CN109125311A - 预防或治疗阿尔茨海默症的药物组合物及其应用 - Google Patents
预防或治疗阿尔茨海默症的药物组合物及其应用 Download PDFInfo
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Abstract
本发明公开一种组合物,组合物包括亚麻油酸、辣木籽油酸、花生四烯酸、b谷甾醇、维生素B1、维生素C、维生素E、维生素B5、维生素B2、维生素B3、天冬氨酸。本发明还公开组合物在制备预防治疗阿尔茨海默症的药物或食品中的应用。本发明的组合物的功能是增加多巴胺和血清素水平;维持细胞膜的流动性、促进葡萄糖代谢、促进ATP产生;抗自由基、抗氧化胁迫;抑制促炎基因;增加乙酰胆碱酯酶抑制剂功能;调整组蛋白的修饰和DNA的修饰。总体结果为减缓记忆损伤、减缓AD进程、促进干细胞更新、减缓神经性炎症、具有缓解和治疗阿尔兹海默症的作用。阿尔兹海默症模型小鼠在食用该配方食物30天后,学习能力和空间定位能力有显著性改善。
Description
技术领域
本发明属于药物、食品领域,具体涉及预防或治疗阿尔茨海默症的药物组合物及其应用。
背景技术
阿尔兹海默症(Alzheimer’s disease(AD))是一种严重危害人类健康的神经退行性疾病,分子水平上主要表现为神经细胞外的Aβ沉淀和细胞内由于磷酸化的Tau蛋白的装配而形成的神经纤维纠缠(NFT)。这两种因素通过复杂过程最终导致神经元死亡,由此造成患者记忆和认知功能的退行性丧失。80岁以上的老年人中,每2人就有1人会罹患阿尔兹海默症,随着中国老龄化社会的来临,阿尔兹海默症患者会急剧增多,预防、减缓或者治疗的该疾病的措施刻不容缓。
目前,美国食品药品监督局(FDA)批准的治疗阿尔兹海默症的药品有:donepezil、galantamine、memantine、rivastigmine、donepezil+memantine。这些药物主要的作用机理是改善神经递质系统或者修改疾病通路,进而缓解症状,并不能治愈(Nature reviewsDrug discovery,2010,9(5):387-398)。近年,多种针对AD的药物在三期临床试验期折戟(Nature Reviews Drug Discovery,2017,16:819),尽管仍有在研药物在实验,但前景依然不明。
AD具有复杂的病理,涉及凋亡、自噬、内吞、炎症、Tau磷酸化、Aβ沉淀、代谢、神经递质等多种过程。因此,研发针对多种过程的复合的制剂也许是可行的。包括研究表明,一些重要的脂肪酸、维生素、氨基酸等在具有维持神经信号转导、增强细胞的能量转化利用、对抗自由基、清除淀粉样沉淀等作用。如果能利用这些物质调制发明一种配方,可以减缓或者阻止神经细胞死亡、改善或者恢复记忆和学习能力、减轻患者症状,起到预防、减缓或者治疗阿尔兹海默症的作用,那将极大减少患者痛苦、治疗成本以及家庭社会医疗负担,将非常有价值。
发明内容
发明目的:本发明的目的是提供一种组合物及其应用,该组合物公开一种包含3种不饱和脂肪酸、8种维生素和4种氨基酸的配方,其功能在于减缓记忆损伤、减缓AD进程。阿尔兹海默症模型小鼠在食用该配方食物30天后,学习能力和空间定位能力有显著性改善。
技术方案:为了解决上述技术问题,本发明所采用的技术方案为:一种组合物,所述组合物包括亚麻油酸、辣木籽油酸、花生四烯酸、β谷甾醇、维生素B1、维生素C、维生素E、维生素B5、维生素B2、维生素B3、天冬氨酸。
进一步地,所述组合物按重量份数包括以下组分:亚麻油酸26.6~29.4份、辣木籽油酸0.95~1.05份、花生四烯酸0.95~1.05份、β谷甾醇0.095~0.105份、维生素B1 0.0142~0.0158份、维生素C 0.0133~0.0147份、维生素E 0.0142~0.0158份、维生素B5 0.019~0.021份、维生素B2 0.0114~0.0126份、维生素B3 0.0034~0.0038份、天冬氨酸2.28~2.52份。
