CN1929853A - 神经保护性膳食补充剂 - Google Patents
神经保护性膳食补充剂 Download PDFInfo
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- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
本发明公开了一种具有神经保护活性的新的膳食补充混合物,其包含一种肽配制品,所述配制品包含以序列1:NMVPFPR或序列2:ASAFQGIGSTHWVYDGVGNS定义的两种肽中的至少一种。
Description
本发明涉及一种新的膳食补充剂,其可用作神经保护剂并口服施用。
在世界范围内老年人数目稳步增长。事实上现在老年人活的更长。因此,与年龄相关的缺陷(例如与年龄相关的记忆减退、认知下降等)正在成为重要的公共健康问题。
EP1325747A2公开了一种膳食补充剂,其包含平衡量的具有神经保护活性的天然物质(例如α-硫辛酸和γ-亚油酸或大豆磷脂)、具有抗炎及抗氧化和糖代谢及脂代谢调节特性的化合物、以及复合B族维生素。
本发明的一个目的是提供一种新的膳食补充混合物,该混合物具有增强的神经保护活性,并预防、改善或对抗神经变性,以及预防、对抗和/或改善认知功能下降。
本发明的另一个目的是提供一种以口服剂型施用的膳食补充剂。
所述具有神经保护活性的新的膳食补充剂包含一种肽配制品,所述配制品包含以序列1:NMVPFPR或序列2:ASAFQGIGSTHWVYDGVGNS定义的两种肽中的至少一种。
所述新的膳食补充混合物可预防或改善与年龄相关的神经变性、与年龄相关的认知下降和与年龄相关的记忆减退。其可用作增强人,优选老年人的记忆、注意力和警惕性的配制品。
所述新的膳食补充混合物基本由分子量小于10kDa的分子组成,并包含由下列序列定义的肽中的至少一种:
序列1:NMVPFPR
序列2:ASAFQGIGSTHWVYDGVGNS。
利用普遍已知的技术进行序列测定,例如质谱分析、串联质谱分析、电泳、色谱分离后的测序等。
所述新的膳食补充混合物可进一步包含额外的分子量小于10kDa的肽。
其可进一步包含氨基酸。
合适的氨基酸例如是天冬酰胺(N)、甲硫氨酸(M)、谷氨酸(E)、缬氨酸(V)、脯氨酸(P)、精氨酸(R)、丙氨酸(A)、半胱氨酸(C)、苯丙氨酸(F)、谷氨酰胺(Q)、甘氨酸(G)、苏氨酸(T)、异亮氨酸(I)、色氨酸(W)、酪氨酸(Y)、苏氨酸(T)、丝氨酸(S)、组氨酸(H)、天冬氨酸(D)、赖氨酸(K)、亮氨酸(L)等。这些氨基酸优选以其光学活性形式使用,最优选使用L-氨基酸。
所述新的膳食补充混合物可进一步包含维生素,例如维生素A、不同的B族维生素、维生素C、维生素D、E和/或K。其还可进一步包含矿物质和/或微量元素,例如钙、镁、铁、铜、钠、锌、锰、碘、钾、硒、铬、钼、氟、氯、磷。更多成分可以是咖啡因和牛磺酸、脂肪酸例如Ω-脂肪酸、α-硫辛酸、磷脂、磷脂酰丝氨酸、植物提取物(例如银杏叶提取物)、石杉碱,神经递质前体如DMAE(二甲氨乙醇)等。
其可进一步包含调味剂、着色剂(如二氧化钛、氧化铁等)和/或防腐剂等。防腐剂可以是:
-羟苯乙酯(对羟基苯甲酸乙酯)
-苯扎氯铵
-苄索氯铵
-苯甲酸
-尼泊金丁酯(对羟基苯甲酸丁酯)
-尼泊金甲酯(对羟基苯甲酸甲酯)
-山梨酸钾
-丙酸
-尼泊金丙酯(对羟基苯甲酸丙酯)
-苯甲酸钠
-丙酸钠
-山梨酸
该混合物可进一步包含可接受的添加剂、填充剂和/或赋形剂,例如微晶纤维素、麦芽糊精、硬脂酸镁、胶体氧化硅、二氧化硅、乳糖、麦芽糖、羧甲基纤维素钠、改性纤维素、植物纤维素、磷酸钙、磷酸钠、植物性甘油、淀粉钠、聚乙烯吡咯烷酮、聚乙烯聚吡咯烷酮、羧甲基纤维素、硬脂酸、明胶、甘露醇、抗坏血酸钠、甘油、米粉、麦芽糊精磷酸二钾等。
