CN103083288A - 通过施用紫檀芪减轻氧化应激并改善工作记忆的方法 - Google Patents
通过施用紫檀芪减轻氧化应激并改善工作记忆的方法 Download PDFInfo
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- CN103083288A CN103083288A CN2012104210086A CN201210421008A CN103083288A CN 103083288 A CN103083288 A CN 103083288A CN 2012104210086 A CN2012104210086 A CN 2012104210086A CN 201210421008 A CN201210421008 A CN 201210421008A CN 103083288 A CN103083288 A CN 103083288A
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Abstract
本发明公开了一种治疗氧化应激的药物组合物，该组合物包括治疗有效量的基本上纯的紫檀芪化合物和生理上可接受的载体。紫檀芪以每千克受试者体重约2.5mg至约10mg之间的量施用。本发明还公开了增强受试者的工作记忆的方法，该方法包括施用有效量的基本上纯的紫檀芪化合物，其中受试者的工作记忆增强且疗效为每千克受试者体重约10mg紫檀芪。
Description
本申请是国际申请号PCT/US2008/075170，国际申请日2008年9月4日，进入中国国家阶段日期为2010年4月6日，中国申请号200880110318.8，发明名称为“通过施用紫檀芪减轻氧化应激并改善工作记忆的方法”的分案申请。
技术领域
本发明涉及一种以有效量的紫檀芪施用于受试者以预防、阻止和逆转神经元和行为老化的影响以及神经退行性疾病的进展的用途方法。具体地，白黎芦醇类似物紫檀芪有效地逆转受试者的运动缺陷和工作记忆。
背景技术
饮食补充水果和蔬菜具有防止和逆转与老化个体有关的缺陷的作用。涉及饮食补充浆果(例如，越橘属(Vaccinium)浆果诸如蔓越莓和蓝莓)的营养疗法逆转和/或预防与老化有关的运动和认知变化。例如，补充蓝莓预防具有伴随APP/PS-1突变的β淀粉样肽产生增加的小鼠的认知行为缺陷(Joseph JA.等人，2003.Nutr.Neurosci.，6：153-162)。浆果的有益作用涉及直接和间接对抗氧化应激物的作用。因此，需要鉴定浆果中的能有效改变氧化介导的运动和认知功能变化的化合物。
已经鉴定出反式-3，5，4’-三羟基芪(下文中称为白黎芦醇)由于其强抗氧化剂活性，而具有多种抗衰老特性。体外试验已显示白黎芦醇是有效的自由基清除剂并抑制低密度脂蛋白氧化(Brito P.等人，2002.FreeRadic Res.36(6)：621-631)。其它芪类(stilbenoid)诸如松芪(pinostilbene)、去氧丹叶大黄素(desoxyrhapontigenin)、紫檀芪(pterostilbene)、白黎芦醇三甲醚和白皮杉醇(piceatannol)通过激活核受体、过氧化物酶体增殖物激活受体α亚型而具有不同程度的生物学活性和降低脂质水平的功效。
反式-3，5-二甲氧基-4’-羟基芪(下文中称为紫檀芪)，是白黎芦醇的天然甲基醚类似物，已经被证明具有类似于白黎芦醇的抗氧化剂活性(Rimando等人，2002.J.Agric.Food Chem.50：3453-3457；Stivala等人，2001.J.Biol.Chem.276(25)：22586-22594)。紫檀芪存在于一些小水果诸如葡萄(Adrian等人，2000.J.Argic.Food Chem.48：6103-6105)和越橘属浆果(兔眼越橘(Vaccinium ashei)Reade和Vaccinium stamineum L.)(Rimando等人，2004.J.Argic.Food Chem.52：4713-4719)以及木本植物(Maurya等人，1977.J.Nat.Prod.47：179-181；Amone等人，1977.J.Chem.Soc.Perkins Trans.19：2116-2118)中。另外，多种植物性药材含有紫檀芪，包括榆绿木(Anogeissus acummata)、剑叶龙血树(Dracaenacochinchinensis)、loureiri龙血树(Dracaena loureiri)、特氏古夷黄木(Guibourtia tessmannii)、大果紫檀(Pterocarpus macrocarpus)、花榈木(Pterocarpus marsupmm)、檀香紫檀(Pterocarpus santalinu)、兔眼越橘(Vaccinium ashei)、湿地越橘(Vaccinium corymbosum)、甜越橘(Vacciniumdeliciosum)、膜质越橘(Vaccinium membranaceum)、卵形越橘(Vacciniumovatum)、乱叶越橘(Vaccinium ovalifoilum)、小叶越橘(Vacciniumparviflorum)、stamineum越橘(Vaccinium stamineum)、笃斯越橘和葡萄(Vitis vinifrea)。紫檀芪还见于非植物来源诸如蜂胶中。
