CN111097010A - 用于抑制乙酰胆碱酯酶的提取物及组合物 - Google Patents
用于抑制乙酰胆碱酯酶的提取物及组合物 Download PDFInfo
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- CN111097010A CN111097010A CN201911023682.7A CN201911023682A CN111097010A CN 111097010 A CN111097010 A CN 111097010A CN 201911023682 A CN201911023682 A CN 201911023682A CN 111097010 A CN111097010 A CN 111097010A
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Abstract
本发明涉及细本葡萄(Vitis thunbergii Sieb.&Zucc)或小叶葡萄(Vitis thunbergii Sieb.&Zucc.var.taiwaniana Lu)的提取物及组合物。所述提取物及组合物可抑制乙酰胆碱酯酶,且因此可用于治疗或预防乙酰胆碱酯酶介导的病症,诸如神经退化性疾病。
Description
技术领域
本发明涉及乙酰胆碱酯酶介导的病症的治疗领域。尤其,本发明涉及用于抑制乙酰胆碱酯酶的提取物及组合物及其在治疗或预防诸如神经退化性疾病的乙酰胆碱酯酶介导的病症中的应用。
背景技术
乙酰胆碱酯酶(AChE)通过水解胆碱激导性突触处的神经传递质乙酰胆碱来终止突触传递(synaptic transmission)。在神经传递期间,Ach从突触前神经元释放到突触间隙中且结合到突触后膜上的ACh受体,中继来自神经的信号。也位于突触后膜上的AChE通过水解Ach来终止信号传递。
胺基甲酸酯即N-甲基胺基甲酸的酯为在数小时内水解且出于医学目的而使用的AChE抑制剂(例如用于治疗青光眼的毒扁豆碱)。已显示数种乙酰胆碱酯酶抑制剂降低乙酰胆碱分解的速率且因此增加其在大脑中的浓度。乙酰胆碱酯酶抑制剂通过增加蕈毒碱及烟碱受体中的ACh的可获得性来增强神经元传递。
可逆抑制剂占据酯解位点(esteratic site)达短时间段(数秒到数分钟)且用于治疗一定范围的中枢神经系统疾病。四氢胺吖啶(THA)及多奈哌齐得到FDA许可以改进阿兹海默氏症(Alzheimer's disease)中的认知功能。多奈哌齐,即2-(1-苄基-哌啶-4-基甲基)-5,6-二甲氧基-茚满-1-酮为乙酰胆碱酯酶抑制剂。多奈哌齐通常指定用于治疗阿兹海默氏症、痴呆及偏头痛。雷斯替明(Rivastigmine)也用于治疗阿兹海默氏及路易体性痴呆(Lewy body dementia),且溴化吡啶斯的明(pyridostigmine bromide)用于治疗重症肌无力。
WO 2006025708公开用于在某些条件下有效提取及纯化来自葡萄藤(欧洲葡萄(Vitis vinifera))的有效成分的方法,其可用于抑制乙酰胆碱酯酶(AChE)的活化、改进退化内存、控制血压及血液循环;包含自葡萄藤提取物中隔离的有效成分的组合物;所述组合物的用途;及用于通过使用所述组合物治疗与哺乳动物中的乙酰胆碱酯酶的抑制活性有关的疾病的方法。Jang MH公开羧基哌喃花色苷A(vitisin A)及毛葡萄甲素A(heyneanol A)以剂量依赖型方式抑制乙酰胆碱酯酶及丁酰胆碱酯酶且展现相较于加兰他敏(galantamine)的抗丁酰胆碱酯酶活性而言的更高的抗丁酰胆碱酯酶活性(PhytotherRes.2008年4月;22(4):544-9)。
然而,已得到认可的乙酰胆碱酯酶抑制剂迄今为止已具有较少治疗前景。因此需要允许抑制AChE的新型治疗。
发明内容
