WO2020143333A1 - 蒲公英甾酮在制备防治老年痴呆的药物中的应用 - Google Patents

蒲公英甾酮在制备防治老年痴呆的药物中的应用 Download PDF

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WO2020143333A1
WO2020143333A1 PCT/CN2019/119368 CN2019119368W WO2020143333A1 WO 2020143333 A1 WO2020143333 A1 WO 2020143333A1 CN 2019119368 W CN2019119368 W CN 2019119368W WO 2020143333 A1 WO2020143333 A1 WO 2020143333A1
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dandelion
preventing
sterone
disease
preparation
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张振强
谢治深
袁永
宋军营
陈晓辉
曾华辉
蒋亚丽
王潘
马金莲
孙丽敏
苏运芳
张俊霞
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河南中医药大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/288—Taraxacum (dandelion)

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  • the invention belongs to the field of medicine, and relates to new uses of known compounds, in particular to the application of dandelion sterone in the preparation of drugs for preventing and treating senile dementia.
  • AD Alzheimer’s disease
  • a ⁇ amyloid beta
  • the more recognized pathological feature is the neurotoxicity of senile plaques formed by the excessive deposition of A ⁇ in the brain, resulting in a large number of death and loss of cholinergic neurons in the central nervous system. Therefore, inhibiting the deposition of A ⁇ or reducing the damage of A ⁇ to neuronal cells has become a research hotspot and one of the main directions of drug development.
  • Dandelion sterone is a natural product of terpenoids. There is no report of dandelion sterone having anti-senile dementia.
  • the purpose of the present invention is to provide the application of dandelion sterone in the preparation of drugs for preventing and treating senile dementia.
  • a pharmaceutical preparation for preventing and treating senile dementia which uses dandelion sterone or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, into a pharmaceutically acceptable preparation dosage form.
  • the formulation is in the form of tablets, capsules, injections or oral liquid.
  • Alzheimer's disease is a disease characterized by primary and progressive degenerative diseases of the central nervous system.
  • the clinical manifestation is the irreversible deterioration of cognitive and memory functions, mainly due to the excessive deposition of A ⁇ in the brain. Neurons cause damage.
  • the present invention finds that dandelion sterone can protect nerve cell damage caused by A ⁇ , and therefore has the prospect of being developed into an anti-senile dementia drug.
  • a ⁇ 25-35 was purchased from Beijing Bosen Biotechnology Co., Ltd.; dimethyl sulfoxide (DMSO) was purchased from Shanghai McLean Biochemical Technology Co., Ltd.; thiazole blue (MTT) was purchased from Dalian Meilun Biotechnology Co., Ltd.; dandelion steroid Ketone was purchased from Chengdu Pfeiffer Biotechnology Co., Ltd.; fetal bovine serum was purchased from Zhejiang Tianhang Biotechnology Co., Ltd.; RPMI-1640 medium was purchased from Hyclone Company.
  • DMSO dimethyl sulfoxide
  • MTT thiazole blue
  • dandelion steroid Ketone was purchased from Chengdu Pfeiffer Biotechnology Co., Ltd.
  • fetal bovine serum was purchased from Zhejiang Tianhang Biotechnology Co., Ltd.
  • RPMI-1640 medium was purchased from Hyclone Company.
  • Preparation of condensed state A ⁇ 25-35 Dissolve 1 mg A ⁇ 25-35 in an appropriate amount of sterile dd H 2 O, and then add medical sterile saline to make the final concentration of A ⁇ 25-35 1mM, and incubate at 37°C for 7 days in a water bath.
  • the medium is RPMI-1640 medium containing 10% fetal bovine serum and 1% double antibody. Transfer the cell suspension to a Petri dish at 37°C and 5% CO. 2. Cultivate under saturated humidity.
  • the C6 cells in the logarithmic growth phase were made into a cell suspension with a concentration of 2.0 ⁇ 10 5 cells/mL and inoculated into 96-well plates at 100 ⁇ L per well. After 24 hours of culture, the cells were treated according to the following groups. hole:
  • Control group change to fresh medium and continue cultivating for 3h;
  • a ⁇ 25-35 group (model group): change to fresh medium and continue cultivating for 3h;
  • Donepezil hydrochloride group (positive drug group): change to fresh medium containing 20 ⁇ M donepezil hydrochloride and continue culturing for 3 hours;
  • Dandelion sterone group change to fresh medium containing 5, 10, 20, 30 ⁇ M dandelion sterone and continue culturing for 3h.
  • the A ⁇ 25-35 group, the donepezil hydrochloride group, and the dandelion sterone group were added with condensed A ⁇ 25-35 at a final concentration of 10 ⁇ M.
  • the cell survival rate of each group is shown in Table 1 (Note: compared with the control group # p ⁇ 0.05, ## p ⁇ 0.01, ### p ⁇ 0.001; compared with the A ⁇ 25-35 group *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001).
  • Donepezil hydrochloride is a drug approved by the US Food and Drug Administration (FDA) for the treatment of Alzheimer's disease. 20 ⁇ M increases the cell survival rate by 3.4%, while 5 ⁇ M dandelion sterone can increase the cell survival rate by 7.4%. As the dose increases, the protective effect is enhanced, 10 ⁇ M can increase approximately 9.5%, 30 ⁇ M increases the survival rate by 11.4%, and there is a statistical difference.
  • dandelion sterone can protect nerve cell damage caused by A ⁇ , and has the prospect of being developed as an anti-senile dementia drug.

