CN107281203A - 娑罗子提取物在制备防治老年痴呆药物中的应用 - Google Patents
娑罗子提取物在制备防治老年痴呆药物中的应用 Download PDFInfo
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- CN107281203A CN107281203A CN201610192547.5A CN201610192547A CN107281203A CN 107281203 A CN107281203 A CN 107281203A CN 201610192547 A CN201610192547 A CN 201610192547A CN 107281203 A CN107281203 A CN 107281203A
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Abstract
本发明公开了娑罗子提取物在制备防治老年性痴呆药物、保健品中的应用,其中娑罗子提取物的活性成分为β‑七叶皂苷。本发明通过实验发现中药材娑罗子提取物能明显改善模型动物记忆障碍、提高学习能力,可以有效改善、调节中枢胆碱能神经,调节自由基代谢等多种作用,对包括阿尔茨海默症、血管性痴呆、混合痴呆等各种老年痴呆症均有确切的疗效。
Description
技术领域
本发明涉及娑罗子提取物的制备方法和用途,特别涉及娑罗子提取物在预防或治疗阿尔茨海默病中的应用,属中药领域范畴。
背景技术
老年性痴呆主要包括阿尔茨海默病(AD)和血管性痴呆(VD),阿尔茨海默病约占60~70%,血管性痴呆约占20~30%。阿尔茨海默病(Alzheimer ’s disease, AD)是一种以进行性痴呆为主的中枢神经系统的退行性疾病。其临床特征为记忆及其他认知功能障碍,早期临床症状包括运动、感觉或协调功能缺陷。AD患者的主要的病理改变为细胞外淀粉样蛋白沉淀形成老年斑、神经元纤维缠结以及广泛神经元突触的缺失、炎症、氧化甚至是坏死。
随着社会的发展和人口的老龄化,阿尔茨海默病的发病随年龄的增长而增加。65岁以上的老人中,阿尔茨海默病的发病率为5%-10%,在85岁以上的老人中,阿尔茨海默病的发病率高达47%-50%。抗阿尔茨海默病药物的研究和开发已成为化学家和药物学家的关注的热点。
AD发病机制复杂,目前国内外尚没有能根本治疗AD的药物,因此早期治疗至关重要。目前已上市的治疗药物主要分为两种,一种为胆碱酯酶抑制剂,如盐酸多奈哌齐、加兰他敏、酒石酸卡巴拉汀、石杉碱甲等;另一种为兴奋性氨基酸受体拮抗剂,如盐酸美金刚。另有抗炎、抗氧化、抗胆固醇、抗β淀粉样蛋白类药物用于AD的辅助治疗。上述药物能短期改善AD患者的症状,但不能缓解疾病的发展,且易形成耐药,不良反应明显;而中医药在防治轻度认知障碍和老年性痴呆具有较好的临床效果,有多途径、多环节整体调节的特点,且使用天然药物的毒副作用小。因此,中药单体或其有效组分的提取应用于AD的防治具有十分重要的意义。
娑罗子为七叶树科植物欧洲七叶树(Aesculus hippocastannum)、日本七叶树(Aesculus turbinata Blume)和中国天师栗(Aesculus Wilsonii Rehd)的果实或种子。欧洲七叶树,又名欧马栗(horse chestnut),其种子和幼枝的外皮可入药,在欧洲应用广泛,早在18世纪即用于解热,19世纪后期可用于治疗痔疮。七叶皂苷(Aescine)是从娑罗子(七叶树种子)中提取的主要活性成分,属于三萜皂苷类药物,含α、β两种异构体,药理研究表明,β-七叶皂苷为其主要的活性异构体,它具有抗渗、消肿、改善血液循环、增加静脉张力、抑制胃排空、清除活性氧和抗肿瘤作用。临床上可广泛应用于慢性静脉功能不全,痔疮、水肿、哮喘等。
研究发现七叶皂苷可促进 SD 大鼠脑源性神经元的生长。本发明人进一步研究发现娑罗子的β-七叶皂苷能明显改善模型动物记忆障碍、提高学习能力,可以有效改善、调节中枢胆碱能神经,调节自由基代谢等多种作用,对包括阿尔茨海默症、血管性痴呆、混合痴呆等各种老年痴呆症均有确切的疗效。