在越橘属浆果的各个种之间紫檀芪水平可以有所不同。如Rimando等人，2004.J.Argic.Food Chem.52：4713-4719所报道的，经越橘属浆果品种的紫檀芪浓度据报道为99ng/gm干样品至520ng/gm干样品。另外，如Rimando等人，Acta Hort.(ISHS).680：137-143所报道的，来自越橘9个品种的冻干浆果显示出每克浆果有0.12μg至2.74μg紫檀芪。同样地，蓝莓种类的紫檀芪浓度在数量上也有所不同。已有报道从1克冻干蓝莓可得到99ng至475ng紫檀芪。
研究已将抗氧化剂的作用与脑老化和行为的有害影响联系在一起。在水果和蔬菜中发现的“次生化学物质”形式的、一般不参与植物初级代谢的抗氧化剂/抗炎多酚化合物的组合已显示出具有预防这些有害效应的功效。因此，需要进一步鉴定水果和植物，具体地是鉴定可防止衰老和认知缺陷的化合物。
化合物紫檀芪已显示对环氧合酶-1具有中度抑制作用，且对环氧合酶-2具有弱抑制作用，表明其具有抗炎活性。(Rimando等人，2002.J.Agric.Food Chem.50：3453-3457.)。另外，紫檀芪已被鉴定可激活过氧化物酶体增殖物激活α亚型(PPARα)——一种被认为介导降低脂质和葡萄糖水平的受体。紫檀芪的PPARα激动剂效应的详情公开在Rimando等人，2005.J.Agric.Food Chem.53：3403-3407和US2006/005723A1中，两篇文献均并入本文作为参考。
紫檀芪已被鉴定能抑制结肠癌变。具体地，在刚断奶的雄性F344大鼠中，紫檀芪抑制氧化偶氮甲烷诱导的结肠异常隐窝病灶生长。另外，紫檀芪抑制HT-29人腺癌细胞系中的诱导型一氧化氮合成酶(iNOS)的表达。(Suh等人，2007.Clin Cancer Res.13(1)350-355.)
在减轻衰老对象的认知改变的尝试中，在本领域中需要确定与未补充对象相比，为衰老对象补充紫檀芪是否将逆转认知和运动缺陷。
毒蕈碱性胆碱能受体介导神经递质乙酰胆碱在中枢和外周神经系统、胃肠系统、心脏、内分泌腺、肺和其它组织中的作用。已经鉴定了5种不同的毒蕈碱性受体亚型，为m1-m5。m1亚型是在大脑皮层中发现的优势亚型，并且被认为参与认知功能的控制。
与认知损害有关的疾病，诸如阿尔茨海默病，伴有大脑中乙酰胆碱的丢失。这被认为是基底前脑中胆碱能神经元变性的结果，胆碱能神经元刺激联络皮层和海马的区域，海马参与高级认知过程。
因此，需要鉴定能增加大脑中乙酰胆碱信号传导作用的化合物。具体地，需要鉴定作为对中枢和外周神经系统中的各种受体亚型都有活性的毒蕈碱性激动剂的化合物。
发明内容
本发明的目的是提供治疗神经元和行为衰老作用并阻止由氧化应激引起的神经退行性疾病进展的组合物。
本发明公开了一种用于治疗氧化应激的药物组合物，其包括治疗有效量的基本上纯的具有下式的化合物：
和生理上可接受的载体。在本发明的实施方式中，紫檀芪以每千克受试者体重约2.5mg至约10mg之间的量施用。在本发明的另一实施方式中，治疗有效量的紫檀芪经越橘属浆果饮食而施用。在另一实施方式中，越橘属浆果是蓝莓。
本发明公开了一种治疗氧化应激的方法，该方法包括施用治疗有效量的基本上纯的具有下式的化合物：
其中受试者的氧化应激被减轻。在本发明的实施方式中，紫檀芪以每千克受试者体重约2.5mg至约10mg之间的量施用。在另一实施方式中，该化合物增加受试者乙酰胆碱受体活性。还在另一实施方式中，所施用的化合物的量在受试者经受氧化应激物时防止经历多巴胺释放的抑制。在另一实施方式中，紫檀芪经越橘属浆果饮食而施用。在另一实施方式中，越橘属浆果是蓝莓。在另一实施方式中，紫檀芪增加毒蕈碱性受体亚型的钙缓冲能力，诸如亚型为m-1。还公开了一种增强受试者工作记忆的方法，该方法包括施用有效量的基本上纯的紫檀芪，其中受试者的工作记忆增强。在一个实施方式中，治疗有效量的紫檀芪为每千克受试者体重约10mg化合物。
附图说明
从下面对附图中所示的本发明的实施方式的详细描述中可最好地理解本发明以及上述和其它目的和优点，其中：
图1绘制了各种芪衍生物的化学结构；
图2是表示在无多巴胺(-多巴胺)或1mM多巴胺(+多巴胺)处理后，在M1转染的COS-7细胞对照细胞和用蓝莓、白黎芦醇、松芪、去氧丹叶大黄素、紫檀芪、紫檀芪葡糖苷、白黎芦醇三甲醚或白皮杉醇预处理的那些细胞中的平均Ca2+恢复率的图。对于每种处理，星号表示无多巴胺处理和多巴胺处理细胞之间的恢复率差异(*＝p＜0.001)；
图3是在其饮食中施用低添加量紫檀芪(0.004％w/w)、高添加量紫檀芪(0.016％w/w)或不添加紫檀芪(对照)的受试者以秒计的到达平台的潜伏期测量的图。对于各饮食组，星号表示试验1和试验2表现之间的差异(*＝p＜0.05)；
图4是在其饮食中施用低添加量紫檀芪(0.004％w/w)、高添加量紫檀芪(0.016％w/w)或不添加紫檀芪(对照)的受试者以米计的到达平台的距离测量的图。对于各饮食组，星号表示试验1和试验2表现之间的差异(*＝p＜0.05)；
