CN105213370B - 苯酞化合物的应用 - Google Patents
苯酞化合物的应用 Download PDFInfo
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- CN105213370B CN105213370B CN201410322601.4A CN201410322601A CN105213370B CN 105213370 B CN105213370 B CN 105213370B CN 201410322601 A CN201410322601 A CN 201410322601A CN 105213370 B CN105213370 B CN 105213370B
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- butylidenephthalide
- acid
- phthalide
- medicament
- mouse
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Abstract
一种使用苯酞化合物（phthalide）于制备药剂的用途，该药剂特别是用以治疗及／或延缓浦肯野细胞（Purkinje cells）退化，且该苯酞化合物是选自以下群组：亚丁基苯酞、亚丁基苯酞的代谢前驱物、亚丁基苯酞的代谢前驱物的医药可接受盐、亚丁基苯酞的代谢前驱物的医药可接受酯、以及前述的任意组合。
Description
技术领域
本发明关于苯酞化合物(phthalide)的应用，尤其关于使用苯酞化合物于治疗及/或延缓浦肯野细胞(Purkinje cells)退化的应用，特别是关于治疗脊髓性小脑萎缩症、阿兹海默症、帕金森氏症的至少一者及/或延缓其发病的应用。
背景技术
神经元(neuron)也可称为神经细胞，是生物体神经系统的结构与功能单位之一，可借助化学信号及电信号与其它细胞进行信息传递，具有各种不同的形状和尺寸，直径为约4微米至约100微米，结构上大致可分为细胞本体、树突(dendrite)、及轴突(axon)三部分，其中树突可将信息带入细胞本体，而轴突则可将信息自细胞本体传出。
浦肯野细胞为存在小脑中负责传送神经冲动功能的神经元，属于γ-氨基丁酸(γ-aminobutyric acid，GABA)神经元的一种，其形态比普通神经细胞大且具有较多的树突，主要功能为神经信息传递及调控纳-钾离子通道。浦肯野细胞与生物体的运动协调功能有关，已知浦肯野细胞的退化(例如，浦肯野细胞死亡、细胞数量减少或损伤、或因细胞树突数量减少而使其信息传递功能下降)会影响其信息传递的功能，故与阿兹海默症、帕金森氏症、及脊髓性小脑萎缩症等神经疾病有关，且为该等神经疾病的进程指标(参见Schilling,K.等人，1991，Electrical activity in cerebellar cultures determines Purkinjecell dendritic growth patterns.Neuron7，891-902，该文献全文并于此处以供参考)。因此，若能抑制浦肯野细胞退化，则可提供治疗如阿兹海默症、帕金森氏症、及脊髓性小脑萎缩症等神经性疾病的功效。
脊髓性小脑萎缩症(spinocerebellar atrophy)是最常见的共济失调疾病之一，其主要症状为小脑共济失调(cerebellar ataxia)，从而导致协调运动障碍、肌肉张力减低、眼球运动障碍、及言语障碍等。脊髓性小脑萎缩症的致病原因主要为遗传或基因突变，使患者体内的特定染色体位置上的Atxin-3(ATXN3)基因的外显子出现异常的CAG序列重复，使所表现的蛋白质中产生长链的麸胺酸(glutamine)，导致细胞凋亡。ATXN3为一种去泛素蛋白酶(deubiquitinating enzyme，DUB)，在泛素-蛋白酶路径中，ATXN3具有防止异常蛋白聚集的功能。根据CAG序列重复在患者染色体中所出现的位置，脊髓性小脑萎缩症主要可分为第一型(SCA1)、第二型(SCA2)、第三型(SCA3)、第六型(SCA6)、第七型(SCA7)和DRPLA型等亚型。其中，SCA3又称为马卡多-约瑟夫氏病(Machado-Joseph disease，MJD)，为脊髓性小脑萎缩症中最常见的亚型，其特征为染色体14q32.1位置上的外显子10(exon10)发生了异常的CAG序列重复。
