸水溶液，梯度洗脱条件见表2。
表2HPLC-ESI-MS2色谱条件
质谱条件：扫描范围m/z 50～1400，实验前校正质量数，目标分子量300和900；实验中采用正负离子模式。样品以0.6ml/min的速度分流进样；干燥气体温度350℃；干燥气体流量9ml/min；雾化压力：0.24MPa(35.0psi)；毛细管电压：3.5kV。初步鉴定锁阳药对精制组分中的化合物见表3。
表3初步鉴定锁阳药对精制组分中的化合物信息
表3基于RRLC-Q-TOF分析分析了锁阳药对精制组分的成分组成，初步指认出12个化合物，其中有效成分大致有表儿茶素、根皮苷、芦丁等黄酮类物质5个，熊果酸等2个萜类物质以及一些有机酸类如没食子酸、脂类如表儿茶素没食子酸酯、糖类等物质。以上结果可作为锁阳药对精制组分成分库。
本发明中提出一种具有抗阿尔茨海默症活性的锁阳药对精制组分制备方法及应用，即涉及三个步骤：(一)粉碎锁阳，得到锁阳粗粉；(二)50％乙醇提取，得到锁阳药对醇提物；(三)对锁阳药醇提物干燥水溶后进行膜分离，制得精制组分。其中提取得到的精制组分对乙酰胆碱酯酶有良好的抑制作用，可作为锁阳药对抗阿尔茨海默症的精制组分起到抑制乙酰胆碱酯酶的作用。本发明是首次通过膜分离技术分离得到锁阳药精制组分，该方法适用性广且价廉易得；同时制作方法明确，保证了中药效用的可靠性，为锁阳药对精制组分抗阿尔茨海默症的后续研究奠定了基础，也为其他中药活性成分的提取及应用提供了新的思路。
可以理解，本发明是通过一些实施例进行描述的，本领域技术人员知悉的，在不脱离本发明的精神和范围的情况下，可以对这些特征和实施例进行各种改变或等效替换。另外，在本发明的教导下，可以对这些特征和实施例进行修改以适应具体的情况及材料而不会脱离本发明的精神和范围。因此，本发明不受此处所公开的具体实施例的限制，所有落入本申请的权利要求范围内的实施例都属于本发明所保护的范围内。
Claims (7)
1.一种具有抗阿尔茨海默症活性的锁阳精制组分制备方法，其特征在于，包括以下步骤，且以下步骤顺次进行：
步骤一、制备粗粉
取干燥洁净的锁阳饮片若干个，将其全部粉碎，过10～30目筛，粗粉备用
步骤二、制备锁阳醇提物
选取锁阳干燥粉碎体1份，以锁阳干燥粉碎体总质量5～50倍的50％～70％乙醇为提取溶剂，采用超声提取法对锁阳干燥粉碎体进行提取，每次提取50～70min，共提取2次，过滤提取液，合并滤液；
步骤三、制备精制组分：
取步骤二中滤液，将滤液蒸干，除去残留有机溶剂，将所得干燥固体一份溶解于纯水中，将所得溶液以截留分子量为1kd～10kd的超滤膜包进行膜分离，浓缩得精制组分。
2.根据权利要求1所述的具有抗阿尔茨海默症活性的锁阳精制组分制备方法，其特征在于，所述步骤一中，将锁阳粉碎至粒径为20目。
3.根据权利要求1所述的具有抗阿尔茨海默症活性的锁阳精制组分制备方法，其特征在于，所述步骤二中，提取溶剂为锁阳干燥粉碎体总质量10倍的50％乙醇，提取时间为60min，提取次数为2次。
4.根据权利要求1所述的具有抗阿尔茨海默症活性的锁阳精制组分制备方法，其特征在于，所述步骤三中，使用截留分子量为3kd的超滤膜包进行膜分离。
5.一种如权利要求1-4中任意一项所述的具有抗阿尔茨海默症活性的锁阳精制组分的应用，其特征在于，所制备的锁阳精制组分应用于治疗阿尔茨海默症的药物。
6.一种如权利要求1-4中任意一项所述的具有抗阿尔茨海默症活性的锁阳精制组分的应用，其特征在于，所制备的锁阳精制组分作为抑制乙酰胆碱酯酶的活性成分的应用。
7.根据权利要求6所述的具有抗阿尔茨海默症活性的锁阳精制组分制备方法，其特征在于，所制备的锁阳精制组分作为抑制乙酰胆碱酯酶的活性成分在制备抗老年痴呆药物方面的应用。
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| 吕鑫等: "锁阳黄酮对阿尔茨海默病大鼠海马组织ROS含量及NADPH氧化酶、NLRP3表达的影响", 中国中医药信息杂志, vol. 30, no. 4, 30 April 2023 (2023-04-30), pages 82 * |
| 慕桂娟;曹俊彦;郑玲艳;韩瑞兰;: "锁阳的研究现状及应用前景", 中国医药导报, vol. 13, no. 22, 5 August 2016 (2016-08-05), pages 33 - 34 * |
| 李鑫洁;程丹;李玲玲;苏磊;鲁艺;: "基于线粒体动力学失衡调控研究锁阳醋酸乙酯提取物对阿尔茨海默症小鼠行为学的改善作用", 药物评价研究, vol. 43, no. 03, 8 March 2020 (2020-03-08), pages 451 * |
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