作为优选,所述组合物按重量份数包括以下组分:亚麻油酸28份、辣木籽油酸1份、花生四烯酸1份、β谷甾醇0.1份、维生素B1 0.015份、维生素C 0.014份、维生素E 0.015份、维生素B5 0.0 20份、维生素B2 0.0 12份、维生素B3 0.0036份、天冬氨酸2.4份。
作为优选,所述组合物按重量份数还包括以下组分:淀粉37.58份,纯净水5份。
所述的组合物的制备方法:按比例称取,常温(25℃)混合,搅拌搓成球状(直径约0.2厘米)。
本发明内容还包括上述的组合物在制备预防治疗阿尔茨海默症的药物或食品中的应用。
其中,所述预防治疗阿尔茨海默症的药物的剂型为片剂、胶囊、缓释片、控释片、口服液、糖浆、滴丸、注射液剂型、冻干粉针剂型,所述食品为任何包含该组合物的营养液、饮料或者固体食物。
本发明内容还包括所述组合物在构建阿尔兹海默症动物模型中的应用。
本发明中配方预防、减缓或者治疗阿尔兹海默症的机理或者证据如下:
1、亚麻油酸(C18:2)
亚麻油酸在AD中低;缺乏导致多巴胺、血清素在前额叶中的减少;该酸的缺乏导致神经性畸形。
2、辣木籽油酸
辣木籽油酸是一种神经酰胺(ceramide),其在轻度认知障碍(MCI)患者脑中水平下降。有证据表明部分MCI患者最终会转化为AD。
3、花生四烯酸(AA)
足量的AA是脑正常活动的必备条件,具有维持海马细胞膜的流动性、抗氧化胁迫(通过激活过氧化酶体生长激活受体γ(PPARγ)。能激活突触融合蛋白3(STX-3),这个蛋白在神经元生长和修复中有作用。花生四烯酸在AD患者的脑中,其消耗速率比正常人更大(The Journal of nutrition 2008,138(12):2515-2520)也就是说AA相关的代谢通路被上调,有文献佐证:负责转化AA的酶cytosolic phospholipase A2(cPLA2)在AD患者的额叶皮质上调。补AA可以减缓AD进程,缓解症状(Psychopharmacology 2009,202(1-3):37-51)。
4、β谷甾醇(β-sitosterol)
增加线粒体内膜的流动性,促进ATP产生,改善AD症状。
5、维生素B1(thiamine)
维生素B1是细胞葡萄糖代谢(三羧酸循环TCA)的关键步骤,缺乏维生素B1会产生和AD类似的症状:认知障碍、葡萄糖代谢的减少、Tau蛋白的磷酸化。
6、维生素C
维生素C能产生自由基陷阱(抗氧化)、抑制促炎基因、减缓神经性炎症、螯合铜铁Zn、抑制β淀粉样(Aβ)纤维化。
7、维生素E
维生素E具有抗氧化性,抵抗由Aβ诱导产生的氧化胁迫,延缓记忆衰退。
8、维生素B5(Pantothenic Acid)(泛酸)
维生素B5是合成乙酰辅酶A(CoA)的重要物质,乙酰辅酶A(CoA)具有将脂肪、蛋白转化为葡萄糖的作用;能增加乙酰胆碱酯酶抑制剂的作用,过量具有副作用,可增加出血。缺乏会导致脱髓鞘(Rucker R.B.et al.Handbook of Vitamins.5th ed.CRC Press;BocaRaton,FL,USA:2013)。
9、维生素B2(Riboflavin)(核黄素)
维生素B2是能量代谢、ATP生成等氧化还原过程中的重要物质(FAD\FMA),缺乏导致个性改变、脑功能紊乱。
10、维生素B3(Niacin)(烟碱酸)
大剂量的烟酸可以逆转AD造成的记忆损失。新近发现:烟酸对线粒体功能、干细胞更新以及对抗神经胁迫非常重要。给AD小鼠喂食烟酸(nicotinamide riboside),可以治疗AD的症状。
11、天冬氨酸
在AD中降低40%。