目前临床上对于浦肯野细胞退化所引起的相关疾病仍无有效的治疗方法，至多仅能通过物理治疗及呼吸系统照护以减少并发症的发生机率，减缓病情恶化的速度。因此，仍极需可有效治疗及/或延缓浦肯野细胞退化相关的神经性疾病的药物。
本发明人研究后发现，苯酞化合物(phthalide)可治疗及/或延缓浦肯野细胞退化，故可用于治疗脊髓性小脑萎缩症、阿兹海默症、帕金森氏症的至少一者及/或延缓其发病。
发明内容
本发明的一个目的，在于提供一种使用一苯酞化合物于制备药剂的用途，其中该药剂用于治疗及/或延缓浦肯野细胞退化，且其中该苯酞化合物是选自以下群组：亚丁基苯酞(n-butylidenephthalide)、亚丁基苯酞的代谢前驱物、亚丁基苯酞的代谢前驱物的医药可接受盐、亚丁基苯酞的代谢前驱物的医药可接受酯、以及前述的组合。
本发明的又一目的，在于提供一种于一个体中治疗及/或延缓浦肯野细胞退化的方法，包含投予该个体有效量的一苯酞化合物，其中该苯酞化合物选自以下群组：亚丁基苯酞、亚丁基苯酞的代谢前驱物、亚丁基苯酞的代谢前驱物的医药可接受盐、亚丁基苯酞的代谢前驱物的医药可接受酯、以及前述的组合。
本发明的详细技术内容及部分实施态样，将描述于以下内容中，以供本发明所属领域具通常知识者据以明了本发明的特征。
附图说明
图1所示为经pEGFP-C1、pEGFP-C1-Ataxin3Q28、pEGFP-C1-Ataxin3Q84转染的细胞经不同条件处理后的荧光显微镜照片；
图2所示为经不同条件处理后斑马鱼的存活率的长条图；
图3所示为经不同条件处理后斑马鱼的行为测试结果的长条图；
图4所示为经不同条件处理后斑马鱼的神经元的共轭焦显微镜照片；
图5A、图5B、图5C为经不同条件处理后的SCA3小鼠进行Local motor测试的结果的曲线图；
图6为经不同条件处理后的SCA3小鼠进行转棒测试的结果的曲线图；
图7为经不同条件处理后的SCA3小鼠的小脑切片的免疫化学组织染色图；
图8为经不同条件处理后的SCA3小鼠的小脑组织的钙结合蛋白的西方墨点图；
图9为经不同条件处理后的SCA3小鼠的小脑组织的经泛素化蛋白的西方墨点图。
具体实施方式
以下将描述根据本发明的部分具体实施态样；但是，在不背离本发明精神下，本发明尚可以多种不同形式的态样来实践，不应将本发明保护范围解释为限于说明书所陈述者。此外，除非文中有另外说明，于本申请文件中所使用的「一」、「该」及类似用语应理解为包含单数及复数形式；所谓「有效量」或「治疗有效量」，是指投予至个体时，可有效至少部分改善怀疑个体的病情的化合物数量；所谓「个体」是指哺乳动物，哺乳动物可为人类或非人动物；所谓「治疗」是包括预防特定疾病或症状、减轻特定的疾病或症状、及/或防止或消除该病症；所谓「延缓浦肯野细胞退化」乙语是指延缓浦肯野细胞的细胞死亡、损伤、及/或信息传递功能下降；单位「毫克/公斤体重」是指每公斤体重个体所须的投药量。
本发明人发现，特定苯酞化合物(phthalide)可治疗及/或延缓浦肯野细胞退化。因此，本发明提供一种使用一苯酞化合物于制备用以治疗及/或延缓浦肯野细胞退化的药剂的用途，其中该苯酞化合物选自以下群组：亚丁基苯酞、亚丁基苯酞的代谢前驱物、亚丁基苯酞的代谢前驱物的医药可接受盐、亚丁基苯酞的代谢前驱物的医药可接受酯、以及前述的组合。