优选地,本发明的膳食补充混合物包含10-30wt%的肽、2-20wt%的氨基酸和达2-76wt%的如上定义的额外的成分、填充剂等。
所述膳食补充混合物以片剂、包衣片剂、胶囊、糊剂、咀嚼片或饮用溶液的形式口服使用。如果使用包衣片剂,该配制品可抵抗胃液,因此可使用肠包衣剂型。所述膳食补充混合物可以以其口服剂型每天使用至少一次。
本发明的膳食补充混合物产品可用于预防、改善、对抗与衰老过程相关的缺陷,优选是哺乳动物,尤其是人,最优选老年人中与衰老过程相关的缺陷。
其可用作保护神经元对抗与衰老过程相关的代谢缺陷和应激的配制品以预防、对抗和/或改善由于缺氧或缺血导致的与年龄相关的神经元损伤后果、由于细胞内钙过载导致的与年龄相关的神经元损伤后果、由如L-谷氨酸导致的与年龄相关的神经元损伤后果和由于氧化应激导致的与年龄相关的神经元损伤后果。
特别地,其也用以预防、对抗和/或改善与年龄相关的神经变性的后果,预防由于细胞应激、神经变性病变和中毒导致的神经元细胞死亡,维持和保持衰老过程中正常的神经元细胞结构,支持和/或改善突触功能和突触密度,预防、对抗和/或改善与年龄相关的突触可塑性和突触密度、作用下降的后果,激活与注意力和记忆力相关的大脑机制,预防、对抗和/或改善认知功能下降,预防、对抗和/或改善记忆功能下降,预防、对抗和/或改善注意力不足,预防、对抗和/或改善与衰老过程相关的警惕性下降,以及支持、维持和/或改善长期记忆力和程序性记忆力以及学习表现、注意力和警惕性,并且用以在衰老过程中保持/支持健康的精神功能。
实施例1:
粉末混合物的制备:
用1.2mm筛网将
-49.490kg粉末,包含6.7%的肽、17.5%的氨基酸和75.8%的乳糖
-6.738kg羧甲基纤维素
-9.607kg微晶纤维素
-0.525kg无水胶体氧化硅
筛选到不锈钢筒中,并用翻滚型混合器以6rpm的混合速度混合10分钟(混合物1)。
用1.2nm筛网将1.015kg硬脂酸镁筛选到含混合物1的不锈钢筒中。随后,用翻滚型混合器以4rpm的混合速度将所有的颗粒混合5分钟(最终混合物)。
粉末混合物的压制(压片)
用约40,000片/小时的压片速度压片机压制混合物。使用圆形、双凸面冲头,其直径11mm。
以这种方式,得到具有以下特性的片剂:
-平均重量: 385.0+/-7.7mg
-硬度: 40-70N
-崩解: 不超过15.00分钟
-脆性: 不超过1.00%
(所有的测试方法都依据欧洲药典)
实施例2
片剂的包衣
在实施例1中获得的片剂可被包衣。
将以下成分用推进式混合器进行混合以形成薄膜包衣悬浮液:
-23.810kg醋酞纤维素(30%水性溶液)
-0.595kg滑石粉
-0.833kg二氧化钛
-1.429kg柠檬酸三乙酯
在转鼓式包衣机(drum coater)中,用薄膜包衣悬浮液包衣片剂至终重量为428.0mg/膜片。
包衣片可用蜂蜡或石蜡打光。
以这种方式,得到具有以下参数的薄膜包衣的白色片剂:
-平均重量: 428.0+/-8.6mg
-崩解: 不超过30.00分钟
-脆性: 不超过1.00%
(所有的测试方法都依据欧洲药典)
实施例3
或者,可将用于压片的粉末混合物(参见实施例1)装填到硬明胶胶囊中。
用385mg的粉末混合物装填0号或1号硬明胶胶囊。从而获得具有以下参数的胶囊:
-平均重量: 462.0+/-28.8mg(1号)
-平均重量: 481.0+/-28.8mg(0号)
-崩解: 不超过15.00分钟
或者,相当量的颗粒可使用2号和3号硬明胶胶囊。
实施例4:
饮用溶液的制备
将-70.72g粉末(包含6.7%的肽、17.5%的氨基酸和75.8%的乳糖)-400.00g蔗糖
-5.00g苯甲酸
