CN103732223A - 用于认知能力下降的医疗食品 - Google Patents
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Abstract
本发明提供了在诊断患有神经变性疾病的成年人中改善认知功能的营养制剂,该营养制剂包含非瑟酮和DHA的组合。
Description
优先权
本申请要求对2011年5月19日提交的美国临时专利申请61/488,003的优先权。
政府的权利
本工作得到美国退伍军人事务部的支持,因而联邦政府在本发明中具有一定的权利。
背景技术
阿尔茨海默病(AD)是大脑的变性疾病。在老年人中它是痴呆的首要原因。AD患者具有增加的与记忆丧失和智力功能有关的问题,其进展到这种地步,其中他们不能作为正常个体。随着智力技能的丧失,患者呈现人格改变、社会不当行为和精神分裂症。对于受害者和他们的家人而言,AD均是灾难性的,这是因为对于不可避免的神经变性目前没有有效的姑息治疗或预防治疗。
在宏观水平下,AD患者的大脑通常更小,有时重量小于1,000克。在微观水平下,AD的组织病理学特征包括神经纤维缠结(NFT,或神经元纤维缠结)、神经炎性斑、和神经元变性。AD患者在大脑皮质的额叶和颞叶皮层、海马的锥体细胞、在扁桃体的内侧、中央内侧、和皮质核中的神经元、在蓝斑中的去甲肾上腺素能神经元、和在基底前脑胆碱能系统中的神经元中呈现神经细胞变性。在胆碱能系统中神经元的丧失导致在AD中胆碱能突触前标记的一致短缺。
微管相关蛋白,称作Tau,已牵连到阿尔茨海默病的病因学。Tau结合于微管并协助它们的形成和稳定。然而,当tau被高磷酸化时,它不能结合,以及微管变得不稳定并开始分裂。在称作神经纤维缠结的形成中未结合的tau凝集在一起。更明确地说,当tau被过度磷酸化并在不适当的氨基酸残基上时,会发展细胞内病变,称作神经纤维缠结前状态(pretangle)。这些病变,随着时间的推移,发展成丝状神经纤维缠结(NFT),其干扰许多细胞内功能。
利用抗tau和抗泛素免疫染色,已定义了NFT的三种不同的成熟状态。在0阶段,存在形态正常的锥体细胞,其显示弥散的或细颗粒细胞质染色(借助于抗tau)。在第1阶段,tau抗体染色一些纤巧细长的内含物;第2阶段表现为借助于抗tau染色的经典的NFT演示;通过遗留缠结(ghost tangle,残壳)来举例说明第3阶段,其中宿主神经元已经死亡,其特点在于减少的抗tau但显著的抗泛素免疫染色。已经表明,在疾病如AD中,认知障碍的程度与神经纤维缠结的存在显著关联。
可以使认知能力下降(其可以是tau蛋白病)减轻的制剂的开发非常有益于临床和研究的目的。
出版物
Cole and Frautschy,The Journal of Nutrition,首次公布于doi:10.3945/jn.109.113910.Greenet al.(2007)J.Neurosci.27(16)4385-95;Maher(2010)InMicronutrients and Brain Health,L.Parker,H.Sies,M.Eggersdorfer,and E.Cardenas,eds.(Boca Raton,FL,CRC Press),pp.189-206,Genes Nutr.2009Sep10;Akaishi et al.(2008)NeurosciLett.444(3):280-5;Maher(2008)Arch BiochemBiophys.476(2):139-44;Maher et al.(2006)P.N.A.S.103(44):16568-73;Maher(2006)Free RadicRes.40(10):1105-11。
发明内容
本发明至少部分地基于新颖的营养制剂的发现,上述制剂可以在诊断患有神经变性疾病的成年人中改善认知功能。感兴趣的疾病包括那些与β-淀粉样蛋白和tau/缠结病理相关的疾病,其可以包括相关于老化或阿尔茨海默病、额颞痴呆、皮克病、和进行性核上麻痹的认知能力下降。本发明的组合物提供了组合剂量的二十二碳六烯酸(DHA)和非瑟酮,其可有效放缓或治疗认知能力下降。
新配方包括非瑟酮和DHA的组合,其出人意料地协同作用。因此,本发明的制剂提供了用于改善认知的新的治疗方法,例如在老年人中以及在诊断患有神经变性疾病的成年人中。在第一方面,本发明的特征在于用于在主体(受试者)中改善认知功能的方法,该方法包括给予主体本发明的营养制剂或组合物。在一种示例性实施方式中,主体已被诊断患有阿尔茨海默病。