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Abstract

蒲公英甾酮在制备防治老年痴呆的药物中的应用。

Description

蒲公英甾酮在制备防治老年痴呆的药物中的应用 技术领域
本发明属于医药领域，涉及已知化合物的新用途，具体涉及蒲公英甾酮在制备防治老年痴呆的药物中的应用。
背景技术
阿尔茨海默症(Alzheimer’s disease,AD)又称老年痴呆症，是一种以进行性智力退化和神经元丢失为特征的疾病。目前全世界约5-10％的65岁以上老人患有该病，约有3500万患者。该疾病患者在确诊后的生存期仅有3到9年，己经成为继心脑血管疾病和癌症之后威胁老年人健康的第三大杀手。AD是一种以中枢神经系统原发性、进行性的退行性病变为主要特征的疾病，临床表现为认知和记忆功能的不可逆性恶化，主要病理因素是脑内过度沉积的Aβ(amyloid beta)神经元的损伤。近年来关于AD的病因病理研究很多，现比较公认的病理学特征是Aβ在脑内过度沉积形成的老年斑产生的神经毒性致使中枢神经系统的胆碱能神经元的大量死亡、丢失等等。因此抑制Aβ的沉积或减轻Aβ对神经元细胞的损伤成为研究的热点，也是药物开发的主要方向之一。
蒲公英甾酮是萜类天然产物，目前尚无蒲公英甾酮具有抗老年痴呆作用的报道。
发明内容
本发明的目的在于提供蒲公英甾酮在制备防治老年痴呆的药物中的应用。
本发明的上述目的是通过下面的技术方案实现：
蒲公英甾酮在制备防治老年痴呆的药物中的应用。
蒲公英甾酮的药学上可以接受的盐在制备防治老年痴呆的药物中的应用。
一种防治老年痴呆的药物制剂，以蒲公英甾酮或其药学上可以接受的盐为药物活性成分，制成药学上可以接受的制剂剂型。
优选地，所述制剂剂型为片剂、胶囊、注射剂或口服液。
有益效果：老年痴呆是一种以中枢神经系统原发性、进行性的退行性病变为主要特征的疾病，临床表现为认知和记忆功能的不可逆性恶化，主要因为脑内过度沉积的Aβ对神经元造成损伤。本发明发现，蒲公英甾酮能够保护Aβ引起的神经细胞损伤，因而具有开发成抗老年痴呆药物的前景。
具体实施方式
一、实验材料
Aβ 25-35购自北京博奥森生物技术有限公司；二甲基亚砜(DMSO)购自上海麦克林生化科技有限公司；噻唑蓝(MTT)购自大连美仑生物技术有限公司；蒲公英甾酮购自成都普菲德生物技术有限公司；胎牛血清购自浙江天杭生物科技股份有限公司；RPMI-1640培养基购自Hyclone公司。
凝聚态Aβ 25-35的制备：将1mg Aβ 25-35先溶于适量无菌dd H 2O中，再加入医用无菌生理盐水使Aβ 25-35终浓度为1mM，37℃水浴孵育7d。
二、实验方法
1、细胞培养
取出保存于液氮冷冻的大鼠神经胶质瘤细胞C6细胞株，迅速置于37℃水浴中振荡至细胞融化后，转入已加入培养基的离心管中，以1000rpm离心5min，弃去上清液，加入少量培养基并轻轻吹吸均匀，培养基为含有10％胎牛血清、1％双抗的RPMI-1640培养基，将细胞悬液移入培养皿，在37℃、5％CO 2、饱和湿度条件下培养。
2、细胞模型的制备
将对数生长期的C6细胞制成浓度为2.0×10 5个/mL的细胞悬液，接种于96孔板中，每孔100μL，培养24h后，按照如下分组进行处理，每组5个复孔：