溶于盛有1500g水的玻璃烧瓶中,该烧瓶装有推进式混合器。形成几乎澄清的溶液(溶液1):
将-85.00mg核黄素(riboflavine)
-17.00g草莓香精
-10.00g Aroma Milk-caramel或2.6g Aroma Orange
溶于盛有溶液1的玻璃烧瓶中,该烧瓶装有推进式混合器。形成几乎澄清的溶液(溶液2)。
将-125.0mg维生素E
悬浮于盛有200.00g水的玻璃烧瓶中,该烧瓶装有推进式混合器。将该悬浮液添加到溶液2中(溶液3)。
将-5.00g海藻酸钠
溶于500.00g温水中,并添加到溶液3中(溶液4)。
用水将溶液4加至5000ml,并在装备有推进式混合器的玻璃烧瓶中进行混合。形成几乎澄清的溶液,将其通过0.45μm薄膜滤器进行过滤以进一步澄清。将该溶液装填于带有螺旋瓶盖的20ml玻璃瓶中。
实施例5:
神经保护作用-在培养基中保护皮层神经元免遭不同的与年龄相关的损伤
5.1方法
在试验前对所有必需物品进行灭菌。购买无菌储备溶液,并且在层流橱(laminar airflow cabinet)中混合终溶液。
用于大批分析的培养基由DMEM(Dulbecco′s Modified EagleMedium)培养基与4.5g葡萄糖/L、5%胎牛血清、0.01%庆大霉素和2mM L-谷氨酰胺组成。培养基中的L-谷氨酰胺是生长和分化所必需的,并且庆大霉素必需加入以防止培养基被支原体或其它有害微生物污染。每次试验,在无菌条件下,在层流橱中制备新鲜的营养培养基。
用于试验的细胞是罗曼褐(Lohman Brown)杂种鸡胚。从当地养鸡者(Schlierbach Geflügel GmbH,奥地利)购买一日龄受精卵,并在适当条件下(12±0.3℃,80±5%的湿度)保存于实验室中。在0胚龄时,将卵转移至育种培养箱中,并于38±0.5℃和55±5%的湿度持续翻转保存至8胚龄。为了分离神经元,每次试验使用3至4枚鸡胚。这些胚胎的胚龄非常关键,因为只有在发育的特定时期脑才会几乎仅含有神经细胞和少于5%的神经胶质(Pettmann,B.,Louis,J.C.和Sensenbrenner,LM.(1979)Nature281:378-380)。
用70%的乙醇擦拭卵,并用大镊子钝端击碎。将胚胎断头后,除去覆盖端脑的组织,并收集脑半球。除去任何lease组织并保留脑膜后,将脑半球转移至含有营养培养基的皿中。然后,通过使用1ml的吸液管并通过在孔径100μm的无菌尼龙筛网上挤压3次,将组织机械分离。
使用标准台盼蓝染料排除试验(PM实验室),可以测定细胞数目和细胞存活力。为了进行细胞计数,1份细胞悬浮液必须用9份的台盼蓝溶液(270IJ I PBS和180IJL 0.5%台盼蓝溶液)稀释。在Bürker-Türk-血细胞计数器中计数存活细胞和染蓝的死亡细胞。细胞总数减去染色的死亡细胞得到存活细胞的量。
为了进行损伤分析,将初始组织培养基从细胞中除去并保存起来。加入含有氰化钠或秋水仙碱(氰化钠0.01M、0.1mM、1mM;秋水仙碱0.1μM、1μM、10μM)的新培养基,并与细胞一起保持30分钟。然后,除去该损伤培养基并将其废弃,重新加入初始培养基,并将该培养物再保持24或48小时的恢复期。此后进行存活力测试。在所描述的实验中,使用聚D-溶素包被的96孔微量滴定板。将含有6×105细胞/ml的80_1培养基添加到事先制备的微量滴定板的每个孔中,这些滴定板已含有80_1物质补充培养基。因此,每孔中最终的细胞数为3×105/ml营养培养基。受损的和未受损的对照仅在整个试验期间在营养培养基中生长。当制备平板时,孔外常规地充满了营养培养基只为了防止蒸发。将平板在37℃、95%的湿度和5%的CO2且不更换培养基的条件下保持至试验结束。在培养基中几个小时后,神经元开始伸展过程。