本发明提供包含以下的组合物:来自细本葡萄(Vitis thunbergii Sieb.&Zucc)茎部(VT-S)的乙醇提取物(Et)的约15.10%±10%莫耳浓度(M)比的葡萄素、约11.51%±10%M比的白藜芦醇、约6.13%±10%M比的霍毕酚(hopeaphenol)及约5.37%±10%M比的羧基哌喃花色苷A。
本发明还提供包含以下的组合物:来自VT-S的乙醇提取物的乙酸乙酯溶离份(Et-EA-fra)的约15.87%±10%莫耳浓度(M)比的白藜芦醇、约15.62%±10%M比的葡萄素、约6.25%±10%M比的霍毕酚及约4.23%±10%M比的羧基哌喃花色苷A。
本发明还提供包含以下的组合物:来自小叶葡萄(Vitis thunbergii Sieb.&Zucc.var.taiwaniana Lu)根部(VTT-R)的乙醇提取物(Et)的约31.53%±10%莫耳浓度(M)比的羧基哌喃花色苷A、约17.31%±10%M比的羧基哌喃花色苷B、约8.72%±10%M比的霍毕酚及约2.92%±10%M比的蛇葡萄素C(ampelopsin C)。
本发明还提供包含以下的组合物:来自VTT-R的乙醇提取物的乙酸乙酯溶离份(Et-EA-fra)的约33.57%±10%莫耳浓度(M)比的羧基哌喃花色苷B、约19.85%±10%M比的羧基哌喃花色苷A、约8.17%±10%M比的霍毕酚及约2.84%±10%M比的蛇葡萄素C。
本发明还提供包含本文所公开的组合物中的任一者的产物。
本发明进一步提供用于抑制乙酰胆碱酯酶的方法,其包含向个体投与本发明的组合物或细本葡萄(VT)或小叶葡萄(VTT)的乙醇提取物(Et)或乙醇提取物的乙酸乙酯溶离份(Et-EA-fra)。
附图说明
图1(A)到(D)显示Et-VT-S(A)、Et-EA-fra-VT-S(B)、Et-VTT-R(C)及Et-EA-fra-VTT-R(D)的HPLC谱图。
图2显示来自细本葡萄茎部(VT-S)的提取物或溶离份(检定系统中的0.1μg添加)的乙酰胆碱酯酶抑制。Hw,热水提取物;Et,乙醇提取物;Et-EA-fra,乙醇提取物的乙酸乙酯溶离份;Et-BuOH-fra,乙醇提取物的正丁醇溶离份;Et-H2O-fra,乙醇提取物的水溶离份。
图3显示来自小叶葡萄(VTT)的提取物或溶离份(检定系统中的0.1μg添加)的乙酰胆碱酯酶抑制。Hw,热水提取物;Et,乙醇提取物;Et-EA-fra,乙醇提取物的乙酸乙酯溶离份;Et-BuOH-fra,乙醇提取物的正丁醇溶离份;Et-H2O-fra,乙醇提取物的水溶离份。
图4显示通过被动回避评估经口投与Et-VT-S或Et-EA-fra-VT-S(200及400mg/kg)及多奈哌齐(5mg/kg)的后小鼠的学习行为,且记录步入潜伏期(step-through latency)。
图5(A)及(B)显示通过水迷宫的探针测试评估经口投与Et-VT-S或Et-EA-fra-VT-S(200及400mg/kg)及多奈哌齐(5mg/kg)的后的小鼠的学习行为,且记录目标象限中的交叉数(%总数)(A)及目标象限中的时间(%总量)(B)。
具体实施方式
整个文献意欲以统一公开内容形式相关,且应理解,考虑本文所描述的所有特点组合,即使未发现特点组合在本文献的相同句子或段落或章节中结合。如下文说明性所描述的本发明可在本文未特定公开的任何一或多种元素、一或多种限制不存在的情况下合适地实践。
除非另外指示,否则技术术语是根据其常见含义使用。若向某些术语赋予特定意义,则下文在使用所述等术语的情形下给出术语定义。
除非另外特定陈述,否则单数形式「一(a/an)」及「所述」可指复数个物品。
术语「乙酰胆碱酯酶」是指降解神经传递质乙酰胆碱、产生胆碱及乙酸根基团的酶。酶催化乙酰胆碱的分解及充当神经传递质的某些其他胆碱酯的分解。AChE在主要神经肌肉接合点处及胆碱激导性类型的化学突触中发现,其中其活性用以终止突触传递。
术语「抑制乙酰胆碱酯酶活性」或「乙酰胆碱酯酶活性抑制」是指更改乙酰胆碱酯酶的功能。