图5是来自在基础水平(-H2O2)和氧化应激(+H2O2，50μM)处理条件下维持在对照、低剂量紫檀芪(0.004％)和高剂量紫檀芪(0.016％)饮食的受试者制备的纹状体切片的多巴胺释放(变化以pmol/mg蛋白质计)的氧化震颤素增强图。对于各饮食组，星号表示无H2O2处理和H2O2处理的纹状体切片之间多巴胺释放的差异(*＝p＜0.01)。
图6A是绘制受试者海马中的紫檀芪量(ng)作为在Morris水迷宫中进行的找到平台的潜伏期(秒)的函数的图。测量在受试者海马中的紫檀芪，并将其与自第3天和第4天的试验2受试者的表现相关联。图6B是绘制受试者海马中的紫檀芪量(ng)作为在Morris水迷宫中进行的受试者到达平台所穿越的距离(米)的函数的图。从第3天至第4天在试验2的受试者的海马中测量紫檀芪。
具体实施方式
对衰老受试者施用补充其饮食的多个紫檀芪剂量。补充了紫檀芪的受试者与未补充紫檀芪的那些受试者相比，显示出改善的精神运动和认知表现。在另一实施方式中，以每千克受试者体重2.5mg紫檀芪对受试者施用低剂量的紫檀芪。在另一实施方式中，以每千克受试者体重10mg紫檀芪对受试者施用高剂量的紫檀芪，受试者在评价工作记忆的实验中显示出最大改进的认知表现。在另一实施方式中，在M1转染的COS-7细胞系中，紫檀芪预处理对抗多巴胺处理对氧化震颤素诱导的去极化后的钙清除的负效应。在本发明的又一实施方式中，施用治疗量的紫檀芪，其中用氧化应激敏感性毒蕈碱性乙酰胆碱受体转染的所述细胞系避免了多巴胺诱导的恢复期缩短。此外，在受试者饮食中施用的紫檀芪增加死后纹状体切片的受试者毒蕈碱性受体的敏感性，其中在经历氧化应激物时多巴胺释放没有减少。
定义
如说明书和权利要求中所使用的，单数形式“一个(a)”、“一个(an)”和“所述(the)”包括复数指代，除非上下文另外明确地说明。例如，术语“细胞(a celll)”包括多个细胞，包括其混合物。
术语芪(stilbene)用于描述具有通式反式-1，2-二苯乙烯、分子式为C6H5CH＝CHC6H5的一类化学类化合物。芪类具有带有两个苯基分支作为侧链的1，2-二苯乙烯的通用结构。来自芪化学类的一个化学衍生物是白黎芦醇，其为反式-3，5，4′-三羟基芪，并绘制在图1中。来自芪化学类的另一化学衍生物是紫檀芪，其可描述为反式-3，5-二甲氧基-4′-羟基芪并绘制在图1中。芪的其它例子包括松芪(反式-3，4′-二羟基-5-甲氧基芪)、去氧丹叶大黄素(反式-3，5-二羟基-4′-甲氧基芪)、紫檀芪葡糖苷、白黎芦醇三甲醚(反式-3，5，4′-三甲醚芪)和白皮杉醇(反式-3，4，3′，5′-四羟基芪)。
术语氧化应激物指与体内多种物质反应引起功能紊乱的活性氧种类。一般来说，羟基与多种有机底物任意反应。氧化应激物的例子为过氧化氢和臭氧。
如本文所使用的术语“工作记忆”指用于存储和检索的快速记忆过程，包括将进入信息在其转变为长期记忆之前保留在短期记忆中所需的过程，包括支持检索已建立的长期(情景)记忆的过程。该术语还指短期记忆、原始记忆、瞬时记忆、操作记忆和短暂记忆。
治疗有效量定义为当施用于受试者时，足以实现这类病况治疗的化合物的量。“治疗有效量”可根据化合物以及要治疗的状况、受试者的年龄和相对健康、给药途径和形式、本领域普通技术人员的判断和其它因素而变化。
对于每种行为措施，使用Systat(SPSS，Inc.，Chicago，IL)进行三组比较的受试者间方差分析(ANOVA)模型来检测在p＜0.05水平的统计学显著性。适当时，天数或试验包括在模型内作为受试者内变量。使用Fisher′s LSD事后分析来进行事后比较以测定饮食组间的差异。
在施用多巴胺后的M1转染细胞系中在钙恢复测定中使用多种芪类似物，这些芪类似物绘制在图1中。白黎芦醇购自Sigma-Aldrich(St.Louis，MO)，而白皮杉醇购自Calbiochem-Novabiochem Corp.(SanDiego，CA)。
通过在乙酸酐和三乙胺中缩合3，5-二甲氧基苯甲醛和4-羟基苯乙酸来合成紫檀芪(反式-3，5-二甲氧基-4’-羟基芪)(改良自Pettit等人，1988，J.Nat.Prod.51：517-527)。反应混合物在氮气氛中加热(150℃)，并持续搅拌。20小时后，反应终止，冷却至室温，并加入浓盐酸(5mL)。形成的沉淀物溶解在50mL氯仿中，并用10％氢氧化钠水溶液萃取。水萃取物用浓盐酸酸化至pH1，并搅拌至少6小时，导致中间产物α-[(3，5-二甲氧基苯基)亚甲基]-4-羟基-(αZ)-苯乙酸沉淀。该中间产物与1.0g铜在10mL喹啉中一起加热(200℃，氮气中6小时)。反应混合物冷却至室温并过滤。将5N盐酸(25mL)加入至滤液中，搅拌1小时，并用氯仿萃取。含不纯的紫檀芪的氯仿萃取液在Horizon HPFC系统(Biotage，Inc.，Charlottesville，VA)上使用硅胶柱以及溶剂系统乙酸乙酯∶己烷(15∶85至100％乙酸乙酯的线性梯度)通过急骤层析纯化。含有纯紫檀芪的馏分组合在一起并真空浓缩。紫檀芪在己烷中重结晶，且其结构由其光谱数据来确认(UV、质谱法和核磁共振波谱法)。