从以下详细描述中和从权利要求中,本发明的其它特点和优点将是显而易见的。
附图说明
图1示出Morris Water Maze结果。
图2示出在探针测试中的保留。
图3示出蛋白质的Western分析。
图4示出在N9小胶质细胞中的非瑟酮(Fis)和DHA。
定义
可以按照已知方法来配制本发明的组合物以制备药用和营养用组合物,其中,将这些材料、或它们的功能衍生物与药用和营养用载体以混合的方式组合。适宜的药物载体和它们的配方,包括其它人蛋白,例如,人血清白蛋白,描述于,例如,Remington'sPharmaceutical Sciences(16.sup.th ed.,Osol,A.ed.,Mack Easton Pa.(1980))。为了形成适用于有效给予的药用组合物,上述组合物将包含有效量的上述化合物以及适量载体。
有效量有所不同,其取决于待治疗主体的健康和身体状况、待治疗主体的分类群(例如,人、非人灵长类等)、主体的神经系统的容量、所期望的保护程度、主治医生对医疗情况的估计、待治疗或预防的病症、以及其它相关因素。
在进一步详细描述本发明的组合物和方法以前,可以理解的是,本发明并不限于所描述的特定方法,因为该方法当然可能会变化。也可以理解的是,除另有说明外,本文中所使用的术语仅用于描述特定实施方式的目的而不是限制性的。
在提供数值范围的情况下,可以理解的是,除非上下文中另有明确规定,上述范围的上限和下限之间的每个中间值(至下限的单位的十分之一),以及在规定范围内的任何其它陈述值或中间值涵盖在本发明。这些较小范围的上限和下限可以独立地包括在较小范围内,并受制于在规定范围内的任何明确排除的限制。
本文讨论的出版物仅提供它们在本申请的提交日期以前的披露内容。此处任何信息均不被解释为承认,凭借先前的发明,本发明无权早于上述出版物。另外,提供的出版物的日期可以不同于实际出版日期,其可能需要被独立地确认。
非瑟酮(2-(3,4-二羟基苯基)-3,7-二羟基-4H-色原-4-酮)是黄色类黄酮多酚,其以非常低的量存在于许多食物中,尤其是草莓。和白藜芦醇一样,它已被报告为激活去乙酰化酶(sirtuin)的化合物。和许多其它多酚一样,它具有多效性抗氧化剂和抗炎活性(参见,例如,Geraets et al.(2009)Biochemical and Biophysical Research Communications382(3):598–603)。
DHA(二十二碳六烯酸;均顺式-二十二碳-4,7,10,13,16,19-六烯酸)是ω-3脂肪酸,其是人大脑皮质、精子、睾丸和视网膜的主要结构成分。它可以合成自α-亚麻酸或直接获自鱼油。
冷水海洋鱼油富含DHA。在能够获得冷水海洋食物的鱼和多细胞生物中的大多数DHA源自光合和异养微藻类,并且它们越在食物链的上端,DHA在生物中变得越来越浓缩。DHA还商业上制备自微藻类:寇氏隐甲藻(Crypthecodinium cohnii)和另一种裂殖壶菌属(Schizochytrium)。在人类中,DHA获自饮食或合成自二十碳五烯酸(EPA,20:5,ω-3),其中经由二十二碳五烯酸(DPA,22:5ω-3)作为中间体。
DHA是在大脑和视网膜中最丰富的ω-3脂肪酸。DHA包含40%的在大脑中的多不饱和脂肪酸和60%的在视网膜中的PUFA。神经元质膜的百分之五十的重量由DHA构成。DHA调节胆碱、甘氨酸、和牛磺酸的载体介导转运,延迟整流钾通道的功能,和包含在突触囊泡中的视紫质的反应(除其它许多功能以外)。DHA缺乏与认知能力下降相关(参见Lukiw et al.(2005)J Clin Invest.115(10):2774–83)。
初步研究表明,DHA可以缓慢在小鼠中阿尔茨海默病的进展。然而,第一次大规模的人体试验表明,在患有轻度至中度阿尔茨海默病的老年人中单独DHA并不放慢心智功能的衰退(Quinn et al.(2010)JAMA304(17):1903–11)。这些试验是用来评估在阿尔茨海默病中的DHA的较大的美国国立卫生研究院(NIH)干预研究的一部分。
具体实施方式
本发明至少部分地基于新颖的营养制剂的发现,上述营养制剂可以改善认知功能,例如在诊断患有神经变性疾病(如早期和中/晚期阿尔茨海默病)的成年人中。非处方营养制剂的开发是高度期望的,既作为预防措施,又用来增强任何药物治疗方法。上述营养制剂还可用于正常主体,例如,寻求改善认知功能的正常成年人。