于根据本发明一具体实施态样中，是使用亚丁基苯酞(butylidenephthalide；BP)以制备用以治疗及/或延缓浦肯野细胞退化的药剂。亚丁基苯酞即下式(I)化合物，在自然状态下同时包含(Z)-亚丁基苯酞((Z)-butylidenephthalide，顺式亚丁基苯酞)及(E)-亚丁基苯酞((E)-butylidenephthalide，反式亚丁基苯酞)二种异构物形式。较佳地，是于本发明使用Z-亚丁基苯酞含量为90％或更高的亚丁基苯酞。
于本文中，所谓「亚丁基苯酞的代谢前驱物」是指一经生物体代谢后会产生亚丁基苯酞的化合物。举例言之，但不以此为限，已知具如下式(II)结构的3-亚丁基-4,5-二氢苯酞(3-butylidene-4,5-dihydrophthalide)，又称“藁本内酯”(ligustilide)，其于生物体代谢后会产生亚丁基苯酞，属亚丁基苯酞的代谢前驱物。
所谓“医药可接受的盐”，是包括所述含有酸官能基的苯酞化合物与有机或无机碱所形成的医药可接受的盐。其中，与无机碱所形成的盐的例子包括，但不限于，碱金属盐(如钠盐、钾盐)、碱土金属盐(如钙盐、镁盐)、过渡金属盐(如铁盐、锌盐、铜盐、锰盐及铝盐)、以及铵盐；与有机碱所产生的盐的例子包括与甲基胺、二甲基胺、三甲基胺、乙基胺、二乙基胺、三乙基胺、异丙基胺、三丙基胺、三丁基胺、乙醇胺、二乙醇胺、2-二甲基胺乙醇、2-二乙基胺乙醇、二环己基胺、离胺酸盐、精胺酸盐、组胺酸盐、咖啡碱、海巴胺(hydrabamine)、胆碱、甜菜碱、乙烯二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌啶、N-乙基哌啶、四甲基铵化合物、四乙基铵化合物、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二环己基胺、二苯甲基胺、N,N-二苯甲基苯乙基胺、1-伊芬胺(1-ephenamine)、N,N-二苯甲基乙烯二胺、聚胺树脂及其类似物等所形成的盐。
所谓“医药可接受的酯”，是指包括所述含有如-OH官能基的苯酞化合物与酸反应所得的酯。该酸可为无机酸例如盐酸、氢溴酸、硫酸、磺胺酸、硝酸、及磷酸的无机酸，和有机酸例如醋酸、三氟醋酸、己二酸、抗坏血酸、天门冬胺酸、苯磺酸、苯甲酸、丁酸、樟脑酸(camphoric acid)、樟脑磺酸(camphorsulfonic acid)、肉桂酸、柠檬酸、二葡萄糖酸、乙烷磺酸、麸胺酸、甘醇酸、甘油磷酸、半硫酸(hemisulfic acid)、己酸(hexanoic acid)、甲酸、2-羟基乙磺酸(isethionic acid)、乳酸、羟基马来酸、苹果酸、丙二酸、扁桃酸、三甲基苯磺酸(mesitylenesulfonic acid)、甲磺酸、萘磺酸(naphthalenesulfonic acid)、烟碱酸、2-萘磺酸、草酸、扑酸(pamoic acid)、果胶酯酸、苯基醋酸、3-苯丙酸、特戊酸、丙酸、丙酮酸、水杨酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、对-甲苯磺酸、十一烷酸等。
可通过任何合合宜方式提供用于本发明的苯酞化合物。举例言之，但不以此为限，可自当归、川芎、藁本萃取纯化而提供3-亚丁基-4,5-二氢苯酞。此外，可自例如当归经萃取纯化而提供或自商业上购买而获得亚丁基苯酞。另外，可先将自市面上购得(例如购自AlfaAesar公司)的亚丁基苯酞(为(Z)-及(E)-亚丁基苯酞的混合物)以适量的硅胶包埋(重量比为亚丁基苯酞：硅胶＝1:3)，随后进行硅胶管柱层析，以正己烷作为移动相冲提，依不同时间点收集冲提出的(Z)-亚丁基苯酞及(E)-亚丁基苯酞，分别提供(Z)-亚丁基苯酞及(E)-亚丁基苯酞。
如上所述，于本发明中，所提供的药剂是具有治疗及/或延缓浦肯野细胞退化的功效，尤其可延缓或避免浦肯野细胞死亡，且可增加浦肯野细胞中蛋白质的泛素化作用，故可用于治疗脊髓性小脑萎缩症、阿兹海默症、及帕金森氏症的至少一者及/或延缓其发病。于本发明的部分实施态样中，该药剂是用于治疗第三型脊髓性小脑萎缩症(SCA3)及/或延缓其发病。如本说明书实施例所示，本发明所提供的药剂可有效延缓或避免患有第三型脊髓性小脑萎缩症的患者小脑中的浦肯野细胞死亡，且可有效改善患者的运动行为。