将本发明的混合物进行安瓿包装用作即可使用(ready-to-use)的溶液。为了得到浓度为1.25、2.5、5、10、20、40、80、160μl/ml的培养基,在DIV 1以合适的浓度向孔中添加所述混合物一次,并与神经元保持至试验结束。在DIV 8开始发生损伤,在DIV 9和DIV 10分别进行细胞存活力的评估。在保持培养基期间,损伤发生后,没有进一步添加物质。
在损伤检测中,在不同的两天、相同的条件下对本发明的混合物进行测试。在每次试验中,对损伤组和损伤对照组生成至少6个特定值,对每一浓度生成2个特定值(总共n=12)。将本发明的混合物补充到浓度为1.25、2.5、5、10、20、40、80、160μl/ml的培养基中。对具有不同损伤的不同试验组进行了研究。
在每次试验结束,用MTT还原比色分析法测量剩余神经细胞的存活力。该分析基于黄色MTT(3-(4,5-二甲噻唑-2-基)-2,5-联苯四唑溴)被线粒体脱氢酶(琥珀酸脱氢酶)还原为深蓝色甲晶体。由于所描述的反应仅在活细胞中被催化,该分析可用于定量细胞存活力。为了测定细胞存活力,向每一孔中加入MTT溶液至终浓度0.5mg/ml。2小时后,可期望获得含MTT的培养基。用3%的SDS裂解细胞,将甲
晶体溶于异丙醇/盐酸中。使用平板读数器(Anthos II)(570nm)以评估光密度。神经元存活力用光密度(OD)表示。
使用描述性统计分析方法。MTT值(OD)用平均值±标准差表示。
5.2结果
首先,使用不同浓度的损伤化合物(氰化钠和秋水仙碱)获得相对于未损伤的神经元为约50%的神经元损伤。以总体损伤是明显但仍允许神经元存活和恢复的方式来选择合适的损伤剂量和损伤时间。过高的剂量将导致快速的神经元死亡,限制了神经保护性物质挽救(rescue)它们的可能性;过低的剂量也不能获得对保护性化合物的可信赖的评估,因为在损伤和未损伤对照之间的差异太小了。
以氰化钠造成中毒30分钟后,对48小时细胞存活力的评估显示本发明仍有显著的神经保护作用,但与24小时后的观察结果相比略低一些(图1和2)。由秋水仙碱引起的细胞骨架破裂也导致了严重的神经变性。24小时后,本发明的0.4mg的低剂量不能呈现显著的挽救,但所有其它剂量以高于损伤对照组约50%的水平提高了神经元存活力。损伤开始后48小时,所有的剂量具有明显的神经保护作用,则在3.2mg的高剂量组中存活力已经比未损伤对照高出100%,这表明多数的神经元可以被挽救(图3和4)。
图1-4表示相对于未处理的损伤对照(=100%),由于使用本发明的混合物导致的存活力的相对变化:
图1:通过暴露于氰化钠诱导细胞毒性缺氧后24小时,本发明不同剂量对神经元存活力的影响。
图2:通过暴露于氰化钠诱导细胞毒性缺氧后48小时,本发明不同剂量对神经元存活力的影响。
图3:通过暴露于秋水仙碱诱导细胞骨架破裂后24小时,本发明不同剂量对神经元存活力的影响。
图4:通过暴露于秋水仙碱诱导细胞骨架破裂后48小时,本发明不同剂量对神经元存活力的影响。
从这些试验得到的总的结论清晰地表明本发明能够保持神经细胞存活,保护它们免受代谢应激和代谢衰竭的损伤,并刺激细胞存活、轴突及其分支的生长。如果由体外的不同毒素诱导的神经元损伤太严重,只能获得轻微的保护,在轻度至中度损伤情况下,可评估显著的剂量依赖效应。
然而,本发明的复合组合物表明所述肽以协同方式发挥作用,结合神经营养性刺激,增加抗凋亡因子和结构蛋白的合成,抑制蛋白酶和代谢调节的异常上调。这些作用的总和表明了这一膳食补充剂在体外保护高度易损的细胞的引人关注的潜力。
实施例6:
老龄大鼠的长期处理(与口服施用生理盐水相比,每天经口管饲处理,进行3个月)
6.1方法
6.1.1处理和行为测试