紫檀芪葡糖苷通过紫檀芪(20mg)与40mg乙酰溴代-α，D-葡萄糖(Sigma-Aldrich，St.Louis，MO)以及氢氧化钾(5mg)在1mL乙醇中混合，并在室温下搅拌两天而合成。紫檀芪葡糖苷使用甲醇∶氯仿(20∶80)作为展开剂通过制层色谱进行纯化。紫檀芪葡糖苷的结构通过质谱法和1H-核磁共振波谱法测定。
白黎芦醇溶液(150mg在3.0ml甲醇中)用重氮甲烷逐滴处理，并通过薄层色谱监测甲基化反应。使用己烷∶乙酸乙酯(8∶2)作为展开剂通过制层色谱纯化去氧丹叶大黄素、松芪和白黎芦醇三甲醚。去氧丹叶大黄素、松芪和白黎芦醇的保留因子值(Rf)分别为0.2、0.25和0.8。这些化合物的结构通过质谱法和核磁共振波谱法来确认。
受试者和饮食制备
42只19月龄雄性Fischer344大鼠获自NIA colony(Harian SpragueDawley，Indianapolis，IN)。这些大鼠单个地圈养在不锈钢网挂笼中，自由进食和饮水，并保持12小时昼/夜循环。给予大鼠一周来适应其新环境，之后将它们进行重量匹配，然后随机置于三种饮食组中的一组总计12-13周(n＝14/组)：对照、低剂量紫檀芪(0.004％，相当于2.5mg/kg体重)，或高剂量紫檀芪(0.016％，相当于10mg/kg体重)。每天观察所有动物的疾病临床体征。
在Harlan Teklad(Madison，WI)通过向对照饮食中加入40mg紫檀芪晶体/kg饮食(0.004％w/w，低剂量)，加入160mg紫檀芪晶体/kg饮食(0.016％w/w，高剂量)而制备紫檀芪饮食。饮食组成见表1。调整对照饮食中的玉米量以补偿紫檀芪的添加量。在运动测试前大鼠维持对照或紫檀芪饮食8周，在21月认知测试前维持9周。
表1
对照饮食-98％基础混料+2％玉米
低剂量紫檀芪饮食-98％基础混料+1.996％玉米(1.96g/kg)+0.004％(0.040g/kg)紫檀芪晶体
高剂量紫檀芪饮食-98％基础混料+1.984％玉米(1.84g/kg)+0.016％(0.160g/kg)紫檀芪晶体
提供下列非限制性实施例以进一步说明本发明的各种实施方式。
实施例1：对抗氧化应激的细胞处理
来源于非洲绿猴肾的细胞系COS-7细胞在添加了10％胎牛血清(FBS)并含有100U/ml青霉素和100ug/ml硫酸链霉素的Dulbecco′sModified Eagle′s Medium(D-MEM)中生长。转染前24小时，用胰蛋白酶收获细胞，计数，并以5×106个细胞/板接种在100mm2组织培养板上。通过DEAE-葡聚糖法用大鼠毒蕈碱性受体亚型1DNA瞬时转染细胞。转染后，细胞在含有80μM氯喹的生长培养基中温育2.5小时以最小化DNA的降解。然后转染细胞在生长培养基中保持48小时，用胰蛋白酶收获，接种至35mm板中的盖玻片中用于钙成像，并温育过夜。
细胞处理
如以前Joseph J.等人，2004.J.Alz.Dis.6：403-411(该文引入本文作为参考)中所述进行蓝莓(BB)提取物(2mg/ml)、芪类[白黎芦醇(50μg/ml)、松芪(50μg/ml)、去氧土大黄甙元(25μg/ml)、紫檀芪(10μg/ml)、紫檀芪葡糖苷(10μg/ml)、白黎芦醇三甲醚(10μg/ml)、白皮杉醇(10μg/ml)]和多巴胺(1mM)的处理。BB提取物和芪类溶解在生长培养基中，随后细胞与处理的生长培养基一起在37℃下温育45分钟，然后施用多巴胺4小时。经过这些温育之后，用无提取物的生长培养基洗涤细胞三次，然后进行试验。
使用带有温度控制的Medical Systems Corp.开放式灌流微型培养箱(37℃)进行钙成像，上述培养箱安装在Nikon Eclipse TE200U显微镜的载物台上并用荧光光源照射。用荷载培养基(99％DMEM1％FBS)中的Fura-2/乙酸基甲酯(2μM)在37℃，5％CO下将转染细胞加样40分钟。
然后使用Simple PCI软件(Compix，Inc.Mars，PA)对750μM氧化震颤素诱导去极化之前和之后的钙流量进行实时分析。然后对每个样品测定响应和恢复率。如下测定响应：检查细胞显示对氧化震颤素反应的[Ca2+]i增加是否超过基线＞30％。仅显示此响应幅度的那些细胞被考虑用于进一步分析。通过评价响应的细胞去极化后Ca2+水平恢复至增加20％的时间(300秒内)来测定恢复率。通过Kruskal-Wallis单向方差分析和Mann-Whitney U检验来分析数据。
多巴胺的施用明显降低了M1转染细胞从[80％基线]的恢复率(对照对多巴胺处理细胞，p＜0.001)(图2)。紫檀芪、紫檀芪葡糖苷、白黎芦醇三甲醚和白皮杉醇防止经受多巴胺诱导的恢复率减小(p＞0.05)，而白黎芦醇、松芪和去氧土大黄甙元没有保护作用(p＜0.001)(图2)。
实施例2：Morris水迷宫