有益效果:与现有技术相比,本发明的优点是:本发明的组合物配方的功能在于:增加多巴胺和血清素水平;维持细胞膜的流动性、促进葡萄糖代谢、促进ATP产生;抗自由基、抗氧化胁迫;抑制促炎基因;增加乙酰胆碱酯酶抑制剂功能;调整组蛋白的修饰和DNA的修饰。总体结果为减缓记忆损伤、减缓AD进程、促进干细胞更新、减缓神经性炎症、具有缓解和治疗阿尔兹海默症的作用。阿尔兹海默症模型小鼠在食用该配方食物30天后,学习能力和空间定位能力有显著性改善(实施例2,图1、图2);需要说明:对照组小鼠日常食物含有本发明配方中的一种或者几种成分,但对AD的改善却不及本配方,说明本配方中的成分具备协同增效作用。概括之,本发明的实验研究发现,阿尔兹海默症模型小鼠在食用本发明的组合物食物30天后,学习能力和空间定位能力有显著性改善。
附图说明
图1、水迷宫训练实验第1~4天的潜伏时间的箱式图;水迷宫训练实验中,小鼠在4天中的潜伏时间(单位:秒(S))。配方组:服用实施例1的配方制剂30天后的小鼠,共10只;对照组:未服用配方的小鼠,共9只。图1中显示为每天训练中潜伏时间的箱式图,虚线和实线分别连接配方组和对照组的潜伏时间的均值,对照组和配方组的潜伏时间的差异用双尾t检验(two-tailed t-test),P表示显著性值;
图2、水迷宫训练实验第5天的滞留时间的箱式图;水迷宫训练实验中,小鼠在第5天测试实验中(撤掉升降台),在各象限滞留时间,观测时间长度为80秒,箱式图所示为各象限滞留时间的百分比,目标象限为第二象限。配方组:服用实施例1的配方制剂30天后的小鼠,共10只;对照组:未服用配方的小鼠,共9只。图中FC为配方组滞留时间均值与对照组滞留时间均值的比值,比值大于1,说明配方组在该象限滞留时间超过对照组。
具体实施方式
下面通过具体的实施例对本发明进一步说明,应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干变型和改进,这些也应视为属于本发明的保护范围。
实施例1:配方的制备
本实施例的配方的组成和成分如表1,共计11中成分,总重32.5796克。各成分购买来源、纯度等级见表1。将表1的各成分常温(25℃)混合,搅拌搓成球状(直径约0.2厘米)、常温晾干。
表1预防、减缓或治疗阿尔兹海默症的配方成分、含量百分比、来源及纯度等级
在喂食小鼠时,与小鼠的日常饲料以32.5796:67.4204的比例称取混合。
实施例2配方的制备
亚麻油酸26.6份、辣木籽油酸0.95份、花生四烯酸0.95份、β谷甾醇0.095份、维生素B1 0.0142份、维生素C 0.0133份、维生素E 0.0142份、维生素B5 0.019份、维生素B20.0114份、维生素B3 0.0034份、天冬氨酸2.28份。
该组合物的制备方法同实施例1。
实施例3配方的制备
亚麻油酸29.4份、辣木籽油酸1.05份、花生四烯酸1.05份、β谷甾醇0.105份、维生素B1 0.0158份、维生素C 0.0147份、维生素E 0.0158份、维生素B5 0.021份、维生素B20.0126份、维生素B3 0.0038份、天冬氨酸2.52份。
该组合物的制备方法同实施例1。
实施例4:实施例1制备的配方在阿尔兹海默症小鼠中减缓和治疗效果评估。
1、实验设计
阿尔兹海默症小鼠B6C3-Tg(APPswePSEN1dE9Nju)/Nju来自南京大学模式动物研究所。对照小鼠9只,服用配方组小鼠10只。配方组小鼠在服用配方制剂30天后开展水迷宫实验,对照组小鼠食用普通饲料。体重45.5±4.5克(g)。年龄:8个月。
2、配方制剂
按照实施例1所述方法制备配方和小鼠食物。配方比例:亚麻油酸(28克/100克)、辣木籽油酸(1克/100克)、花生四烯酸(1克/100克)、β谷甾醇(0.1克/100克)、维生素B1(15毫克/100克)、维生素C(14毫克/100克)、维生素E(15毫克/100克)、维生素B5(20毫克/100克)、维生素B2(12毫克/100克)、维生素B3(3.6毫克/100克)、天冬氨酸(2.4克/100克)。配方与小鼠的日常饲料以32.5796:67.4204的比例称取混合。日常饲料中包含30%聚乙二醇+0.5%吐恩80(Tween80)+5%丙二醇+64.5%二次蒸馏水。