所有试验在18月龄(±1月龄)的Long Evans大鼠中进行。将大鼠随机分配至不同组中,或用本发明的混合物处理或用生理盐水处理作为对照。每组的动物数为12-15只。用如实施例5中定义的本发明的混合物或生理盐水经口管饲每天1次,对两组试验组的动物都处理3个月。在每月最后4个处理日里(第27-30个处理日=第1-4个试验日;第56-60个处理日=第5-8个试验日以及第87-90个处理日=第9-12个试验日),在MWM中进行行为学测试以评估动物的学习和记忆功能。
所使用的MWM由圆形游泳池组成,该游泳池直径170厘米,高45厘米。附加的内置铝环用于隐藏所有将电脑系统与隐藏的平台相连的电缆。这不必给动物提供迷宫内标记,标记可能影响正常的学习行为。该池子的内表面涂成黑色,这样从外面不能检测到透明的耐热有机玻璃(Plexiglas)平台。淹没在水中的平台(直径15厘米)总是位于池中完全相同的位置,东南象限。使用发光二极管检测每只大鼠的游泳路径,二极管的信号可被连接到个人电脑上的摄像机检测到,使得能够持续跟踪游泳路径。特别设计的软件(ART3)可以计算游泳路径的长度、到达隐藏平台的潜伏期、在象限中花费的时间、经过目标区域的情况和所有其它适于评估学习和记忆功能的参数。将发现所述平台的逃逸潜伏期(Eescape Latency)以及游泳路径的长度用于统计计算本发明的混合物对学习功能的影响。在每个跟踪(训练)天,每只大鼠进行4次游泳试验。根据Kruskal和Wallis应用h-检验,或在正态分布值下应用方差分析(ANOVA)和用于post hoc分析的Scheffe检测进行统计分析。
6.1.2组织学检查
在MWM中完成行为学试验后,利用超剂量的戊巴比妥(Nembutal)立即处死每组4-6只大鼠。为了得到合适的组织学标本,用生理盐水和福尔马林进行穿心灌注。为了完成固定,将脑转移至10%福尔马林中,然后包埋在石蜡中。在切片机上切成厚度为3μm(Bregma水平~-4.00mm)的切片,并与抗囊状蛋白突触泡蛋白的抗体一起温育。利用酶反应(APC法,过氧化物酶缀合的二抗、二氨基联苯胺用作底物)可显示出免疫反应。
由于事实上在突触密度和突触泡蛋白免疫反应性之间存在良好相关性,因此使用成像分析系统(LUCIA-Nikon Photo Systems,奥地利)进行突触数的光学显微定量。在清楚定义的海马分区(CA1辐射层、CA2辐射层、CA3辐射层、CA3透明层、齿状回侧切面(dentate gyrus lateral blade)和齿状回中切面(dentate gyrusmedial blade))以及内嗅皮层(第2和3层)进行成像分析。出于该目的,对突触泡蛋白免疫反应斑点的数目和这些点的全部面积进行测量和统计计算(Kruskal-Wallis ANOVA)。
6.2结果
6.2.1在MWM中的行为学测试
6.2.1.1逃逸潜伏期
逃逸潜伏期被定义为将动物置于游泳池中到成功找到MWM中的隐藏平台之间的时间。如上述,动物必需利用额外的迷宫标记获得定向。逃逸潜伏期是对学习和记忆的测量。
在第1个训练期,施用1个月后,在两组试验组之间不能检测到明显差异。然而,存在这样一个明显的趋势,即用本发明的混合物处理的动物完成任务更快,但训练4天后结果是相同的。
在第二个月结束时,本发明的混合物组和生理盐水处理对照组在训练的第一天存在统计学上的显著差异(p=0.0049)。这表明了长期记忆力的稳定性,最可能也是改善的过程学习。用本发明的混合物处理的大鼠从第一个试验起记住了最初的平台位置,换句化说,在一个月的时期内它们没有忘记该位置,并且由于它们已经知道任务的程序,它们比对照组完成得更好。由于在训练的第一天它们显示出极低的逃逸潜伏期,在第二月末进一步提高是不可能的,这是由游泳速度的限制导致的天花板效应所致。对照组动物在训练期间显示出持续的提高,但在最后一天它们仍劣于经本发明的混合物处理的动物。在3个月处理期末,以本发明的混合物处理的大鼠开始仍具有比对照组更低的潜伏期。然而,两组之间都显示非常好的表现并且没有进一步提升的空间。