Morris水迷宫(MWM)是检测受试者的空间学习和记忆的方法。由Richard Morris开发的MWM是一种对年龄和饮食敏感的学习范式，需要受试者基于远端线索对位于圆形水池(直径134cm×高度50cm，保持在23℃)表面(2cm)以下的隐藏平台(直径10cm)进行定位，并从以前的试验记住其位置。从水中逃避至平台上的准确航行受到奖励，为此受试者使用远端线索诸如招贴画、试验者、计算机、笼架来有效定位。在9周的处理期间，每天进行MWM的工作记忆部分(Brandeis等人，1989.Int J Neurosci.48：29-69；Morris R.，1984.J Neurosci Methods.11：47-60.)，连续4天，分为早晨和下午两节，每节两次试验，两次试验之间有10分钟的试验间间隔。大鼠随机测试，条件是来自每组的一个受试者先后被测试。在每次试验开始时，在4个随机开始位置之一处将受试者轻轻地浸泡在水中。每个受试者允许有120秒来逃离至平台上；如果该受试者不能在此时间内逃离，则将其引向平台。一旦受试者到达平台，使其在那停留15秒(试验1；参考记忆或获取试验)。在试验之间(10min)受试者返回至其家笼。试验2(工作记忆或恢复试验)使用与试验1相同的平台位置和开始位置。对表现进行录像，并用图像跟踪软件(HVS Image，UK)进行分析，该软件能够测量潜伏期(秒)(找到平台的时间)、路线长度(em)以及游泳速度(cm/sec；潜伏期/路线长度)。使用的迷宫和范式的详细说明公开在Shukitt-Hale等人，1998.Experimental Gerontology，33：615-624中，并且该文引入本文作为参考。
如上所述给予紫檀芪饮食的大鼠受试者与对照饮食饲养组相比，显示提高的空间记忆表现(图3和4)。在饮食组之间，对于试验1或试验2而言，找到平台的潜伏期或距离没有差异。然而，对各组第3和第4天(依赖记忆多于依赖学习的时间)进行两次试验潜伏期或距离之间的独立t检验，以便确定不同饮食组是否显著地改善其从试验1至试验2的表现，即工作记忆改善的指标。高剂量紫檀芪组显示在试验1和2之间找到平台的潜伏期有显著差异(p＜0.05)，即，试验2潜伏期显著小于试验1，显示这些大鼠展示了一次尝试学习，即使有10分钟的滞留间隔(图3)。在对照组中没有发现此一次尝试学习，而低剂量紫檀芪组从试验1至试验2有改善的趋势(p＝0.09)。另外，低剂量和高剂量紫檀芪组都显示在试验1和试验2之间找到平台的距离有显著差异(p＜0.05)，即，试验2距离显著小于试验1(图4)。对照组从试验1至试验2未显示此种改善(p＞0.05)。因此，紫檀芪以剂量依赖方式逆转衰老对认知表现尤其是工作记忆的有害效应。
受试者海马组织中的紫檀芪
从Morris水迷宫测试后2-3周处死的受试者提取海马脑组织。组织样本在-80℃下保存，并在提取前在冰中融化。组织在500μL磷酸盐缓冲液(pH7.4)中匀浆，然后离心(7000g，4℃，15min)。收集上清液并重复匀浆。合并的上清液用乙酸乙酯萃取(500μL×2)。乙酸乙酯萃取物在氮气流中干燥。
干燥的提取物用30μL N，O-双[三甲基甲硅烷基]三氟乙酰胺：二甲基甲酰胺(BSTFA∶DMF，1∶1；Pierce Biotechnology，Inc.，Rockford，IL)处理，并在70℃下加热40min。衍生样品通过气相色谱-质谱法(GC-MS)用于分析紫檀芪。在JEOL GCMate II装置(JEOL USA Inc.，Peabody，MA)上使用J&W DB-5毛细管柱(内径0.25mm，膜厚度0.25μm，长度30m；Agilent Technologies，Foster City，CA)进行GC-MS。以下列的温度程序运行GC：开始190℃，以20℃/min速度增加至239℃，并在此温度下保持3分钟，以0.2℃/min的速度增加至242℃，然后以25℃/min的速率最终增加至300℃，并在此温度下保持1.5min。载气为超高纯度氦气，流速为1mL/min。注入口、GC-MS界面和电离室分别为250、230和230℃。注入量为1μL，不分流进样。以正电子冲击(70eV)，低分辨率模式获取质谱。使用m/z328，313，297和147从重建离子色谱图测定和定量紫檀芪。从紫檀芪的标准样品(保留时间，12.5min)的校准曲线进行定量。GC-MS分析进行两次。海马紫檀芪仅在高剂量紫檀芪组中能检测到，且为1.352±0.465ng/组织样本。
为了检验在高剂量紫檀芪大鼠的MWM行为和脑中紫檀芪水平之间是否存在关系，将海马紫檀芪水平与试验1和试验2潜伏期和距离表现进行相关，详情见图6A和6B。已知海马在空间学习和记忆，尤其是试验2工作记忆中具有作用，并发现在海马紫檀芪水平和试验2第3天和第4天表现的潜伏期(r＝-0.764，p＝0.010)和距离(r＝-0.734，p＝0.016)之间有显著的负相关；即，当紫檀芪水平增加时，找到平台的潜伏期和距离减小。
实施例3：多巴胺释放