本文描述的营养制剂包含这样的成分,其协同提供神经保护作用以抵抗不期望的炎症和丝状神经纤维缠结(NFT)(其干扰许多细胞内功能)的发展。在动物模型3xAD转基因小鼠中,营养制剂的成分的共同给予会在较长的一段时间内保持和/或改善认知功能(或认识性能),表明成分的组合可用于治疗和/或减少伴随AD和其它tau蛋白病(taouopathy)的症状。
可以单独或连同其它营养或药物组合物一起来使用或给予上述营养制剂。适用于连同本发明的制剂一起给予的营养或药物组合物包括有效改善认知或减少伴随神经系统疾病(例如,阿尔茨海默病和其它tau蛋白病)的症状的营养或药物组合物。可以将本发明的组合物给予哺乳动物,例如小鼠,包括用于神经疾病的小鼠模型,人等。
在一些优选的实施方式中,口服给予制剂。在一种可替换的实施方式中,胃肠道外给予制剂。在这些方面的进一步的实施方式中,作为单位剂型来给予制剂。可以基于两种药剂的重量/剂量单位来定义本发明的组合产品。基于重量,非瑟酮与DHA的比率通常为约20:1至约1:20,约10:1至约1:10,约5:1至约1:5。约2:1至约1:2;以及在一些实施方式中为约1:6、约1:10、约1:15或约1:20。
在一种示例性实施方式中,制剂的单位剂量包含至少约25mg、至少约100mg、至少约500mg、至少约1g、至少2g、至少约5g、或至少约10g的量的DHA。制剂的单位剂量可以包含至少约10mg、至少约50mg、至少约100mg、至少约250mg、至少约500mg、至少约1g、至少约2g、至少约5g、或至少约10g的量的非瑟酮。可以利用本领域已知的方法来制备营养制剂。可选地,除了非瑟酮和DHA以外,营养制剂进一步包含一种或多种抗氧化剂,例如抗坏血酸、辅酶Q等。
在一种示例性实施方式中,制剂的单位剂量包含至少约25mg、至少约100mg、至少约500mg、至少约1g、至少2g、至少约5g、或至少约10g的量的DHA。制剂的单位剂量可以包含至少约10mg、至少约50mg、至少约100mg、至少约250mg、至少约500mg、至少约1g、至少约2g、至少约5g、或至少约10g的量的非瑟酮。可以利用本领域已知的方法来制备营养制剂。关于营养制品的另外的信息可以参见NaturalProducts Association(美国天然产品协会)。
表1展示本发明(instant,即时)营养组合物关于组合物中存在的DHA和非瑟酮的量的某些优选的实施方式。上述组合物,其优选用于人口服消费,被设想用于日常消费来治疗现有的认知障碍(例如,AD)或在“正常”主体(即,具有尚未确诊有认知障碍的主体或没有认知障碍的主体(优选60岁以上))中改善认知。用于这些组合物的另外的递送方案包括每天两次、每两天一次、每三天一次,以及每周一次。
表1
组合物# | 非瑟酮(mg) | DHA(mg) |
1 | 100 | 100 |
2 | 100 | 150 |
3 | 100 | 200 |
4 | 100 | 250 |
5 | 100 | 300 |
6 | 100 | 350 |
7 | 100 | 400 |
8 | 100 | 450 |
9 | 100 | 500 |
10 | 100 | 550 |
11 | 100 | 600 |
12 | 100 | 650 |
13 | 100 | 700 |
14 | 100 | 750 |
15 | 100 | 800 |
16 | 100 | 850 |
17 | 100 | 900 |
18 | 100 | 950 |
19 | 100 | 1000 |
20 | 150 | 100 |
21 | 150 | 150 |
22 | 150 | 200 |
23 | 150 | 250 |
24 | 150 | 300 |
25 | 150 | 350 |
26 | 150 | 400 |
27 | 150 | 450 |
28 | 150 | 500 |
29 | 150 | 550 |
30 | 150 | 600 |
31 | 150 | 650 |
32 | 150 | 700 |
33 | 150 | 750 |
34 | 150 | 800 |
35 | 150 | 850 |
36 | 150 | 900 |
37 | 150 | 950 |
38 | 150 | 1000 |
39 | 175 | 100 |