可以任何合宜的用量施用本发明所提供的药剂，端视投予个体的需求而异。举例言之，当使用于人体以治疗及/或延缓浦肯野细胞退化时，药剂的用量，以亚丁基苯酞计，为每天约30毫克/公斤体重至约2,000毫克/公斤体重，较佳为每天约100毫克/公斤体重至约1,000毫克/公斤体重。但，对于急性患者而言，其用量可视实际需要而酌增，例如增加至数倍或数十倍。此外，所投予的药剂的总量可视需要于单次投药程序中全部给予，或于多次投药程序中分别给药。
于本发明中，所提供的药剂可呈任何形式，并以任何合宜的方式施用。举例言之，但不以此为限，可经由口服、鼻腔给药、脑内注射、静脉注射、腹腔注射、皮下注射、及/或皮下或组织间缓释剂型等方式施用至一需要的个体。其中，由于口服投药剂型便于病人按时自行服用，故于本发明的一较佳实施态样中，是以口服剂型提供该药剂，例如：锭剂、胶囊剂、颗粒剂、散剂、流浸膏剂、溶液剂、糖浆剂、悬液剂、乳剂、及酊剂等。视使用形式及用途而定，该药剂可更包含一医药可接受的载剂。于本发明的部分实施态样中，是以橄榄油作为载剂。
以制备适于口服投药的剂型为例，该药剂中可含有任何不会不利影响所含活性成分(即，亚丁基苯酞、其代谢前驱物、及/或前述之医药可接受盐及/或酯)的活性的医药可接受载剂，例如：油性溶剂、稀释剂、安定剂、吸收延迟剂、崩散剂、乳化剂、抗氧化剂、粘合剂、润滑剂、吸湿剂等。可利用任何合宜的方法，将该组合物制成适于口服投药的剂型。
至于制备适于静脉注射或皮下注射的剂型，该药剂可例如包含一或多种等张溶液、盐类缓冲液(如磷酸盐缓冲液或柠檬酸盐缓冲液)、助溶剂(solubilizer)、乳化剂、以及其他载剂等成分，以制成一静脉输注液、乳剂静脉输注液、干粉注射剂、悬液注射剂、或干粉悬液注射剂等。
除了上述佐剂外，该药剂可视需要另含有调味剂、调色剂、着色剂等添加剂，以提高所得药剂服用时的口适感及视觉感受；另可添加合宜用量的保存剂、防腐剂、抗菌剂、抗真菌剂等，以改善药剂的储存性。此外，视需要地，可于本发明所提供的药剂中并含一或多种其他活性成分，例如抗氧化剂(如维他命E)、神经滋养因子(neurotrophic factor)等，以进一步加强本发明药剂的功效或增加制剂配方的运用灵活性与调配度，只要该其他活性成分对药剂内所含的苯酞化合物的所欲功效没有不利的影响即可。
此外，可以一日一次、一日多次、或数日一次等不同投药频率施用本发明所提供的药剂，端视投予个体的需求而异。
本发明亦提供一种于一个体中治疗及/或延缓小脑浦肯野细胞退化的方法，其是包含对该个体施用一有效量的一苯酞化合物，其中该苯酞化合物选自以下群组：亚丁基苯酞、亚丁基苯酞的代谢前驱物、亚丁基苯酞的代谢前驱物的医药可接受盐、亚丁基苯酞的代谢前驱物的医药可接受酯、以及前述的组合。其中，有关该活性成分的选用以及其性质、施用型态与剂量，均如上述的说明。
在此下列实施例进一步例示说明本发明。其中该等实施例仅提供作为说明，而非用以限制本发明的保护范围。
[实施例]
[实施例1]体外细胞试验
细胞转染
本实验测试亚丁基苯酞以及3-亚丁基-4,5-二氢苯酞对SCA3蛋白质表现程度的影响。首先，将含有绿色荧光蛋白的pEGFP-C1-Ataxin3Q84(即，具异常CAG重复数目(84Q)的Ataxin基因的质体)或pEGFP-C1-Ataxin3Q28质体(即，具正常CAG重复数目(28Q)的Ataxin基因的质体)(购自Addgene公司，美国)，通过转染试剂(2000Transfection Reagent，InvitrogenTM)转染至人类胚胎肾脏细胞(Human embryonickidney，HEK)293T((Bioresource Collection and Research Center，台湾)或神经干细胞(Neural stem cell，NSC)中。