如Joseph等人，1988.Brain Res.，454：140-8；Joseph等人，1988.Brain Res.，454：149-55；Joseph J.等人，1990.Brain Res.，537：40-48；Joseph等人，1996.Free Radic.Biol.Med.，20：821-30(这些文献引入本文作为参考)所公开的，来自过冷纹状体切片的K+诱发的多巴胺释放(K+-ERDA)的毒蕈碱性增强是受体敏感性和纹状体功能的指标，且其对衰老和氧化应激敏感。另外，如Joseph等人，1998.J.Neurosci.，18：8047-8055；Joseph等人，1999.J.Neurosci.，19：8114-8121；Youdim等人，2000.Nutr Neurosci.，3：383-97；Shukitt-Hale等人，2005.Age.，27：49-57；Shukitt-Hale等人，2006.Nutrition，22：295-302(这些文献引入本文作为参考)所公开的，多巴胺释放的毒蕈碱性增强对饮食补充物敏感。通过检验纹状体K+-ERDA的氧化震颤素增强的差异来评价获自对照和补充组的纹状体组织的保护能力。在行为测试后2-3周在来自饲以高剂量、低剂量和对照饮食的受试者脑的新鲜解剖并横切(300μm，McIlwain组织切片机)的纹状体切片上进行多巴胺释放。切片置于含有改良Krebs-Ringer基础释放培养基(BRM)的小玻璃瓶中，上述培养基已经用95％O2/5％CO2发泡30min并含有21mM NaHCO3、3.4mM葡萄糖、1.3mM NaH2PO4、1mM EGTA、0.93mM MgCl2、127mM NaCl和2.5mM KCl(低KCl)(pH7.4)。一半组织用50μM H2O2处理以评价氧化应激条件下饮食的效果。切片置于灌注室中，并保持在37℃，并用BRM灌注30分钟。此平衡期后，培养基转换为含有(以mM计)KCl30(高KCl)、CaCl2.2H2O 1.26(代替EGTA)、NaCl57和0或500μM氧化震颤素的培养基，然后评价K+-ERDA的增强。通过与电化学检测连接的HPLC测定多巴胺释放数量，并表示为pmol/mg蛋白质，如根据Lowry法测定。
在各组之间多巴胺释放(氧化震颤素增强的纹状体K+-ERDA)显著不同，这取决于饮食和H2O2处理[F(5，58)＝2.34，p＜0.05](图5)。在基础条件下，在饮食组之间没有差异(p＞0.05)。然而，与无H2O2处理的对照饮食组相比，在H2O2处理的对照饮食组中的多巴胺释放显著减少(p＜0.05)，而在施用了治疗量的低剂量或高剂量紫檀芪的受试者中，在H2O2处理后没有看到差异。
尽管本发明已经参照阐述实施方式的细节进行了说明，但这些细节并不意图限制所附权利要求所限定的本发明的范围。要求保护专有所有权或特权的本发明的实施方式如所附权利要求进行限定。
Claims (4)
1.一种增强受试者工作记忆的方法，该方法包括施用有效量的基本上纯的紫檀芪化合物，其中受试者的工作记忆增强。
2.如权利要求1所述的方法，其中所述治疗有效量的紫檀芪为每千克受试者体重约10mg化合物。
3.如权利要求1所述的方法，其中紫檀芪与药物载体一起施用。
4.如权利要求1所述的方法，其中紫檀芪与营养食品载体一起施用。
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| US97059107P | 2007-09-07 | 2007-09-07 | |
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| US12/136,341 US20090069444A1 (en) | 2007-09-07 | 2008-06-10 | Method to Ameliorate Oxidative Stress and Improve Working Memory Via Pterostilbene Administration |
| US12/136,341 | 2008-06-10 | ||
| CN2008801103188A CN101820869B (zh) | 2007-09-07 | 2008-09-04 | 通过施用紫檀芪减轻氧化应激并改善工作记忆的方法 |
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| CN2008801103188A Active CN101820869B (zh) | 2007-09-07 | 2008-09-04 | 通过施用紫檀芪减轻氧化应激并改善工作记忆的方法 |
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| CN (2) | CN103083288B (zh) |
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| BR (1) | BRPI0816317A2 (zh) |
| CA (1) | CA2698661C (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112618520A (zh) * | 2021-01-14 | 2021-04-09 | 姚大纯 | 紫檀芪或白藜芦醇在制备用于治疗或改善孤独症谱系障碍的药物中的应用 |
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| US20090069444A1 (en) * | 2007-09-07 | 2009-03-12 | The United States Of America, As Represented By Th E Secretary Of Agriculture | Method to Ameliorate Oxidative Stress and Improve Working Memory Via Pterostilbene Administration |