术语「乙酰胆碱酯酶介导的病症」是指特征在于异常乙酰胆碱酯酶活性或当调节时改善其他异常生物化学过程的正常乙酰胆碱酯酶活性的病症。乙酰胆碱酯酶介导的病症可由抑制乙酰胆碱酯酶活性完全或部分介导。详言的,乙酰胆碱酯酶介导的病症为其中抑制乙酰胆碱酯酶活性对潜在病症产生一些效果的病症,例如乙酰胆碱酯酶抑制剂投与引起经治疗的患者中的至少一些的某种改善。
术语「神经退化性」广泛地用于神经元的结构及/或功能的进行性损失。包括阿兹海默氏症、帕金森氏症(Parkinson's disease)及亨廷顿氏病(Huntington's disease)的多种神经退化性疾病是由于神经退化性过程而发生,且当前不可治愈,导致神经元的进行性退化及/或死亡。连接多种神经退化性疾病的普遍特点在于其全部涉及类淀粉蛋白的聚积,所述等类淀粉蛋白为共享特异性结构特质的纤维蛋白质聚集物。类淀粉蛋白为不溶性的且产生于自然地存在于身体中的至少18种不适当折迭型式的蛋白质及多肽。此等折迭异常结构更改其适当组态以使得其错误地与彼此或其他细胞组分相互作用,形成不溶性原纤维。迄今为止,类淀粉蛋白已与超过20种严重人类疾病的病理学相关联,此是因为器官中的类淀粉蛋白原纤维的异常聚积可能导致类淀粉变性。
术语「疾病」及「病症」在本文中可互换使用。
术语「治疗(treatment/treating)」涵盖预防性亦即防治性或治疗性亦即洽愈性及/或姑息性治疗。因此术语「治疗(treatment/treating)」包含已发展所述病况、特别地呈显性形式的患者的治疗性治疗。治疗性治疗可为对症治疗以便缓解特定适应症的症状,或可为病因治疗以便逆转或部分逆转适应症的病况或以便阻止或减缓疾病进展。因此,本发明的化合物、组合物及方法可例如用作一段时间内的治疗性治疗以及慢性疗法。另外,术语「治疗(treatment/treating)」包含防治性治疗,亦即处于发展上文提及的病况的风险下的患者的治疗,由此降低所述风险。
术语「治疗有效量」意谓本发明化合物(i)治疗或预防特定疾病或病况、(ii)减轻、改善或消除特定疾病或病况的一或多种症状或(iii)预防或推迟本文所描述的特定疾病或病况的一或多种症状的发作的量。
神经退化性疾病涵盖涉及神经系统的受影响区域中的神经元的结构及/或功能的进行性损失的各种病症,其通常伴有神经元损失。细本葡萄的根、茎及叶列举为用于治疗肝炎、黄疸、腹泻及关节炎的民间药中的食品材料。本发明出乎意料地发现细本葡萄的提取物的组合物在治疗及/或预防神经退化性疾病方面有效。
在一个实施方面中,本发明提供包含以下的组合物:约15.10%±10%莫耳浓度(M)比的葡萄素、约11.51%±10%M比的白藜芦醇、约6.13%±10%M比的霍毕酚及约5.37%±10%M比的羧基哌喃花色苷A。
在一个实施例中,组合物进一步包含约2.27%±10%莫耳浓度(M)比的蛇葡萄素C及视情况选用的约0.81%±10%M比的羧基哌喃花色苷B。在一个实施例中,组合物获自细本葡萄(VT)的乙醇提取物。在另一实施例中,组合物获自细本葡萄茎部(VT-S)的乙醇提取物。
在一个实施方面中,本发明提供包含以下的组合物:约15.87%±10%莫耳浓度(M)比的白藜芦醇、约15.62%±10%M比的葡萄素、约6.25%±10%M比的霍毕酚及约4.23%±10%M比的羧基哌喃花色苷A。
在一个实施例中,组合物进一步包含约2.11%±10%莫耳浓度(M)比的蛇葡萄素及视情况约0.91%±10%M比的羧基哌喃花色苷B。在一个实施例中,组合物获自细本葡萄(VT)的乙醇提取物的乙酸乙酯溶离份。在另一实施例中,组合物获自细本葡萄茎部(VT-S)的乙醇提取物的乙酸乙酯溶离份。
在另一实施方面中,本发明提供包含以下的组合物:约31.53%±10%莫耳浓度(M)比的羧基哌喃花色苷A、约17.31%±10%M比的羧基哌喃花色苷B、约8.72%±10%M比的霍毕酚及约2.92%±10%M比的蛇葡萄素C。
在一个实施例中,组合物进一步包含约1.46%±10%莫耳浓度(M)比的葡萄素及约1.43%±10%M比的白藜芦醇。在一个实施例中,组合物获自小叶葡萄(VTT)的乙醇提取物。在另一实施例中,组合物获自小叶葡萄根部(VTT-R)的乙醇提取物。