40 | 175 | 150 |
41 | 175 | 200 |
42 | 175 | 250 |
43 | 175 | 300 |
44 | 175 | 350 |
45 | 175 | 400 |
46 | 175 | 450 |
47 | 175 | 500 |
48 | 175 | 550 |
49 | 175 | 600 |
50 | 175 | 650 |
51 | 175 | 700 |
52 | 175 | 750 |
53 | 175 | 800 |
54 | 175 | 850 |
55 | 175 | 900 |
56 | 175 | 950 |
57 | 175 | 1000 |
58 | 200 | 100 |
59 | 200 | 150 |
60 | 200 | 200 |
61 | 200 | 250 |
62 | 200 | 300 |
63 | 200 | 350 |
64 | 200 | 400 |
65 | 200 | 450 |
66 | 200 | 500 |
67 | 200 | 550 |
68 | 200 | 600 |
69 | 200 | 650 |
70 | 200 | 700 |
71 | 200 | 750 |
72 | 200 | 800 |
73 | 200 | 850 |
74 | 200 | 900 |
75 | 200 | 950 |
76 | 200 | 1000 |
77 | 250 | 100 |
78 | 250 | 150 |
79 | 250 | 200 |
80 | 250 | 250 |
81 | 250 | 300 |
82 | 250 | 350 |
83 | 250 | 400 |
84 | 250 | 450 |
85 | 250 | 500 |
86 | 250 | 550 |
87 | 250 | 600 |
88 | 250 | 650 |
89 | 250 | 700 |
90 | 250 | 750 |
91 | 250 | 800 |
92 | 250 | 850 |
93 | 250 | 900 |
94 | 250 | 950 |
95 | 250 | 1000 |
96 | 300 | 100 |
97 | 300 | 150 |
98 | 300 | 200 |
99 | 300 | 250 |
100 | 300 | 300 |
101 | 300 | 350 |
102 | 300 | 400 |
103 | 300 | 450 |
104 | 300 | 500 |
105 | 300 | 550 |
106 | 300 | 600 |
107 | 300 | 650 |
108 | 300 | 700 |
109 | 300 | 750 |
110 | 300 | 800 |
111 | 300 | 850 |
112 | 300 | 900 |
113 | 300 | 950 |
114 | 300 | 1000 |
可以以常规方式并利用一种或多种生理用载体或赋形剂来配制按照本发明使用的营养制剂。在制剂中使用的药剂(agent)和它们的生理用盐和溶剂化物可以加以制备,以通过各种方法来给予。在一种示例性实施方式中,口服给予营养制剂(理想为固体或液体)。在一种可替换的实施方式中,胃肠道外(例如,静脉内、皮下、肌内、颅内、眶内、眼部、心室内、囊内、脊柱内、脑池内、腹腔内、或经粘膜)给予。按照给予途径,可以以各种方式来配制组合物。
对于口服,制剂可以采用以下形式,例如,片剂或胶囊剂,其是通过常规方式加以制备,并借助于药用赋形剂如粘合剂(例如,预凝胶化玉米淀粉、聚乙烯吡咯烷酮或羟丙基甲基纤维素);填充剂(例如,乳糖、微晶纤维素或磷酸氢钙);润滑剂(例如,硬脂酸镁、滑石粉或二氧化硅);崩解剂(例如,马铃薯淀粉或淀粉羟乙酸钠);或湿润剂(例如,月桂硫酸钠)。可以通过本领域中众所周知的方法来包衣片剂。还包括棒和其它咀嚼制剂。
用于口服的液体制剂可以具有以下形式,例如,溶液、糖浆剂或混悬剂,或它们可以提供为干燥产品,在使用前用水或其它载体加以制成。在一种实施方式中,可以配制液体制剂,用于连同果汁(例如,苹果汁)一起来给予。可以通过常规方式来制备上述液体制剂,其中借助于药用添加剂如悬浮剂(例如,山梨醇糖浆剂、纤维素衍生物或氢化食用脂肪);乳化剂(例如,卵磷脂或阿拉伯胶);非水性载体(例如,杏仁油、油酯、乙醇或分馏植物油);以及防腐剂(例如,对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或山梨酸)。其它适宜的非水性载体可以包括神经保护食物,例如,鱼油、亚麻籽油等。上述制剂还可以包含缓冲盐、增香剂、着色剂和甜味剂(在适当的情况下)。