| US9737495B2 (en) * | 2009-06-22 | 2017-08-22 | Indus Biotech Private Limited | Process for obtaining purified pterostilbene and methods of use thereof |
| US20100119499A1 (en) * | 2009-09-17 | 2010-05-13 | Kneller Bruce W | Stilbene-based compositions and methods of use therefor |
| US20110280850A1 (en) * | 2010-05-12 | 2011-11-17 | Starr Elizabeth I | Compositions Containing DNA Repair Enzyme And Anogeissus Extract |
| US20120237494A1 (en) * | 2010-09-30 | 2012-09-20 | Daly Susan M | Compositions Containing Zinc PCA And Anogeissus Extract |
| EP2537513A3 (en) * | 2011-03-11 | 2015-04-29 | ELC Management LLC | Use of anogeissus extract for fibrillin production in skin |
| US9439875B2 (en) * | 2011-05-11 | 2016-09-13 | The United States Of America, As Represented By The Secretary Of Agriculture | Anxiolytic effect of pterostilbene |
| US20130072509A1 (en) * | 2011-09-15 | 2013-03-21 | ChromaDex Inc. | Pterostilbene and statin combination for treatment of metabolic disease, cardiovascular disease, and inflammation |
| WO2013051459A1 (ja) * | 2011-10-02 | 2013-04-11 | キユーピー 株式会社 | ＲＮＡ干渉によるｍＲＮＡ発現の抑制を促進する促進剤およびその用途 |
| JP5901547B2 (ja) | 2012-03-28 | 2016-04-13 | 富士フイルム株式会社 | 組成物、これを含む皮膚外用剤、又は機能性食品 |
| EP3063163B1 (en) | 2013-10-30 | 2022-08-10 | Chromadex Inc. | Nicotinamide riboside compositions for topical use in treating skin conditions |
| US20190076376A1 (en) | 2015-07-10 | 2019-03-14 | University Of Miami | Methods for treating mucopolysaccharidosis |
| US11260069B2 (en) * | 2016-08-22 | 2022-03-01 | Elysium Health, Inc. | Nicotinamide riboside and pterostilbene compositions and methods for treatment of neurodegenerative disorders |
| US9975915B1 (en) | 2016-11-11 | 2018-05-22 | The Queen's University Of Belfast | Crystalline forms of nicotinoyl ribosides, modified derivatives thereof, and phosphorylated analogs thereof, and methods of preparation thereof |
| US11071747B2 (en) | 2016-11-29 | 2021-07-27 | University Of Iowa Research Foundation | Use of NAD precursors for breast enhancement |
| MX2019006278A (es) | 2016-11-29 | 2019-08-21 | Univ Iowa Res Found | Uso de precursores de nad para mejorar la salud materna y/o salud de la descendencia. |