3、配方用法:以上述配方制剂和小鼠日常饲料的混合物喂食小鼠,每12小时一次,每次足额补给。
4、水迷宫实验
Morris水迷宫(Morris water maze,MWM)实验强迫实验动物游泳,学习寻找隐藏在水中平台的一种实验,主要用于测试实验动物对空间的学习记忆能力。
实验:直径1.5米的恒温游泳池1台,温度控制在25℃;可升降站台设置在第二象限。小鼠连续训练4天,训练中,将升降台抬升出水面。将小鼠放入池中,记录其找到升降台的时间,此为潜伏时间,如果小鼠在60秒后仍未找到升降台,则引导小鼠去升降台,停留10秒。在第5天,撤掉升降台,然后记录小鼠在各象限所滞留的时间,观测总时间为80秒。
5、实验结果
采用实施例1制备的组合物可有效改善AD小鼠的学习能力和记忆能力。在阿尔兹海默症模型小鼠(AD小鼠)的水迷宫试验中验证了配方的效果。在30天内,相比于对照小鼠,服用本发明配方的阿尔兹海默症模型小鼠,其学习能力和空间定位能力都有了显著改善(图1和图2)。
在学习能力方面(图1),潜伏时间越短,说明学习能力越好。本次水迷宫实验中,对照组和服用配方组的潜伏时间随时间逐渐降低,说明训练时间越长,学习效果越大,符合预期,水迷宫实验整体有效。重要的是:服用配方组30天后,其潜伏时间显著小于对照组(P<0.05,n=19)(图1),说明服用配方能增加AD小鼠学习效率,说明其学习能力被改善。
在空间定位能力方面(图2),小鼠在目标象限(本次实验为第2象限)滞留的时间越长,说明其空间定位能力越好。实验中,在30天后,服用配方的AD小鼠的空间定位能力整体能力比对照组提升27%(图2)。
整体显示了良好的改善和治愈效果。
上述仅为本发明优选的实施例,并不不限制于本发明。对于所属领域的技术人员来说,在上述说明的基础上还可以做出其他不同形式的变化或变动。这里无需也无法对所有的实施例来举例说明。而由此方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之内。
Claims (7)
1.一种组合物,其特征在于,所述组合物包括亚麻油酸、辣木籽油酸、花生四烯酸、b谷甾醇、维生素B1、维生素C、维生素E、维生素B5、维生素B2、维生素B3、天冬氨酸。
2.根据权利要求1所述的一种组合物,其特征在于,所述组合物按重量份数包括以下组分:亚麻油酸26.6~29.4份、辣木籽油酸0.95~1.05份、花生四烯酸0.95~1.05份、 b谷甾醇0.095~0.105份、维生素B1 0.0142~0.0158份、维生素C 0.0133~0.0147份、维生素E 0.0142~0.0158份、维生素B5 0.019~0.021份、 维生素B2 0.0114~0.0126份、维生素B3 0.0034~0.0038份、天冬氨酸2.28~2.52份。
3.根据权利要求2所述的组合物,其特征在于,所述组合物按重量份数包括以下组分:亚麻油酸28份、辣木籽油酸1份、花生四烯酸1份、b谷甾醇0.1份、维生素B1 0.015份、维生素C 0.014份、维生素E 0.015份、维生素B5 0.020份、维生素B2 0.012份、维生素B3 0.0036份、天冬氨酸2.4份。
4.根据权利要求3所述的组合物,其特征在于,所述组合物按重量份数还包括以下组分:淀粉37.58份,纯净水5份。
5.权利要求1~4任一项所述的组合物在制备预防治疗阿尔茨海默症的药物或食品中的应用。
6.根据权利要求5所述的应用,其特征在于,所述预防治疗阿尔茨海默症的药物的剂型为片剂、胶囊、缓释片、控释片、口服液、糖浆、滴丸、注射液剂型、冻干粉针剂型,所述食品为任何包含该组合物的营养液、饮料或者固体食物。
7.根据权利要求5所述的应用,其特征在于,所述组合物在构建阿尔兹海默症动物模型中的应用。
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