用于口服的制剂可以提供为单位剂型,例如,作为片剂、胶囊剂等。可以将它们提供在泡罩包装或多剂量容积中。还可以适当地配制用于口服的制剂以产生活性化合物的控制释放。
对于口腔或舌下给予,制剂可以具有以常规方式配制的片剂或锭剂的形式。制剂可以制备成通过注射来胃肠道外给予,例如,通过推注或连续输注。可以以单位剂型,例如,以安瓿剂,或以多剂量容器,来提供用于注射的制剂,其具有添加的防腐剂。制剂可以采用这样的形式如混悬剂、溶液或乳剂(在油性或水性载体中),并且可以包含配制剂如悬浮剂、稳定剂和/或分散剂。可替换地,活性组分可以具有粉末形式,用于在使用前借助于适宜的载体,例如,无菌无热原的水,来配制制剂。
制剂还可以制备成直肠组合物如栓剂或滞留型灌肠剂,例如,包含常规栓剂基质如可可脂或其它甘油酯。
制剂还可以提供为长效制剂。可以通过植入(例如皮下或肌内)或通过肌内注射来给予这样的长效制剂。因而,例如,可以用适宜的聚合物或疏水性材料(例如作为在可接受的油中的乳剂)或离子交换树脂来制备制剂,或作为微溶衍生物,例如,作为微溶盐。
可以将制剂提供于包装或分配器装置中,该包装或分配器装置可以包含一个或多个包含活性组分的单位剂型。包装可以,例如,包括金属或塑料箔,如泡罩包装。包装或分配器装置可以伴随有用法说明。
本发明的治疗制剂还可以包含载体或赋形剂,其许多是本领域技术人员已知的。可以使用的赋形剂包括缓冲液(例如,柠檬酸盐缓冲液、磷酸盐缓冲液、乙酸盐缓冲液、和碳酸氢盐缓冲液)、氨基酸、脲、醇、抗坏血酸、磷脂、蛋白质(例如,血清白蛋白)、EDTA、氯化钠、脂质体、甘露醇、山梨醇、和丙三醇。
可用于制备制剂的方法是本领域中已知的并且可以参见,例如,Remington'sPharmaceutical Sciences(Gennaro,ed.,Williams&Wilkins,Baltimore,Md.)。
本发明另外提供了用于在主体中治疗神经变性疾病的方法,该方法涉及将治疗有效量的本发明的组合物给予主体,以治疗疾病。本发明进一步提供了用于在主体中减少与神经变性疾病相关的症状的方法,该方法涉及将治疗有效量的本发明的组合物给予主体,以减少疾病的症状。
通常,本发明的组合物可以通过如下方式来发挥作用,例如,通过(i)消除认知障碍,(ii)减轻认知障碍的一种或多种症状,(iii)放缓认知障碍的进展,(iv)延迟认知障碍的症状的发作,以及(v)降低认知障碍的发作的可能性。
重要的是,已发现,在本发明的应用中,制剂的成分的组合比单种成分更加有效。如本文描述的结果所指明的,本发明的特定制剂的疗效程度是完全没有预料到的,这表明,这些独特的组合协同提供神经保护作用。虽然方便给予,但不是必须将营养制剂的药剂或成分复合在一起来给予主体。实际上,可以同时或以足够接近的顺序给予它们,以致同时在血流中达到所有成分的所期望的剂量水平。
通常,通过在介质中将成分的适当浓度的贮备剂(例如,在溶液或固体中)结合在一起来配制营养制剂。可以一起、快速连续地、或以一定时间间隔来给予成分。可以测试组合物以确定在原代、次生、或永生化神经细胞(例如,呈现正常神经细胞的分子和生化特性的细胞、或呈现神经系统疾病的至少一些分子和生化特性的细胞)的体外细胞培养系统中它是否是有效的营养制剂。用于评估制剂效果的上述细胞和方法是本领域中已知的,以及示例性细胞和方法描述于实施例中。生化和物理标准可以用来测量营养制剂减轻与老化和炎症相关的不良事件的能力。生化和物理标准可以另外用来测量营养制剂在这些细胞培养系统中减轻与疾病相关的有害效应的能力。
动物模型同样可用于评估营养制剂的效力。可以利用动物模型,例如,用于AD的动物模型,来体内评估营养制剂。用于AD的动物模型的实例是表达人ApoE的E4等位基因的小鼠,表达蛋白Tau的人形式的小鼠,以及其它转基因小鼠系,其中淀粉样前体蛋白(APP)基因的表达受到影响(Reaume et al.,J.Biol.Chem.,271:23380-23388,1996;Hsiao et al.,Science,276:99-102,1996;以及Games et al.,Nature,373:523-527,1995)。利用动物模型,还可以评估营养制剂在预防或减轻AD的效果方面的效力。在早年和在症状开始发展以后,在将营养制剂给予这些小鼠以后,在上述小鼠中评估的营养制剂对改善行为和生化症状的影响。评估了小鼠的学习和记忆障碍的发展或进展以及病理生理和生化异常如在大脑的皮质和边缘结构中斑块的存在。症状的发作或进展的预防、或现有症状的改善,表明营养制剂可有效治疗人的阿尔茨海默病。