在另一实施方面中,本发明提供包含以下的组合物:约33.57%±10%莫耳浓度(M)比的羧基哌喃花色苷B、约19.85%±10%M比的羧基哌喃花色苷A、约8.17%±10%M比的霍毕酚及约2.84%±10%M比的蛇葡萄素C。
在一个实施例中,组合物进一步包含约1.18%±10%莫耳浓度(M)比的白藜芦醇及约0.98%±10%M比的葡萄素。在一个实施例中,组合物获自小叶葡萄(VTT)的乙醇提取物。在另一实施例中,组合物获自小叶葡萄根部(VTT-R)的乙醇提取物。
在另一实施方面中,本发明提供包含本文所公开的组合物中任一者的产物。
在另一实施方面中,本发明提供用于抑制乙酰胆碱酯酶的方法,其包含向个体投与本发明的组合物或细本葡萄或小叶葡萄的乙醇提取物或乙醇提取物的乙酸乙酯溶离份。在一个实施例中,乙酰胆碱酯酶抑制可预防或治疗神经退化性疾病。神经退化性疾病的实例包括但不限于帕金森氏症、阿兹海默氏症、亨廷顿氏病、痴呆、普里昂疾病、运动神经元疾病、脊髓小脑失调(SCA)、脊髓性肌萎缩(SMA)、肌萎缩性侧索硬化(ALS)及路易体疾病。
细本葡萄及小叶葡萄的提取物及自其获得的组合物可调配有医药学上可接受的载剂、赋形剂、稀释剂及/或盐作为用于投与的医药组合物或药剂。
医药学上可接受的载剂、稀释剂、赋形剂及/或盐意谓载剂、稀释剂、赋形剂及/或盐必须与调配物的其他成分兼容,对本文所描述的提取物及组合物的治疗效益无不利影响,且对其接受者无害。
用于实践本发明的本文所描述的提取物及组合物或其医药组合物的投与可通过全身性及/或局部递送化合物的任何方法进行。此等方法包括经口途径、非经肠途径等。
本发明的用于局部投与本文所描述的提取物及组合物的载剂包括但不限于矿物油、液体石蜡脂、白石蜡脂、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡、诸如乳糖的糖及水。可替代地,医药组合物可在含有悬浮或溶解于一或多种医药学上可接受的载剂中的本文所描述的提取物及组合物的合适乳剂或乳膏中调配。合适载剂包括但不限于矿物油、脱水山梨糖醇单硬脂酸酯、聚山梨醇酯60、鲸蜡酯蜡、十六醇十八醇、2-辛基十二醇、苄醇及水。
视待处理的具体病况、病症或疾病而定,可投与额外的治疗剂以及本文所描述的提取物及组合物。彼等额外的试剂可按任何次序作为多给药方案的部分由含本文所描述的提取物及组合物的组合物依序投与(连续或间断投与)。可替代地,彼等试剂可为与单个组合物中的本文所描述的提取物及组合物混合在一起(同时或并行投与)的单剂型的部分。
对于经口投与,可用于本发明的医药组合物可采取溶液、悬浮液、锭剂、丸剂、胶囊、粉剂、细粒、半固体、持续释放的调配物、酏剂、气溶胶及其类似物的形式。采用含有以下的锭剂:诸如柠檬酸钠、碳酸钙及磷酸钙的各种赋形剂,以及诸如淀粉、优选马铃薯或树薯淀粉的各种崩解剂,及特定复合物硅酸盐,以及诸如聚乙烯吡咯啶酮、蔗糖、明胶及阿拉伯胶的结合剂。另外,诸如硬脂酸镁、月桂基硫酸钠及滑石的润滑剂通常非常可用于制锭目的。类似类型的固体组合物也用作软填充及硬填充的明胶胶囊中的填充剂;在此方面优选材料也包括乳糖或奶糖以及高分子量聚乙二醇。当需要水性悬浮液及/或酏剂以用于经口投与时,本文所描述的提取物及组合物可与以下组合:各种甜味剂、调味剂、着色剂、乳化剂及/或悬浮剂,以及诸如水、乙醇、丙二醇、甘油及其各种相似组合的稀释剂。
调配物的选择视各种因素而定,诸如药物投与的模式(例如对于经口投与,呈锭剂、丸剂或胶囊形式的调配物为优选的)及药物物质的生物可用性。