将细胞培养于含有10％胎牛血清(Gibco)的DMEM培养基(Dulbecco’s modified Eagle’s medium，Thermo)，于5％CO2的37℃培养箱中。之后，以浓度5微克/毫升的亚丁基苯酞(A10353，购自Alfa Aesar，美国；纯度95％)或3-亚丁基-4,5-二氢苯酞(5393-015M1，购自pharmaron，中国)处理细胞24小时后，使用荧光显微镜观察各组细胞中GFP-ATXN3蛋白质聚集的情形。实验以野生型(wild type)细胞及经绿色荧光蛋白(GFP)转染的细胞作为对照组。实验结果显示于图1。
如图1所示(右下角的比例尺为100微米)，未经GFP转染的细胞不会发出荧光，而经质体转染的细胞则可明显观察到荧光表现，显示实验所使用的细胞可成功表现GFP及ATXN3。此外，经亚丁基苯酞或3-亚丁基-4,5-二氢苯酞处理的细胞的荧光表现Ataxin3Q84的程度明显降低，相较于未经药物处理的组别，显示亚丁基苯酞及3-亚丁基-4,5-二氢苯酞可减少ATXN3蛋白质的数量。
[实施例2]斑马鱼活体内试验
(1)测试安全剂量
本实验使用斑马鱼做为动物模式，实验组使用的斑马鱼品系为Tg(HuC:GFP)，此品系特征为初级感觉神经元(Rohon-Beard cells)会产生荧光，故方便进行观察，控制组则使用野生型品系，全部鱼种皆由TZCAS(中研院台湾斑马鱼中心(Taiwan Zebrafish CoreFacility at Academia Sinica)，台湾)及TZCF(台湾斑马鱼中心(Taiwan Zebrafish CoreFacility)，台湾)提供。首先，测试亚丁基苯酞对于斑马鱼的毒性，注射不同剂量的亚丁基苯酞至斑马鱼，于28.5℃进行培养，并于48小时后观察其存活率。
结果如图2所示，野生型斑马鱼的存活率为100％，而经500毫克/公斤亚丁基苯酞注射的斑马鱼的存活率约50％，经250毫克/公斤及50毫克/公斤亚丁基苯酞注射的斑马鱼的存活率都大于75％，但在经ATXN3MO或H2O注射后，斑马鱼的存活率有些微下降，推测可能是因注射时感染或鱼卵品质不佳。由此实验结果可知，浓度250毫克/公斤以下的亚丁基苯酞对斑马鱼为安全剂量。
(2)斑马鱼行为测试
本实验使用ATXN3基因的吗啉基DNA片段(morpholinos，Gene Tools，美国；以下称为ATXN3MO)以消除斑马鱼的内源性ATXN3的表现，以引起神经损伤效果。MO为DNA结构进行修饰而成，具有阻断mRNA转译蛋白功能，可使生物不表现特定目标蛋白。实验所用的ATXN3MO的序列为5'-TCCTCCTCGTCCAGCTGCTGTGCTA-3'(SEQ ID NO.：1)，所使用的标准品控制组的序列为5'-CCTCTTACCTCAGTTACAATTTATA-3'(SEQ ID NO.：2)(以下称为Ct MO)。注射前，将MO溶解于ddH2O，储存于-20℃备用。在斑马鱼的鱼卵出生约1小时内，进行微注射，并于注射完24至48小时(hour post fertilization，hpf)后，以300奈莫耳浓度/微升的ATXN3MO、或ATXN3MO合并250毫克/公斤亚丁基苯酞、125毫克/公斤亚丁基苯酞、或62.5毫克/公斤亚丁基苯酞微注射处理鱼卵，48小时后，以滴管尖(tip)刺激鱼尾，并测量刺激致鱼尾移动所需的次数。
实验结果如图3所示，相较于野生型(简称Wt)、Ct MO、及控制组(Mock)，注射ATXN3MO的组别的斑马鱼的刺激鱼尾致移动的次数明显较高，而在经亚丁基苯酞注射后则有回复的现象，由此可知亚丁基苯酞具有恢复疾病斑马鱼的行为能力的效果，且其中又以浓度250毫克/公斤的效果最明显。
(3)共轭焦显微镜试验
以300奈莫耳浓度/微升ATXN3MO、250毫克/公斤亚丁基苯酞、或ATXN3MO合并250毫克/公斤亚丁基苯酞、125毫克/公斤亚丁基苯酞、或62.5毫克/公斤亚丁基苯酞微注射处理鱼卵，48小时后，将鱼体封入玻片中，以共轭焦显微镜进行活体荧光运动神经元拍摄。