虽然无需在相同赋形剂中、以相同形式来给予营养制剂的所有成分,或在一天中的精确的同一时间递送,但应这样给予成分,以致它们同时存在于待治疗主体中(例如,存在于作为治疗靶的细胞中),因而,通常以方便剂型来提供包括两种成分的一种制剂。
本发明的营养制剂可以是在试剂盒中的成分。这些试剂盒还可以包括将制剂给予主体的说明,以及可选地可以包括一种或多种其它营养制品,例如,银杏、鱼油、苹果汁、亚麻籽油、以及在本领域中已知的其它营养食品或制剂。这些试剂盒可以另外包括用法说明、和/或其它营养食品或制剂。
通过以下非限制性实施例来进一步说明本发明。在整个本申请中列举的所有参考文献、专利和公开的专利申请的内容以引用方式结合于本文。
本文已仅参照某些实施例和实施方式描述了本发明,没有进行努力以详尽描述本发明的所有可能的实施例和实施方式。实际上,本领域技术人员将明了,可以对上述实施例和实施方式进行各种添加、删除、修改和其它变化,而不偏离如在以下权利要求中详述的本发明的精神和范围。意图是所有上述添加、删除、修改和其它变化包括在以下权利要求的范围内。
实施例
已报告,富含ω3脂肪酸DHA的鱼油不能有效地治疗轻度至中度的、具有广泛的β-淀粉样蛋白斑块和缠结的阿尔茨海默病患者。已经表明,DHA可以减少β-淀粉样蛋白的积累,但在具有β-淀粉样蛋白和缠结(tau蛋白病理)的动物模型,3xAD转基因小鼠中,当病理发展时,随着时间的推移,DHA似乎失去疗效。我们发现,仅鱼油不足以治疗3xAD Tg小鼠。
非瑟酮,富含在草莓中的天然类黄酮,是神经保护剂,并且可以在各种动物模型(包括老化小鼠和β-淀粉样蛋白斑块积聚转基因小鼠)中改善认知功能。我们已测试了单独0.6%DHA、单独500ppm非瑟酮以及联合的DHA+非瑟酮作为食品补充剂(在进餐时间(in chow))递送到具有合并的淀粉样蛋白和tau蛋白病理的老年3xAD Tg小鼠。对约9月龄至13-14月龄进行上述研究。DHA+非瑟酮改善了认知缺陷,但单独DHA或单独非瑟酮则没有(图1)。
如图1所示,Morris水迷宫实验(Morris Water Maze)结果表明,当用对照坏(高红花油)饮食并具有或没有DHA(绿色)或非瑟酮(淡蓝色)对12-13月龄3xAD Tg小鼠进行测试时,没有及时(潜伏期)改善,以使用另外的训练块(blocks of training)发现隐藏的平台,但在一起使用DHA+非瑟酮的情况下随着时间的推移会出现显著的改善。
图2示出,在探针测试中,非瑟酮和DHA的膳食组合改善了保留。在此测试中,除去平台,并允许小鼠游泳60秒,同时量化在目标象限中的时间。在此测试中单独非瑟酮也改善了保留,但(非瑟酮和DHA的)组合导致最佳性能。
图3示出以与在图1行为研究中相同饮食来研究的相同3xAD三重小鼠的大脑的蛋白质的Western分析。兴奋性突触标记PSD-95受到单独DHA(趋势)但没有受到非瑟酮的部分保护(增加),但受到DHA+非瑟酮的显著保护(p<0.001)。
这些数据表明,结合DHA和非瑟酮或鱼油和非瑟酮的治疗是用于认知缺陷的协同治疗。因为β-淀粉样蛋白和tau/缠结病理发生在正常老化和在阿尔茨海默病诊断以前许多年,所以DHA和非瑟酮可以有效地放慢随老化或阿尔茨海默病的认知能力下降,或有效治疗具有β-淀粉样蛋白和/或tau蛋白病相关的认知缺陷的这些或其它病症,包括额颞痴呆、皮克病、进行性核上麻痹。
为了证明两种药剂的协同活性和建立用于临床研究的适当的固定剂量比率,已在模拟的炎症条件下(即,10μg/ml LPS)将不同量的非瑟酮和DHA加入N9小胶质细胞。在24小时以后,利用Griess测定,在培养基中测量NO释放,以NO2表示。结果表示为在仅用LPS处理的细胞的培养基中的NO2的%。发现,两种药剂的组合对炎症具有强大的协同效应,尤其是在指定的酶比率下。
这些数据表明,DHA和非瑟酮的组合可以提供抗炎活性的协同改善。有效比率包括但不限于那些比率,其中以至少5μM的浓度提供非瑟酮,以及其中DHA与非瑟酮的比率可以为至少约1:2、1:5、1:10或更大。