发明内容
本发明的目的在于提供娑罗子提取物β-七叶皂苷在制备预防或治疗老年性痴呆药物、保健品中的应用,其β-七叶皂苷分子式为C55H86O24,如下式所示
β-七叶皂苷主要包含七叶皂苷Ia和七叶皂苷Ib两种成分,其中七叶皂苷Ia的R1为Tig,R2为-COCH3,R3为-H;七叶皂苷Ib的R1为Ang,R2为-COCH3,R3为-H。
本发明所述的防治老年性痴呆的药物或保健品,其特征在于:其剂型为丸剂、颗粒剂、片剂、糖浆剂、合剂、胶囊剂、酊剂、茶剂、注射剂。
本发明所述的防治老年性痴呆的药物或保健品,其特征在于:可制成注射剂、片剂、缓释片、滴丸、颗粒剂、粉针剂、胶囊剂、微粒剂。优选剂型为片剂、滴丸、粉针剂、胶囊剂。可与任何一种或一种以上药剂学上辅料如淀粉、糊精、乳糖、微晶纤维素、羟丙甲基纤维素、聚乙二醇、硬脂酸镁、微粉硅胶、木糖醇、乳糖醇、葡萄糖、甘氨酸、甘露醇、甘氨酸等混合制成的各种剂型。
本发明所述的防治老年性痴呆的药物或保健品,其特征在于:所述老年性痴呆为阿尔茨海默病、血管性痴呆、阿尔茨海默病和血管性痴呆并存的混合性痴呆一种或几种。
本发明所述的防治老年性痴呆的药物或保健品,其特征在于:所述老年性痴呆主要为阿尔茨海默病。
本发明提供的娑罗子提取物可以用于制备保健食品添加剂和/或保健食品,可以制备成保健食品的各种剂型,例如片剂、胶囊剂、口服液、保健饮料、保健茶等;也可以作为食品添加剂,应用于食物(如面包、面条等)、保健茶、保健饮料等。
具体实施方式
下面通过具体实施例对该发明作进一步的描述。
实施例1: 体外研究证明娑罗子提取物能抑制Aβ的神经毒性对AD具有治疗作用
1.细胞株及试剂
大鼠嗜铬细胞瘤SH-SY5Y细胞(购自ATCC)、DMEM/F12、胎牛血清 、MTT、盐酸多奈哌齐(在美国 Sigma购买)、石杉碱甲(在美国 Sigma购买)、七叶皂苷钠(山东绿叶制药有限公司)
2.药物配制
①七叶皂苷钠用DMSO溶解后用生理盐水稀释,配成浓度为1 mg /mL、5mg /mL、10mg /mL
②Aβ25-35用三蒸水配制成100 μmol /L,过滤,分装,-20℃ 冻存;使用前配制成所需浓度,并在37℃孵育7 d。
③阳性药:盐酸多奈哌齐和石杉碱甲溶于空白血清,盐酸多奈哌齐配制浓度为5mg/ml,石杉碱甲,为0. 45mg /ml。
3.模型建立
取对数生长期SH-SY5Y细胞,1mL 0.25%胰酶消化、离心后用完全培养基重悬,密度为105mL-1 ,接种于96孔板( 100μL)或24孔板( 1mL)。待80% 融合时吸去旧培养液,加入新培养液,并将细胞分为15组,加入Aβ25-3530μmol/L,作用24h后加不同浓度的七叶皂苷钠,温度37℃培养24h。
4.神经元细胞活力检测
每组设3个平行样本,取均值。96孔板分别培养相应时间, 每孔加入 20 μl MTT(浓度为5 mg/ml),调零孔只加培养液。37℃继续培养4 h后,以扣板法扣除液体,每孔再加入150μl DMSO,37 ℃振荡10 min ,待紫色结晶充分溶解后,置酶标仪上,以滤过波长490 nm,测各孔光吸收值(OD)。然后以OD值求细胞存活率。
细胞存活率(%) =实验组OD/对照组OD×100%
5.神经元凋亡率检测
Annexin-V/PI双染法使用流式细胞仪检测神经元凋亡率。收集神经元离心(2000rpm离心5min);PBS洗涤细胞二次(2000rpm离心5min)收集1~5×105细胞;加入500μL的BindingBuffer悬浮细胞;加入5μL Annexin V-FITC混匀后,加入5μL Propidium Iodide,混匀;室温、避光、反应5~15min;流式细胞仪检测。
6.结果
6.1 MTT提示Aβ25-35明显降低神经元的生存率,娑罗子提取物能抑制Aβ的神经毒性:
Aβ25-35浓度为30 μmol /L 时,与空白对照组比较,模型组细胞生存率为( 65. 8±3.9) %,出现明显的下降( P<0. 001),说明造模成功;与模型组比较,娑罗子提取物中剂量组(88.1± 5.1) %和高剂量组( 87.4± 4.4) %的细胞生存率均明显的上升( P<0.01),说明娑罗子提取物能抑制Aβ的神经毒性。
6.2 AV/PI结果显示白芍苷能减少Aβ25-35导致的神经细胞凋亡,Aβ25-35浓度为30 μmol /L时,与空白对照组比较,模型组细胞生存状态出现明显变化,凋亡率增加明显,可达45% 以上;与模型组比较,娑罗子提取物中剂量组(27.8%)和高剂量组的凋亡率(26.4%)明显的减少( P<0. 05),说明白芍苷能抑制Aβ的导致的神经细胞凋亡。
7.结论
娑罗子提取物能保护Aβ25-35对SH-SY5Y细胞的损伤,增加SH-SY5Y细胞的存活率。
实施例2:在体研究证明娑罗子提取物对APP/PS1双转基因痴呆小鼠具有治疗作用
1材料
1.1实验动物
5月龄APP/PS1双转基因小鼠48只,雄性,体重25±2g,SPF级,相同遗传背景C57BL/6J小鼠8只为正常对照。
1.2实验药物及试剂
阳性对照药物选用盐酸多奈哌齐(商品名称:安理申),5mg/片,使用前将片剂研成粉末,以双蒸水配制成灌胃药液0.65mg/kg·d- 1;石杉碱甲胶囊用双蒸水配制成灌胃药液,配制浓度为0.026mg/kg·d- 1。乙酰胆碱酯酶 ( AChE)试剂盒、胆碱乙酰转移酶(ChAT)试剂盒、SOD活性试剂盒、MDA含量试剂盒、GSH含量试剂盒。下述“本发明中药有效组分”是指实施例1和实施例2中的中药有效组分。注射用七叶皂苷钠(批号:1509015,山东绿叶制药股份有限公司)
1.3主要仪器
DMS-2型Morris水迷宫仪数据自动采集及处理系统,BH-2型生物显微镜,DpxView Pro型计算机彩色图像处理系统,石蜡切片装置,全自动封闭式组织脱水机,包埋机,病理组织漂烘仪,Image-Pro Plus图像分析系统,高速冷冻低温离心机。
2方法
2.1分组与给药
按体重一致原则,随机将APP/PS1双转基因小鼠分为模型组、娑罗子提取物低剂量组(1mg/kg/d)、娑罗子提取物中剂量组(4mg/kg/d)、娑罗子提取物高剂量组(8mg/kg/d)、盐酸多奈哌齐组(0.65mg/kg/d)和石杉碱甲组(0.026mg/kg·d),每组8只;相同遗传背景的同月龄C57BL/6J小鼠8只作为正常对照组。正常组和模型组给以等体积蒸馏水灌胃,每日1次。各组小鼠灌胃8周,至7月龄时进行Morris水迷宫试验。
2.2脑组织样品处理
小鼠于末次行为学测试后,禁食12h,进行脑组织取材。对脑组织进行病理及免疫组化染色、组织含量测定等实验。
2.4统计学处理
所得数据以均数±标准差表示,采用统计软件SPSS18.0进行统计分析,组间数据比较用单因素方差分析,采用LSD、Dunnett′sC(方差不齐时)检验,以P<0.05为差异有显著性意义。行为学Morris水迷宫测定中定位航行试验采用重复测量设计的方差分析,空间探索试验采用单因素方差分析。
3实验结果
3.1 Morris水迷宫实验中娑罗子提取物对APP/PS1双转基因小鼠学习记忆能力影响结果显示,与空白对照组比较,模型组的逃避潜伏期显著延长(P<0.01),平台停留时间和目标象限停留时间显著减少(P<0.05);与模型组比较,娑罗子提取物中剂量组(P<0.01)、高剂量组(P<0.01)和阳性药组(P<0.05)逃避潜伏期显著延长,娑罗子提取物中剂量组的目标象限穿越次数、平台停留时间、目标象限停留时间和穿越平台次数显著减增加,说明娑罗子提取物可以提高大鼠学习记忆能力;与阳性药比较,娑罗子提取物中剂量组潜伏期比阳性药组短、平台停留时间比阳性药组长和穿越平台次数比阳性药组多,说明娑罗子提取物中剂量组对大鼠学习记忆能力的提高作用比阳性药好(见表1)。
表1娑罗子提取物对APP/PS1双转基因小鼠空间学习记忆能力的影响