实验结果显示，野生型的斑马鱼中没有特殊的神经损伤，且只注射亚丁基苯酞及Ct MO也未出现明显的神经损伤；但在注射Ataxin-3MO后，会导致斑马鱼的神经信号明显减弱，由此证明Ataxin-3MO具有神经损伤效果且具有专一性。此外，如图4所示，以250毫克/公斤亚丁基苯酞治疗ATXN3MO斑马鱼，具有维持运动神经元数量的效果。其中，图4所示数据为存活数/总只数*100％所得。
[实施例3]小鼠活体内试验
本实验使用MJD84.2基因转殖小鼠(即，经人类84CAG重复ATXN3基因转殖的小鼠，简称SCA3小鼠)进行实验。MJD84.2基因转殖小鼠为研究脊髓性小脑萎缩症的动物模型，这类小鼠会在出生后4周内出现步态异常的情况，之后会开始陆续出现轻度震颤、中度活动能力减退、前/后肢不正常收缩(约24周龄)、及有无力趴地的情况。
(1)MJD84.2基因转殖小鼠的治疗
将二周龄的MJD84.2基因转殖小鼠随机分为5个组别，每组6只，分别以如下列条件进行处理2周：(1)未处理；(2)喂食橄榄油(即，仅喂食佐剂)；(3)喂食亚丁基苯酞100毫克/公斤/每天分两次喂食(bid)；(4)喂食亚丁基苯酞500毫克/公斤/每天分两次喂食(bid)；(5)喂食3-亚丁基-4,5-二氢苯酞100毫克/公斤/每天分两次喂食(bid)；另以野生型小鼠(WT)作为控制组。2周后，开始进行，Local motor及转棒测试。
(2)Local motor测试
进行Local motor测试，以测试小鼠的运动能力。
使10周龄的小鼠于转棒(rotarod)上进行了测试，每3周测试一次。接着，将小鼠放置在一个透明的压克力盒2小时，使它自由移动，利用机器VersaMax420(AccuscanInstrumentsInc，USA)进行1小时的行为测试后，进行数据分析统计。
实验结果如图5A、5B、及5C所示，相较于未处理及经橄榄油喂食组，经亚丁基苯酞或3-亚丁基-4,5-二氢苯酞喂食组的小鼠的总移动距离(图5A)、移动次数(图5B)、及移动时间(图5C)都较长，显示其运动能力较佳。本实验结果显示亚丁基苯酞及3-亚丁基-4,5-二氢苯酞可改善MJD84.2基因转殖小鼠的运动行为。
(3)转棒(rotarod)测试
进行转棒测试，以测试小鼠的平衡能力及抓握能力。测试之前，先使小鼠练习二星期后，再进行第一次行为测试，此实验为利用IITC转棒(IITC Life Science Inc，美国)进行测试。使10周龄的小鼠于转棒(rotarod)上进行了测试，每3周测试一次，条件为在300秒内从4至40转进行线性加速，记录小鼠自转棒掉落(latency to fall)的时间(秒)。每次试验持续最多5分钟，在每次测验之间使小鼠至少休息15分钟，以避免疲劳。转棒试验后，记录小鼠的体重。小鼠去每天进行3次试验，连续四天，以每天平均自转棒掉落下降的时间进行统计分析。
实验结果如图6所示，相较于未处理及经橄榄油喂食组，在经亚丁基苯酞或3-亚丁基-4,5-二氢苯酞喂食的组别中，小鼠的平衡能力及抓握能力较佳，显示亚丁基苯酞及3-亚丁基-4,5-二氢苯酞可改善MJD84.2基因转殖小鼠的运动行为。
[实施例4]组织化学染色试验
将八周龄的MJD84.2基因转殖小鼠(即，具有经修饰的ATXN3gene)随机分为5个组别，每组6只，并以下列条件进行处理：(1)未处理；(2)喂食橄榄油；(3)喂食亚丁基苯酞100毫克/公斤/每天分两次喂食(bid)；(4)喂食亚丁基苯酞500毫克/公斤/每天分两次喂食(bid)；(5)喂食3-亚丁基-4,5-二氢苯酞100毫克/公斤/每天分两次喂食(bid)。之后，分别在第20周及24周时牺牲小鼠并进行小脑切片染色及组织蛋白萃取(参见实施例5)，以3.7％福尔马林隔夜固定小鼠全脑组织后，将样品包埋入石蜡中。使用Quanto套组(Thermo，美国)将样品进行切片(4微米)并安装在显微镜幻灯片上。