如本文所使用的术语「非经肠」是指包括静脉内、肌肉内、腹膜内、胸骨内、皮下、髓内及关节内注射及输注的投与模式。用于非经肠注射的医药组合物可包含医药学上可接受的无菌水溶液或非水溶液、分散液、悬浮液或乳液以及用于在即将使用时复原成无菌可注射溶液或分散液的无菌粉剂。水溶液尤其适合于静脉内、肌肉内、皮下及腹膜内注射目的。在此方面,所采用的无菌水性介质全部皆可容易地通过熟习此项技术者熟知的标准技术获得。合适的水性及非水性载剂、稀释剂、溶剂或媒剂的实例包括水、乙醇、多元醇(诸如甘油、丙二醇、聚乙二醇及其类似物)、羧甲基纤维素及其合适的混合物、植物油(诸如橄榄油)及诸如油酸乙酯的可注射有机酯。可例如通过使用诸如卵磷脂的包衣物质、通过在分散液的情况下维持所需粒度且通过使用界面活性剂来维持适当的流动性。
可用于本发明的医药组合物也可含有佐剂,诸如但不限于防腐剂、润湿剂、乳化剂及分散剂。微生物作用的预防可通过包括诸如对羟基苯甲酸酯、氯丁醇、苯酚山梨酸及其类似物的各种抗菌剂及抗真菌剂来确保。还可需要包括诸如糖、氯化钠及其类似物的等张剂。可注射医药形式的延长吸收可通过包括诸如单硬脂酸铝及明胶的延迟吸收的试剂来实现。
当采用鞘内或硬膜外途径时,通过慢输注进行的投与为特别适用的。
除了活性化合物的外,悬浮液可含有悬浮剂作为例如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇及脱水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂及黄蓍以及其混合物。
出于经皮(例如局部)投与的目的,以类似于上文非经肠溶液的其他方式制备稀释无菌水溶液或部分水溶液。
其他医药学上可接受的载剂包括但不限于无毒固体、半固体或液体填充剂、稀释剂、囊封材料或任何类型的调配物助剂包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、诸如人类血清白蛋白的血清蛋白质、缓冲物质诸如磷酸盐、甘胺酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解液诸如鱼精蛋白硫酸盐、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶态二氧化硅、三硅酸镁、聚乙烯吡咯啶酮、纤维素类物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段共聚物、聚乙二醇及羊毛脂。
固体医药赋形剂包括但不限于淀粉、纤维素、滑石、葡萄糖、乳糖、蔗糖、明胶、麦芽、稻米、面粉、白垩、硅胶、硬脂酸镁、硬脂酸钠、甘油单硬脂酸酯、氯化钠、脱脂奶粉及其类似物。液体及半固体赋形剂可选自甘油、丙二醇、水、乙醇及各种油,包括石油、动物、植物或合成源的彼等油,例如花生油、大豆油、矿物油、芝麻油等。特别用于可注射溶液的优选液体载剂包括水、盐水、水性右旋糖及二醇。
用一定量的活性成分制备各种医药组合物的方法为已知的,或应鉴于本发明而对熟习此项技术者显而易见。其他合适的医药赋形剂及其调配物描述于Remington'sPharmaceutical Sciences,由E.W.Martin编辑,Mack Publishing Company,第19版(1995)中。
一般熟习此项技术者应了解,本文所描述的提取物及组合物的医药学上有效量可凭经验测定且可以纯形式或在所述等形式存在的情况下以医药学上可接受的盐、酯或前药形式采用。试剂可作为与一或多种医药学上可接受的赋形剂组合的医药组合物投与患者。应理解,当向例如人类患者投与时,本发明的试剂或组合物的总日用量应由主治医师在合理医学判断的范畴内决定。对于任何具体患者的特定治疗上有效剂量层级应视各种因素而定:待达成的细胞反应的类型及程度;所采用的特定试剂或组合物的活性;所采用的特定试剂或组合物;患者的年龄、体重、一般健康、性别及饮食;投与时间、投与途径及试剂分泌速率;治疗持续时间;与特定试剂组合或同时使用的药物;及医学技术中熟知的相似因素。
可替代地,本文所描述的提取物及组合物可调配有食品级载剂赋形剂、稀释剂及/或盐作为保健食品或膳食增补剂。上述载剂赋形剂、稀释剂及/或盐可用于本发明的保健食品或膳食增补剂中。保健食品或膳食补充剂可以各种形式存在,包括但不限于锭剂、胶囊、囊剂、粉剂、包括奶霜的饮品、包括点心棒的固体食物等。