| EP3793602A4 (en) * | 2018-05-15 | 2022-04-20 | Alkahest, Inc. | Treatment of aging-associated disease with modulators of leukotriene a4 hydrolase |
| JP7345312B2 (ja) * | 2019-08-09 | 2023-09-15 | キユーピー株式会社 | 発酵乳 |
| KR102718991B1 (ko) * | 2020-09-25 | 2024-10-16 | 씨제이제일제당 (주) | 스틸벤계 화합물을 포함하는 항콕시듐증 조성물 및 이의 용도 |
| JP2024542963A (ja) | 2021-11-01 | 2024-11-19 | アルカヘスト，インコーポレイテッド | 加齢関連疾患の予防及び治療のためのロイコトリエンａ４加水分解酵素（ｌｔａ４ｈ）のベンゾジオキサン調節剤 |
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| US20050038125A1 (en) * | 2003-08-15 | 2005-02-17 | Smit Hobbe Friso | Method for the treatment of arthritis and pain |
| JP4633572B2 (ja) * | 2004-07-30 | 2011-02-16 | イスクラ産業株式会社 | 糖尿病改善剤 |
| US20060057231A1 (en) * | 2004-08-19 | 2006-03-16 | Rimando Agnes M | Pterostilbene as a new agonist for the peroxisome proliferator-activated receptor alpha isoform |
| US20090069444A1 (en) * | 2007-09-07 | 2009-03-12 | The United States Of America, As Represented By Th E Secretary Of Agriculture | Method to Ameliorate Oxidative Stress and Improve Working Memory Via Pterostilbene Administration |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112618520A (zh) * | 2021-01-14 | 2021-04-09 | 姚大纯 | 紫檀芪或白藜芦醇在制备用于治疗或改善孤独症谱系障碍的药物中的应用 |
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| BRPI0816317A2 (pt) | 2017-07-25 |
| AU2008296293A1 (en) | 2009-03-12 |
| CN101820869B (zh) | 2012-12-12 |
| JP2010538077A (ja) | 2010-12-09 |
| US20090069444A1 (en) | 2009-03-12 |
| EP2200597B1 (en) | 2014-11-12 |
| US20120035272A1 (en) | 2012-02-09 |
| US8809400B2 (en) | 2014-08-19 |
| ES2526648T3 (es) | 2015-01-14 |
| CN101820869A (zh) | 2010-09-01 |
| WO2009032870A2 (en) | 2009-03-12 |
| HK1148932A1 (zh) | 2011-09-23 |
| CA2698661A1 (en) | 2009-03-12 |
| WO2009032870A3 (en) | 2009-05-22 |
| HK1185257A1 (zh) | 2014-02-14 |
| JP5608082B2 (ja) | 2014-10-15 |
| US9028887B2 (en) | 2015-05-12 |
| EP2200597A4 (en) | 2010-09-08 |
| EP2200597A2 (en) | 2010-06-30 |
| CN103083288B (zh) | 2016-04-13 |
| US20140256827A1 (en) | 2014-09-11 |
| KR20100075468A (ko) | 2010-07-02 |
| CA2698661C (en) | 2016-03-29 |
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