6.2.1.2对长期记忆力的研究
对试验4第4天和试验1第5天之间以及试验4第8天和试验1第9天之间,在逃逸潜伏期上的差异的分析:
对长期记忆力(第一个月末的最后测试日的最后试验和第2个月末的第一个训练日的第一次试验之间潜伏期的差异;第二个月末的训练日的最后试验和3个月处理期末的第一个训练日的第一次试验之间潜伏期的差异)的评估显示用本发明的混合物处理的大鼠在提高长期记忆力上具有明显趋势。如果第一个月的最后训练日的最后试验的逃逸潜伏期与第2个月期间的第一个训练日的第一次试验的潜伏期相比,本发明的混合物处理的动物在表现上提高了差不多10秒。相反,对照组动物略低。将2个月期间的最后训练日末的最后试验与该处理结束后的第一个训练日的第一次试验之间的表现进行比较,结果再次显示本发明的混合物组的表现提高了超过10秒。生理盐水处理对照组几乎没有显示出变化,这表明在本发明的混合物处理的大鼠中长期记忆力得到提高。
分别对一个月后的第一个训练日、处理2个月后的第一个训练日和处理3个月后的第一个训练日之间的逃逸潜伏期进行分析:
作为用于长期记忆力的第二种测量方法,将真正的第一个学习天与处理2个月和3个月后的第一个训练日之间的差异进行评估。这将用作测量逃逸潜伏期总提高的方法,比较首次用于试验的大鼠与重复训练的大鼠进行比较。差异越大反映出长期记忆力越好;小的差异表明在不进行训练的处理期间,动物忘记了所述平台的位置。
图5(训练第1天(1个月处理)和第5天(2个月处理)之间逃逸潜伏期的差异;数据以平均数±标准差表示。**=P<0.01)证明在真正的第一个训练日(首次用于实验的大鼠首次置于MWM中)和处理2个月后的重复训练之间存在差异。与第一个处理日相比,本发明的混合物处理的动物与第一个训练日相比,提高了差不多25秒或近50%,而生理盐水处理的对照仅显示大约12秒或低于25%的提高。将第一个训练日和处理期(3个月)结束后的第一个训练日的重复训练之间的逃逸潜伏期进行比较,两组之间没有显示出显著的差异。仍然存在趋势支持本发明的混合物的处理,但数据清楚地表明重复训练最终导致在所有处理组中的成功。必须考虑到所有的试验都是在老龄,但在其它方面健康且没有任何明显神经紊乱的动物中进行的。因此,可预期延长训练将持续增加两个处理组的认知力。
图5:第1天和第5天之间逃逸潜伏期的差异
6.2.1.3游泳路径长度的评估
由于运动差异可以使得逃逸潜伏期发生偏差,并因此也计算了游泳路径长度。增加游泳速度或降低游泳速度将模拟学习和记忆方面的其它变化。游泳路径的长度是学习和记忆力独立的测量方法,不依赖于游泳速度。
数据证实了在2个月处理期结束后的第一个训练日,本发明的混合物处理的大鼠和对照之间统计学上的显著差异(p=0.0133)。这表明先前分析的数据是可靠的,且本发明的混合物处理不依赖于任何运动行为的改变提高认知力(图6)。
图6:在测试第1-4、5-8和9-12天在Morris水迷宫中游泳路径长度。数据以平均数±标准差表示。*=P<0.01[MO=本发明混合物;con=对照]
对试验4第4天和试验1第5天之间以及试验4第8天和试验1第9天之间,在游泳路径长度上的差异进行分析:
第一组训练期间的最后试验与处理2个月后的第二次训练期间的第一次试验的游泳路径长度的比较,精确地反映出了在评估逃逸潜伏期时所观察到的情况。在本发明的混合物处理组中,游泳路径长度缩短了约2.1米,这意味着甚至在没有训练4周后他们仍能较更精确地通过。对照组需要多出1.4米来找到所述平台,这反映出在最初地恢复中存在某种程度的困难,或者换句化说,它们需要重新学习到达靶的精确的和最短方向。