组别 | 数量 | 逃避潜伏期(s) | 目标象限穿越次数 | 平台停留时间(s) | 目标象限停留时间(s) | 穿越平台次数 |
空白对照组 | 8 | 22.1±2.7 | 3.8±0.3 | 0.7±0.1 | 12.7±1.2 | 3.2±0.4 |
模型组 | 8 | 39.7±4.6## | 2.6±0.2 | 0.4±0.1# | 7.8±0.8# | 2.0±0.3 |
娑罗子提取物低剂量组 | 8 | 33.1±3.5 | 3.1±0.3 | 0.5±0.1 | 10.7±1.0 | 2.8±0.2 |
娑罗子提取物中剂量组 | 8 | 28.3±3.4** | 4.0±0.5* | 0.8±0.1* | 11.9±1.2* | 4.1±0.5* |
娑罗子提取物高剂量组 | 8 | 30.2±3.1** | 3.7±0.3 | 0.6±0.1 | 10.3±1.3 | 3.0±0.4 |
盐酸多奈哌齐组 | 8 | 32.7±3.4* | 3.9±0.4 | 0.7±0.1* | 12.5±1.4* | 3.1±0.3 |
石杉碱甲组 | 8 | 29.2±2.8** | 4.1±0.3* | 0.6±0.1 | 12.1±1.1* | 2.7±0.3 |
与空白对照组比较,#P<0.05、##P<0.01;与模型组比较*P<0.05
3.2娑罗子提取物对APP/PS1双转基因小鼠海马内胆碱乙酰转移酶(AchE)和乙酰胆碱酯酶(ChAT)活性的影响结果显示,与空白对照组比较,模型组的Ach含量显著降低、AchE活性显著增加、ChAT活性显著减少;与模型组比较,娑罗子提取物中剂量组(P<0.01)、高剂量组(P<0.05)和阳性药组(P<0.05)、石杉碱甲组(P<0.05)的Ach含量显著增加,娑罗子提取物高剂量组(P<0.01)和阳性药组(P<0.05)的AchE活性显著减少,娑罗子提取物和阳性药组ChAT活性显著增加;说明娑罗子提取物可以改善、调节中枢胆碱能神经系统(见表2)。
表2娑罗子提取物对APP/PS1双转基因小鼠海马内Ach、AchE和ChAT含量的影响
组别 | 剂量mg/kg | Ach(ug/ml) | AchE( U/mg) | ChAT( U/mg) |
空白对照组 | 121.24±9.21 | 0.584±0.042 | 0.065±0.007 | |
模型组 | 87.25±9.03## | 0.788±0.051## | 0.041±0.003## | |
娑罗子提取物低剂量组 | 1.0 | 95.33±10.28 | 0.703±0.052 | 0.060±0.008* |
娑罗子提取物中剂量组 | 4.0 | 116.07±11.06** | 0.695±0.049 | 0.067±0.007** |
娑罗子提取物高剂量组 | 8.0 | 104.66±10.19* | 0.643±0.040** | 0.061±0.004* |
盐酸多奈哌齐组 | 0.65 | 109.64±12.52* | 0.652±0.047* | 0.059±0.005* |
石杉碱甲组 | 0.026 | 111.30±11.70* | 0.668±0.039* | 0.063±0.006* |
与空白对照组比较,##P<0.01;与模型组比较*P<0.05、**P<0.01
3.3娑罗子提取物对APP/PS1双转基因小鼠海马中老年斑(SP)的影响结果显示,与空白对照组比较,模型组小鼠海马中SP数量显著增加(P<0.001);与模型组比较,娑罗子提取物中剂量组(P<0.05)、高剂量组(P<0.001)和阳性药组小鼠海马中SP数量显著减少,说明娑罗子提取物可减少APP/PS1双转基因小鼠海马中老年斑沉积(见表3)。
表3 娑罗子提取物对APP/PS1双转基因小鼠海马中老年斑(SP)的影响
组别 | 剂量mg/kg | 动物数量 | SP数量(个) |