Claims (16)
1.一种组合物,包含有效结合量的非瑟酮和二十二碳六烯酸(DHA)。
2.根据权利要求1所述的组合物,其中,按重量计,非瑟酮与DHA的比率为约1:20至20:1。
3.根据权利要求2所述的组合物,其中,按重量计,非瑟酮与DHA的比率为约1:1至1:20。
4.根据权利要求3所述的组合物,其中,按重量计,非瑟酮与DHA的比率为约1:5至1:20。
5.根据权利要求4所述的组合物,其中,所述组合物包含至少500mg的DHA。
6.根据权利要求5所述的组合物,其中,所述组合物包含至少约1g的DHA。
7.根据权利要求6所述的组合物,其中,所述组合物包含至少约5g的DHA。
8.根据权利要求1-7中任一项所述的组合物,其中,所述组合物基本上由非瑟酮和DHA组成。
9.根据权利要求1-8中任一项所述的组合物,其中,所述组合物是膳食补充剂。
10.根据权利要求1-8中任一项所述的组合物,其中,所述组合物配制成给予主体。
11.根据权利要求1-8中任一项所述的组合物,其中,所述组合物配制成用作食物添加剂。
12.根据权利要求1-8中任一项所述的组合物,其中,将所述组合物配制为液体。
13.一种用于改善主体的认知功能的方法,所述方法包括给予根据权利要求1-12中任一项所述的组合物。
14.根据权利要求13所述的方法,其中,所述主体患有神经变性疾病。
15.根据权利要求14所述的方法,其中所述神经变性疾病是阿尔茨海默病。
16.根据权利要求13所述的方法,其中,口服给予所述制剂。
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US201161488003P | 2011-05-19 | 2011-05-19 | |
US61/488,003 | 2011-05-19 | ||
PCT/US2012/038720 WO2012159092A2 (en) | 2011-05-19 | 2012-05-18 | Medical food for cognitive decline |
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CN103732223A true CN103732223A (zh) | 2014-04-16 |
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CN201280024259.9A Pending CN103732223A (zh) | 2011-05-19 | 2012-05-18 | 用于认知能力下降的医疗食品 |
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US (1) | US9254280B2 (zh) |
EP (1) | EP2709611A4 (zh) |
JP (1) | JP2014515928A (zh) |
KR (1) | KR20140057485A (zh) |
CN (1) | CN103732223A (zh) |
AU (1) | AU2012254988A1 (zh) |
BR (1) | BR112013028820A2 (zh) |
CA (1) | CA2833219A1 (zh) |
IL (1) | IL229108A0 (zh) |
MX (1) | MX2013013512A (zh) |
WO (1) | WO2012159092A2 (zh) |
Cited By (1)
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CN108272791A (zh) * | 2018-03-26 | 2018-07-13 | 深圳大学 | 漆黄素在制备抑制Tau蛋白异常聚集的药物中的应用 |
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US9682048B1 (en) | 2010-10-12 | 2017-06-20 | Gene S. Rosen | Multi-component formulations for the treatment of cognitive decline including Alzheimer's disease |