对照组：更换为新鲜培养基继续培养3h；
Aβ 25-35组(模型组)：更换为新鲜培养基继续培养3h；
盐酸多奈哌齐组(阳性药组)：更换为含20μM盐酸多奈哌齐的新鲜培养基继续培养3h；
蒲公英甾酮组：更换为含5、10、20、30μM蒲公英甾酮的新鲜培养基继续培养3h。
按照上述分组继续培养3h后，Aβ 25-35组、盐酸多奈哌齐组、蒲公英甾酮组添加终浓度为10μM的凝聚态Aβ 25-35，对照组加入等体积溶媒，继续培养18h后，各组加入20μL MTT溶液(浓度为5mg/mL)，37℃下继续培养4h。
继续培养4h后，小心吸弃孔内上清液，每孔加入150μL DMSO，震荡10min，使结晶充分溶解；选择490nm波长，在酶联免疫检测仪上测定各孔光吸收值(OD值)，取5个复孔OD值平均数，计算细胞存活率，对照组记为100％。
4、数据处理及分析
采用SPSS19.0软件，多组间比较采用单因素方差分析检验，组间两两比较采用q检验。以P＜0.05为差异有统计学意义。
三、实验结果
各组细胞存活率如表1所示(注：与对照组比较 #p<0.05， ##p<0.01， ###p<0.001；与Aβ 25-35组比较*p<0.05，**p<0.01，***p<0.001)。
表1.蒲公英甾酮对Aβ 25-35诱导的细胞损伤的影响
Figure PCTCN2019119368-appb-000001
与对照组相比，Aβ 25-35组细胞存活率显著降低，说明细胞造模成功；与Aβ 25-35组相比，盐酸多奈哌齐组、蒲公英甾酮组细胞存活率显著升高。盐酸多奈哌齐是美国食品与药物管理局(FDA)批准的用于治疗阿尔茨海默病的药物，20μM约使细胞存活率提升3.4％，而5μM蒲公英甾酮便能使细胞存活率提升7.4％，随着剂量增加保护作用增强，10μM约能提升9.5％，30μM约使存活率提升11.4％，且具有统计学差异。为了排除蒲公英甾酮促进细胞增殖引起的假阳性，我们进行了没有Aβ干预下的蒲公英甾酮对细胞活力的影响测试，结果如表2所示，蒲公英甾酮在5、10、20、30μM浓度下对细胞活力无影响(P﹥0.05)，这一结果表明蒲公英甾酮并没有引起细胞增殖。
表2.蒲公英甾酮对C6细胞增殖活力的影响
Figure PCTCN2019119368-appb-000002
因此，综合表1、2结果可以认为，蒲公英甾酮能够保护Aβ引起的神经细胞损伤，具有开发成抗老年痴呆药物的前景。

Claims (4)

  1. 蒲公英甾酮在制备防治老年痴呆的药物中的应用。
  2. 蒲公英甾酮的药学上可以接受的盐在制备防治老年痴呆的药物中的应用。
  3. 一种防治老年痴呆的药物制剂，以蒲公英甾酮或其药学上可以接受的盐为药物活性成分，制成药学上可以接受的制剂剂型。
  4. 根据权利要求3所述的药物制剂，所述制剂剂型为片剂、胶囊、注射剂或口服液。
PCT/CN2019/119368 2019-01-10 2019-11-19 蒲公英甾酮在制备防治老年痴呆的药物中的应用 WO2020143333A1 (zh)

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