相关领域中的一般技术者将容易地显而易见,可在不脱离本发明的范畴或其任一实施例的情况下对本文所描述的方法及应用作出其他适合的修改及调适。提供以下实例以进行说明但不限制本发明。
实例
实例1细本葡萄及小叶葡萄的提取及纯化
描述细本葡萄(VT)的提取。将细本葡萄茎部(VT-S)在50℃烘箱干燥3天且机械研磨成精细粉末,通过10目筛。粉末状VT-S在室温每次用乙醇(W/V=1:5)提取7天,且将乙醇提取物过滤且在减压下蒸发,产生乙醇提取物(Et-VT-S)。对于溶离份制备,使干燥粉末状VT-S(14kg)进行上述方法,得到乙醇提取物(ET-VT-S,412.3g),将其溶解于H2O中且随后连续用乙酸乙酯(EA)及正丁醇(BuOH)分配,获得Et-EA-fra-VT-S(83.5g)、Et-BuOH-fra-VT-S(117.7g)及Et-H2O-fra-VT-S(195.2g)。对于热水提取,在回流下用18L蒸馏水提取粉末状VT-S样品(5.5kg)3小时。一旦冷却到室温,则过滤提取物且在减压下低于45℃通过旋转式蒸发器蒸发。随后将其冻干以产生热水提取物(Hw-VT-S,356g)且储存于-20℃直到进一步使用。
描述小叶葡萄(VTT)的提取。将小叶葡萄(VTT)的根(R)、茎(S)及叶(L)在50℃烘箱干燥3天且机械研磨成精细粉末,通过10目筛。VTT-R、VTT-S及VTT-L的各粉末状样品在室温每次用乙醇(W/V=1:5)提取7天。各乙醇提取物过滤且在减压下蒸发以产生各乙醇提取物(Et)。对于溶离份制备,将Et-VTT-R(665.3g)溶解于H2O中且随后连续用乙酸乙酯(EA)及正丁醇(BuOH)分配,获得Et-EA-fra-VTT-R(507g)、Et-BuOH-fra-VTT-R(20.7g)及Et-H2O-fra-VTT-R(97g)。Et-EA-fra-VTT-R经硅胶管柱(150cm×12cm)进一步层析,用正己烷与EA的溶剂混合物递增极性作为溶离剂溶离。收集二十五个溶离份。溶离份24经RP-18管柱(5cm×60cm)进一步层析,且用水-甲醇(1:1到0:1)溶离,得到八个溶离份,fra 24A到fra 24H。通过半制备型HPLC进一步纯化fra 24E,分别产生(+)-霍毕酚及(+)-羧基哌喃花色苷A。通过半制备型HPLC进一步纯化fra 24F,产生(-)-羧基哌喃花色苷B。对于热水提取,在回流下用1L蒸馏水各别地提取VTT-R、VTT-S及VTT-L的各粉末状样品(各100g)3小时。一旦冷却到室温,过滤各提取物且在减压下低于45℃通过旋转式蒸发器蒸发。随后将其冻干以产生热水提取物(Hw-VTT-R、Hw-VTT-S及Hw-VTT-L)且储存于-20℃直到使用。
在VT及VTT的提取物或溶离份中通过HPLC识别主要化合物。管柱,LiChrospher100RP-18e(4mm内径×250mm,5μm);移动相,0.05%三氟乙酸-CH3CN(0min,95:5;50min,55:45;60min,55:45;61min,95:5;70min,95:5);流动速率,1.0mL/min;管柱温度,40℃;侦测,280nm。图1显示Et-VT-S(A)、Et-EA-fra-VT-S(B)、Et-VTT-R(C)及Et-EA-fra-VTT-R(D)的HPLC谱图。
VT及VTT的提取物或溶离份中所识别的主要化合物的重量比及莫耳浓度可基于HPLC谱图中所示的面积比来计算。结果显示如下。
表1.Et-VT-S中的经识别化合物
表2.Et-EA-fra-VT-S中的经识别化合物
表3.Et-VTT-R中的经识别化合物
表4.Et-EA-fra-VTT-R中的经识别化合物
实例2抑制乙酰胆碱酯酶(AChE)的活性