图7所示为SCA3小鼠免疫化学组织染色小脑的切片染色结果，其中，未治疗组及经橄榄油喂食组显示明显的浦肯野细胞缺失，但经亚丁基苯酞或3-亚丁基-4,5-二氢苯酞治疗的组别的小鼠，其浦肯野细胞数量显著多于未治疗组别及橄榄油组，此实验结果显示亚丁基苯酞及3-亚丁基-4,5-二氢苯酞治疗可可延缓或避免浦肯野细胞死亡。
[实施例5]西方墨点法
取于实施例4牺牲的SCA3小鼠的全脑组织，进一步分离出小脑组织，并进行蛋白质萃取。将所得纯化蛋白质分别使用抗-泛素(ubiquitin)抗体以及抗-钙结合蛋白(calbindin)抗体进行西方墨点法分析，以测定各组别的SCA3小鼠的小脑组织的泛素及钙结合蛋白的蛋白质含量变化。实验以β-肌动蛋白作为内控制组。
如图8所示，相较于未治疗组及经橄榄油喂食组，经亚丁基苯酞或3-亚丁基-4,5-二氢苯酞治疗的组别的小鼠其钙结合蛋白的蛋白质表现量明显较高。已知钙结合蛋白为浦肯野细胞的标记物(marker)，此实验结果与切片结果皆显示浦肯野细胞的数量增加，证实亚丁基苯酞及3-亚丁基-4,5-二氢苯酞可减缓SCA3疾病进程。
此外，如图9所示，相较于未治疗组及经橄榄油喂食组，经亚丁基苯酞治疗的组别的小鼠其经泛素进行泛素化(ubiquitin ubiquitination)的蛋白质的含量明显较高，显示亚丁基苯酞具有增加泛素进行泛素化的能力，亦即，可增加小脑神经细胞中蛋白质的泛素化作用，故可增加错误蛋白通过蛋白酶体(proteasome)代谢的效率，减缓SCA3的疾病进程。
以上实施例的结果显示，使用本发明所涉特定苯酞化合物可治疗及/或延缓浦肯野细胞退化，故可治疗脊髓性小脑萎缩症、阿兹海默症、帕金森氏症及/或延缓其发病。
上述实施例仅是用以例示说明本发明的原理及功效，而非用于限制本发明。任何熟于此项技艺的人士均可在不违背本发明的技术原理及精神的情况下，对上述实施例进行修改及变化，都应当包含在本发明的保护范围内。
<110> 长弘生物科技股份有限公司
<120> 苯酞化合物的应用
<130> 无
<160> 2
<170> PatentIn version 3.5
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<211> 25
<212> DNA
<213> 人工序列
<220>
<223> ATXN3 MO
<400> 1
tcctcctcgt ccagctgctg tgcta 25
<210> 2
<211> 25
<212> DNA
<213> 人工序列
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<223> 控制组MO
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cctcttacct cagttacaat ttata 25
Claims (7)
1.一种使用一苯酞化合物于制备用于治疗脊髓性小脑萎缩症及／或延缓其发病的药剂的用途，其特征是，该苯酞化合物选自以下群组：亚丁基苯酞、亚丁基苯酞的代谢前驱物、以及前述的任意组合，且该亚丁基苯酞的代谢前驱物是3-亚丁基-4,5-二氢苯酞。
2.根据权利要求1的用途，其特征是，该苯酞化合物为亚丁基苯酞。
3.根据权利要求2的用途，其特征是，该亚丁基苯酞包含90%或更高的Z-亚丁基苯酞。
4.根据权利要求1的用途，其特征是，该苯酞化合物是3-亚丁基-4,5-二氢苯酞。
5.根据权利要求1的用途，其特征是，该药剂更包含橄榄油作为载剂。
6.根据权利要求1至5中任一项的用途，其特征是，该药剂是呈以下剂型：口服、鼻腔给药、静脉注射、皮下或组织间缓释。
7.根据权利要求1至5中任一项的用途，其特征是，该药剂是用于治疗第三型脊髓性小脑萎缩症及／或延缓其发病。
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