如果将第二期(处理2个月后)的最后测试日的最后训练的表现与在3个月末的第一个训练日的第一次试验的表现进行比较,游泳路径长度差不多短了2米。这再次表明本发明的混合物在长期记忆力功能上的强烈影响。对照组动物没有显示任何进一步的提高。
6.2.2.突触密度的组织学评估
突触泡蛋白免疫反应“斑点”的数目
用本发明的混合物进行3个月的处理期导致在所研究区域中的4个区域的突触密度有统计学上的显著增长。在CA3辐射层和齿状回侧切面,至少存在在本发明的混合物处理的动物中增加突触素密度的强烈趋势,且仅在CA3辐射层中所述处理没有导致突触密度增加。
突触泡蛋白免疫活性区域的评估
前面的评估计数了每个单独的免疫反应斑点,与此不同,现在测量所有被突触泡蛋白免疫反应活性覆盖的区域,与对血管和组织破裂进行校正后的脑切片的所有区域进行比较。结果反映了通过免疫反应斑点计数获得的数据,仅有的例外是对内嗅皮层的影响略低于显著水平(p=0.0550)。所有其它的差异仍保持显著,并且可以对在本发明的混合处理的大鼠中突触密度增加的总趋势进行确认。
图7:海马结构的不同区域中突触泡蛋白免疫活性的面积占对照值的百分比。100%=在生理盐水对照组中计数的免疫反应斑点数。竖棒表示平均数±标准差。*=P<0.05[MOI=本发明混合物;CON=对照]
在Morris水迷宫中进行的行为学测试结果显示自第二个月末在本发明的混合物处理组和对照组之间存在统计学上的显著差异。用本发明的混合物处理的动物发现Morris水迷宫中隐藏的平台比对照组要快。这表明本发明的混合物提高了健康老龄大鼠的长期记忆力。数据表明长期摄食生长因子样肽耐受良好,并能给脑提供神经营养刺激。在本试验中显示出的用本发明的混合物提高的认知力与海马中形态学变化相关。总之,本发明提供了一种新的补充剂,其可帮助在衰老过程中维持记忆和学习能力,并可能减少与衰老过程相关的认知功能下降的危险。
实施例7:
在健康老年人中认知功能的增强
7.1方法
本研究中包括6名健康成年人(4女、2男),年龄63.0:3.6年(范围:51-76岁)。记录样本的体重、身高、体重指数(BMI)和其它生物学特征。
在选入之前,在所有受试者中进行医学和心理测验评估、定量EEG和ECG以及实验室分析。没有受试验者达到老年性痴呆的DSM-IV和/或NINCDS-ADRDA标准(American PsychiatricAssociation,1994;McKhann et al.,1984)。在研究前和研究期间,所有受试验者完全没有使用药物。从所有的研究参与者获得书面通知同意书。该研究由Institutional Review Board主持,并根据Good Clinical Practice guidelines进行。
该试验是开放标签、探索性试验,其目的在于评估本发明的混合物以单剂量口服施用对健康老年人脑机能的影响。共包括6名均大于50岁的受试者。每个参与者的研究持续时间为2天。在第1天、施用本发明的混合物前24小时对参与者进行认知评估,并在第2天、施用本发明的混合物后6小时进行第二次、处理后评估。所有研究参与者都接受本发明的混合物单口服剂量(180mg)。
7.2结果
对于接受研究的受试验者在基线处的平均MMSE得分为28.4±0.4分。用本发明的混合物处理后观察到在ADAS-记忆得分上的显著提高(基线处6.9±1.0的遗漏对处理后4.9±1.0的遗漏;p<0.01)。这一记忆改善对于单词识别项目上也具有统计学显著性(2.8±0.6遗漏对1.5±0.7遗漏;p<0.05)-图8
图8:通过在健康老年受试者中利用ADAS的记忆项目评估本发明对记忆力的影响。ADAS记忆得分(遗漏)表示单词回忆和单词识别项的总和。