AChE可水解合成基质碘化乙酰硫胆碱(AChI)以产生硫胆碱及乙酸。在硫胆碱与DTNB(5,5'-二硫基双-(2-硝基苯甲酸))反应的后,产生黄色硫基-2-硝基苯甲酸。总计100μL反应溶液用于96孔微定量盘中的AChE抑制检定。将9μL AChE、1μL提取物或溶离份(0.1μg)及50μL 100mM磷酸盐缓冲液(pH 7.5)预混合15min,且随后添加20μL 1mM AChI达15min。添加20μL 2mM DTNB达15min,且通过ELISA读取器量测450nm处的吸亮度。
图1显示来自细本葡萄茎部(VT-S)的提取物或溶离份在抑制乙酰胆碱酯酶(AChE)中的活性。图2显示来自小叶葡萄(VTT)的提取物或溶离份在抑制AChE中的活性。图2及3的结果展现检定系统中的0.1μg提取物或溶离份的添加显示不同的乙酰胆碱酯酶抑制活性。在相同的0.1μg添加物处的提取物及溶离份当中,Et-VT-S及Et-EA-fra-VT-S(图1)以及Et-VTT-R及Et-EA-fra-VTT-R(图2)显示有效的乙酰胆碱酯酶抑制。用于AChE抑制的0.1μg Et-VT-S及Et-EA-fra-VT-S(图1)分别为64%±1.2%及82%±2.4%。用于AChE抑制的0.1μgEt-VTT-R及Et-EA-fra-VTT-R(图2)分别为68%±0.2%及74%±2%。
白藜芦醇、霍毕酚、羧基哌喃花色苷B及羧基哌喃花色苷A在抑制乙酰胆碱酯酶中的IC50值示于表5中。白藜芦醇及白藜芦醇寡聚物(羧基哌喃花色苷A、羧基哌喃花色苷B及霍毕酚)的用于50%抑制AChE活性的浓度全部高于1μM。
在图2中,用于AChE抑制的0.1μg Et-VT-S及Et-EA-fra-VT-S分别为64%±1.2%及82%±2.4%。0.1μg Et-VT-S的提取物中的经识别化合物的量(表1)基于面积比含有0.504μM白藜芦醇、0.0677μM霍毕酚、0.0089μM羧基哌喃花色苷B及0.0593μM羧基哌喃花色苷A。0.1μg Et-EA-fra-VT-S的提取物中的经识别化合物的量(表2)含有0.696μM白藜芦醇、0.069μM霍毕酚、0.01μM羧基哌喃花色苷B及0.0467μM羧基哌喃花色苷A。结果显示VT-S中的提取物或溶离份的组合物展现低于用于AChE抑制的各化合物浓度的浓度,且提取物或溶离份中的经识别化合物具有用于AChE抑制的额外的效果。
在图3中,用于AChE抑制的0.1μg Et-VTT-R及Et-EA-fra-VTT-R(图3)分别为68%±0.2%及74%±2%。0.1μg Et-VTT-R的提取物中的经识别化合物的量(表3)基于面积比含有0.0627μM白藜芦醇、0.0962μM霍毕酚、0.1911μM羧基哌喃花色苷B及0.348μM羧基哌喃花色苷A。0.1μg Et-EA-fra-VTT-R的提取物中的经识别化合物的量(表4)含有0.0518μM白藜芦醇、0.0902μM霍毕酚、0.3705μM羧基哌喃花色苷B及0.2191μM羧基哌喃花色苷A。结果显示VTT-R中的提取物或溶离份的组合物展现低于用于AChE抑制的各化合物浓度的浓度,且提取物或溶离份中的经识别化合物具有用于AChE抑制的额外的效果。
实例3由莨菪碱诱导阿兹海默氏症的动物模型
在10天诱导阿兹海默症的前,执行小鼠中的利用标准生理盐水的经口管饲作为阴性对照组。在阳性对照中,利用经口管饲将多奈哌齐(5mg/kg)喂给小鼠。在实验组中,利用经口管饲将样品以200及400mg/kg的剂量喂给小鼠。
在阴性对照组、阳性对照组及实验组中的30分钟经口管饲的后,自第11天到第19天向小鼠腹膜内投与1mg/kg莨菪碱。在第13天(记忆采集试验)及第14天(记忆保持试验)进行被动回避测试,且在第17天到第19天进行水迷宫测试。在第20天处死小鼠。