FR3005419B1 (fr) | 2013-05-13 | 2015-09-04 | Agronomique Inst Nat Rech | Utilisation d'une association de deux composes pour le traitement et/ou la prevention de troubles osseux |
US10183053B1 (en) | 2017-06-19 | 2019-01-22 | Gene S. Rosen | Multi-component formulations |
WO2019018937A1 (en) | 2017-07-26 | 2019-01-31 | Yacyshyn Vincent | REMOVAL OF CONTAMINANT POLYPHENOLS FROM START LOAD POLYPHENOLS |
US11173187B2 (en) | 2018-11-13 | 2021-11-16 | Immortazyme Company Ltd. | Concentrated oil-based polyphenol composition and a method of producing the oil-based polyphenol composition |
US20220133700A1 (en) * | 2020-10-29 | 2022-05-05 | Thomas Winston | Compositions and methods for treating neurological disorders |
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- 2012-05-18 CA CA2833219A patent/CA2833219A1/en not_active Abandoned
- 2012-05-18 MX MX2013013512A patent/MX2013013512A/es not_active Application Discontinuation
- 2012-05-18 EP EP12786198.7A patent/EP2709611A4/en not_active Withdrawn
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- 2012-05-18 AU AU2012254988A patent/AU2012254988A1/en not_active Abandoned
- 2012-05-18 BR BR112013028820A patent/BR112013028820A2/pt not_active IP Right Cessation
- 2012-05-18 KR KR1020137030528A patent/KR20140057485A/ko not_active Application Discontinuation
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JP2014515928A (ja) | 2014-07-07 |
US20140142172A1 (en) | 2014-05-22 |
US9254280B2 (en) | 2016-02-09 |
MX2013013512A (es) | 2014-06-05 |
WO2012159092A3 (en) | 2013-01-24 |
WO2012159092A2 (en) | 2012-11-22 |
BR112013028820A2 (pt) | 2017-01-31 |
EP2709611A2 (en) | 2014-03-26 |
CA2833219A1 (en) | 2012-11-22 |
KR20140057485A (ko) | 2014-05-13 |
AU2012254988A1 (en) | 2013-10-17 |
EP2709611A4 (en) | 2014-10-29 |
IL229108A0 (en) | 2013-12-31 |
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