空白对照组 | 8 | 2.8±0.6 | |
模型组 | 8 | 51.6±6.7### | |
娑罗子提取物低剂量组 | 1.0 | 8 | 43.1±4.8 |
娑罗子提取物中剂量组 | 4.0 | 8 | 22.9±3.5* |
娑罗子提取物高剂量组 | 8.0 | 8 | 15.7±2.4*** |
盐酸多奈哌齐组 | 0.65 | 8 | 19.5±3.1** |
石杉碱甲组 | 0.026 | 8 | 20.7±3.3** |
与空白对照组比较,###P<0.001;与模型组比较*P<0.05、**P<0.01
3.4娑罗子提取物对APP/PS1双转基因小鼠海马SOD活性、MDA含量、GSH含量的结果显示与空白对照组比较,模型组的SOD活性显著减少、MDA含量显著增加;与模型组比较,娑罗子提取物中剂量组(P<0.01)、高剂量组(P<0.05)和阳性药盐酸多奈哌齐组(P<0.05)SOD活性显著增加,娑罗子提取物中剂量组和阳性药盐酸多奈哌齐组(P<0.05)MDA含量显著减少,说明娑罗子提取物可以提高大鼠海马组织的抗氧化能力(见表4)。
表4 娑罗子提取物对小鼠海马中SOD活性、MDA含量、GSH含量影响
组别 | 剂量mg/kg | SOD(U/mgprot) | MDA(nmol/mgprot) | GSH(mg/gprot) |
空白对照组 | 37.32±3.22 | 2.88±0.24 | 5.24±0.94 | |
模型组 | 32.29±3.04# | 4.19±0.43# | 4.37±0.87 | |
娑罗子提取物低剂量组 | 1.0 | 35.31±6.33 | 4.03±0.37 | 4.93±0.24 |
娑罗子提取物中剂量组 | 4.0 | 42.74±8.29** | 3.29±0.20* | 4.64±0.37 |
娑罗子提取物高剂量组 | 8.0 | 37.44±10.08* | 3.52±0.44 | 4.88±0.61 |
盐酸多奈哌齐组 | 0.65 | 36.63±5.74* | 3.25±0.13* | 4.51±0.89 |
石杉碱甲组 | 0.026 | 34.31±6.77 | 3.67±0.28 | 4.98±0.67 |
与空白对照组比较,#P<0.05;与模型组比较*P<0.05、**P<0.01
本发明采用娑罗子提取物作为制备治疗阿尔茨海默病的药物,采用相关药理学试验进行娑罗子提取物防治阿尔茨海默病的药效学评价,分别从改善中枢胆碱能神经系统、抑制β淀粉样蛋白(Aβ)形成和沉积、神经保护方面,阐明娑罗子提取物多途径、多靶点治疗阿尔茨海默病的用途。
Claims (6)
1.娑罗子提取物β-七叶皂苷在制备预防或治疗老年性痴呆药物、保健品中的应用,其特征在于β-七叶皂苷分子式为C55H86O24,如下式所示
β-七叶皂苷主要包含七叶皂苷Ia和七叶皂苷Ib两种成分,其中七叶皂苷Ia的R1为Tig,R2为-COCH3,R3为-H;七叶皂苷Ib的R1为Ang,R2为-COCH3,R3为-H。
2.根据权利要求1所述,其特征在于所述老年性痴呆为阿尔茨海默病、血管性痴呆、阿尔茨海默病和血管性痴呆并存的混合性痴呆一种或几种。
3.根据权利要求2所述,其特征在于娑罗子提取物主要用于治疗阿尔茨海默症的药物、保健品中的应用。
4.根据权利要求1述防治老年痴呆的药物或保健品的制备方法,其特征在于:其剂型为注射剂、丸剂、颗粒剂、片剂、糖浆剂、合剂、胶囊剂、酊剂、茶剂。
5.根据权利要求4所述,其特征在于可与任何一种或一种以上药剂学上辅料如淀粉、糊精、乳糖、微晶纤维素、羟丙甲基纤维素、聚乙二醇、硬脂酸镁、微粉硅胶、木糖醇、乳糖醇、葡萄糖、甘氨酸、甘露醇、甘氨酸等混合制成的各种剂型。
6.根据权利要求1至5所述,其特征在于制剂可以是口服、非肠道、直肠、鼻内给药的形式,也可以制成气雾剂、吸入剂等给药的形式。
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