以200及400mg/kg的剂量经口投与Et-VT-S或Et-EA-fra-VT-S的后的小鼠的学习行为是通过第13天(记忆采集试验)及第14天(记忆保持试验)的被动回避来评估,且结果示于图4中。记忆采集试验中的小鼠的步入潜伏期在所有组中显示无显著的差异(P>0.05)。然而,本发明组(多奈哌齐、Et-VT-S及Et-EA-fra-VT-S)及空白组中的小鼠显示相较于对照组的彼等步入潜伏期及差异而言的更长的步入潜伏期及显著的差异(P<0.05)。经口投与Et-VT-S或Et-EA-fra-VT-S的后的小鼠的学习行为是通过第17天到第19天的水迷宫来评估。第19天的探针测试的结果示于图5中。探针测试中的本发明组(多奈哌齐、Et-VT-S及Et-EA-fra-VT-S)及空白组中的小鼠显示提高目标象限中的交叉数(图5A)及目标象限中的时间(图5B)且具有相较于对照组的彼等差异而言的显著的差异(*P<0.05、**P<0.01、***P<0.001)。结果显示Et-VT-S及Et-EA-fra-VT-S的干预展现莨菪碱诱导的阿兹海默氏小鼠模型中的学习及记忆行为的改善。
Claims (16)
1.一种组合物,其包含约15.10%±10%莫耳浓度(M)比的葡萄素(viniferin)、约11.51%±10%M比的白藜芦醇(resveratrol)、约6.13%±10%M比的霍毕酚(hopeaphenol)及约5.37%±10%M比的羧基哌喃花色苷A(vitisin A)。
2.根据权利要求1所述的组合物,其进一步包含约2.27%±10%莫耳浓度(M)比的蛇葡萄素(ampelopsin)及视情况约0.81%±10%M比的羧基哌喃花色苷B。
3.根据权利要求1所述的组合物,其获自细本葡萄(Vitis thunbergii Sieb.&Zucc)茎部的乙醇提取物。
4.一种组合物,其包含约15.87%±10%莫耳浓度(M)比的白藜芦醇、约15.62%±10%M比的葡萄素、约6.25%±10%M比的霍毕酚及约4.23%±10%M比的羧基哌喃花色苷A。
5.根据权利要求4所述的组合物,其进一步包含约2.11%±10%莫耳浓度(M)比的蛇葡萄素C及视情况约0.91%±10%M比的羧基哌喃花色苷B。
6.根据权利要求4所述的组合物,其获自细本葡萄茎的乙醇提取物的乙酸乙酯溶离份。
7.一种组合物,其包含约31.53%±10%莫耳浓度(M)比的羧基哌喃花色苷A、约17.31%±10%M比的羧基哌喃花色苷B、约8.72%±10%M比的霍毕酚及约2.92%±10%M比的蛇葡萄素C。
8.根据权利要求7所述的组合物,其进一步包含约1.46%±10%莫耳浓度(M)比的葡萄素及约1.43%±10%M比的白藜芦醇。
9.根据权利要求7所述的组合物,其获自小叶葡萄(Vitis thunbergii Sieb.&Zucc.var.taiwaniana Lu)根部的乙醇提取物。
10.一种组合物,其包含约33.57%±10%莫耳浓度(M)比的羧基哌喃花色苷B、约19.85%±10%M比的羧基哌喃花色苷A、约8.17%±10%M比的霍毕酚及约2.84%±10%M比的蛇葡萄素C。
11.根据权利要求10所述的组合物,其进一步包含约1.18%±10%莫耳浓度(M)比的白藜芦醇及约0.98%±10%M比的葡萄素。
12.根据权利要求10所述的组合物,其获自小叶葡萄根部的乙醇提取物。
13.一种产品,其包含如权利要求1到12中任一权利要求所述的组合物。
14.一种根据权利要求1到12中任一项的组合物或细本葡萄或小叶葡萄的乙醇提取物或所述乙醇提取物的乙酸乙酯溶离份在制造用于抑制乙酰胆碱酯酶的药剂的用途,其包含向个体投与。
15.根据权利要求14的用途,其中乙酰胆碱酯酶的抑制可预防或治疗神经退化性疾病。
16.根据权利要求15的用途,其中所述神经退化性疾病为帕金森氏症(Parkinson'sdisease)、阿兹海默氏症(Alzheimer's disease)、亨廷顿氏病(Huntington's disease)、痴呆、普里昂(prion)疾病、运动神经元疾病、脊髓小脑失调(SCA)、脊髓性肌萎缩(SMA)、肌萎缩性侧索硬化(ALS)或路易体疾病(Lewy body disease)。
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