根据该研究的结果,经过单剂量施用后,本发明的混合物支持和提高健康老年受试验者的记忆力。本发明的混合物诱导的提高在单词识别任务和ADAS的总记忆单项分值(subscore)上达到显著值,但在单词回忆项上没有达到显著值。本发明的混合物还以非显著的方式增强在SKT的认知任务中的表现(涉及注意力和记忆功力两方面)。单独的SKT任务包括搭积木、计数标志和识别记忆等项目,在用本发明的混合物处理后可观察到最佳效果。这些效果表明本发明可在成年老龄人中增强注意力和记忆功能而没有认知力损害。
本发明的结果表明本发明的混合物支持了健康老年志愿者的脑功能,在认知力(记忆力和注意力)上具有明显的积极作用。因此,本发明的混合物似乎构成了一种有用的膳食补充剂以支持和提高老年受试验者的认知力。
Claims (15)
1、具有神经保护活性的膳食补充混合物,其包含一种肽配制品,该配制品包含以序列1:NMVPFPR或序列2:ASAFQGIGSTHWVYDGVGNS定义的两种肽中的至少一种。
2、权利要求1的膳食补充混合物,进一步包含额外的氨基酸。
3、权利要求1的膳食补充混合物,包含分子量低于10kDa的另外的肽。
4、权利要求1的膳食补充混合物,包含微量元素和/或矿物质和/或维生素和/或咖啡因和/或牛磺酸和/或脂肪酸和/或磷脂和/或磷脂酰丝氨酸和/或植物提取物。
5、权利要求1的膳食补充混合物,进一步包含可接受的添加剂和/或赋形剂和/或填充剂和/或着色剂和/或调味剂。
6、一种口服剂型,其包含权利要求1-5中任一项的膳食补充混合物和可接受的添加剂和/或赋形剂和/或填充剂和/或着色剂和/或调味剂和/或溶剂。
7、包含权利要求1的膳食补充混合物的口服剂型,其包含2-20wt%的肽。
8、权利要求7的口服剂型,进一步包含10-30wt%的氨基酸。
9、权利要求1-8中任一项的膳食补充混合物在预防、改善与年龄相关的记忆损伤和/或与年龄相关的认知力下降和/或良性老年性遗忘中的应用。
10、权利要求1-5中任一项的膳食补充混合物在保护神经元对抗与衰老过程相关的代谢缺陷和应激中的应用。
11、权利要求1-5中任一项的膳食补充混合物在预防、对抗和/或改善由于缺氧或缺血导致的与年龄相关的神经元损伤后果、由于细胞内钙过载导致的与年龄相关的神经元损伤后果、由L-谷氨酸和兴奋性中毒事件导致的与年龄相关的神经元损伤后果和由于氧化应激导致的与年龄相关的神经元损伤后果中的应用。
12、权利要求1-5中任一项的膳食补充混合物在预防、对抗和/或改善与年龄相关的神经变性的后果;预防由于细胞应激、神经变性病变和中毒导致的神经元细胞死亡;维持和保持衰老过程中正常的神经元细胞结构;支持和/或改善突触功能和突触密度;预防、对抗和/或改善与年龄相关的突触可塑性和突触密度下降的后果中的应用。
13、权利要求1-5中任一项的膳食补充混合物在激活与注意力和记忆力相关的大脑机制中的应用。
14、权利要求1-5中任一项的膳食补充混合物在预防、对抗和/或改善认知功能下降;预防、对抗和/或改善记忆功能下降;预防、对抗和/或改善注意力不足;预防、对抗和/或改善与衰老过程相关的警惕性下降;以及支持、维持和/或改善长期记忆力和程序记忆力以及学习表现、注意力和警惕性中的应用。
15、权利要求1-5中任一项的膳食补充混合物在衰老过程中保持/支持健康的精神功能中的应用。
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CN110051001A (zh) * | 2019-04-26 | 2019-07-26 | 复旦大学附属华山医院 | 一种用于改善记忆的膳食补充剂 |
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