CN105636582A - 用非诺贝特及其类似物治疗神经退行性疾病 - Google Patents
用非诺贝特及其类似物治疗神经退行性疾病 Download PDFInfo
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Abstract
本文提供通过施用非诺贝特及其类似物治疗或预防神经退行性疾病的方法。
Description
相关申请的交叉引用
本申请要求于2013年9月18日提交的美国临时申请No.61/879,553的权益，此处以其整体作为参考并入本文。
背景技术
神经退行性疾病可以是偶发的或家族性的，并且随着年龄变老其发生增加。因此，因为随着人口平均寿命的增加，神经退行性疾病的发生增加。预测多达四分之一到美国人在他们的有生之年发展神经退行性病症。然而，一般来说，引起所述病症的潜在机制没有完全理解，极少的有效治疗选择可用于预防或治疗神经退行性疾病。
发明内容
此处提供一种诱导增殖物激活受体γ共激活子-1α(PGC-1α)在神经细胞或神经细胞群体中表达的方法。所述方法包括使所述神经细胞(例如，神经元或神经胶质细胞)或神经细胞群体与有效量的非诺贝特或其类似物接触。所述非诺贝特或其类似物减少一种或多种氧化应激的影响和/或提供一种或多种抗炎作用。此外，所述非诺贝特或其类似物增加磷酸化AMPK的水平，增加了线粒体数目，和/或增加了细胞活力。
此处还提供一种通过对受试对象施用有效量的非诺贝特或其类似物，而治疗或预防受试对象中的神经退行性疾病的方法。可选地，所述方法包括选择患有中枢神经系统神经退行性疾病(例如，具有该疾病的早期)或处于患中枢神经系统神经退行性疾病风险的受试对象。有效量的非诺贝特或其类似物诱导PGC-1α在神经细胞中表达。可选地，所述方法包括确定与对照受试对象相比所述受试对象具有降低水平的PGC-1α的步骤。所述确定步骤可在施用非诺贝特或其类似物之前、之后或既在之前又在之后进行。
还提供一种用于筛选促进神经保护的试剂的方法。所述方法包括使细胞与一种或多种待筛选的试剂接触，并且检测所述细胞中PGC-1α的水平或活性。PGC-1α水平或活性的增加表明所述试剂促进神经保护。
一种或多种本发明的实施方式的细节在附图中展示并在下面进行描述。从说明书和附图出发以及从权利要求出发，其它的特征、目的和优点是显而易见的。
附图说明
图1显示非诺贝特诱导PGC-1α上调并提供神经保护。图1A显示当用非诺贝特处理MN9D细胞4小时，并提取总RNA用于PGC-1α基因表达的结果。在用10或20μΜ的非诺贝特处理MN9D细胞时检测到PGC-1αmRNA表达的显著成倍增加。(*，p<0.05，处理组与未处理的对照相比)。图1B显示通过MitoTracker96孔检验检测到的、线粒体含量在用非诺贝特处理的MN9D细胞中增加。图1C显示用非诺贝特预处理4小时，然后进行12小时6-OHDA应激的MN9D细胞的细胞活力数据。通过MTS检验进行细胞活力的检测。(*p<0.05，**p<0.01，处理组与未处理的对照相比)。
图2显示在BV2细胞中，非诺贝特诱导PGC-1α上调并提供抗炎作用。图2A显示在用非诺贝特预处理4小时，然后再用脂多糖(LPS)进行4小时处理的BV2细胞中的PGC-1α的表达水平。PGC-1α的表达通过RT-PCR检测。(*p<0.05，**p<0.01，LPS+非诺贝特处理与无非诺贝特的LPS处理比较)。图2B显示BV2细胞中IL-Ιβ的表达。(*p<0.05，**p<0.01，LPS+非诺贝特处理与无非诺贝特的LPS处理比较。)
图3显示PGC-1α介导的非诺贝特的抗炎作用。使BV2细胞与20nM靶向PGC-1α的siRNA温育4小时，然后与20μΜ非诺贝特再温育18小时。然后用100ng/mlLPS处理细胞4小时。图3A显示为RT-PCR提取的总RNA以确定PGC-1α的表达水平。图3B类似地显示IL-ΙβmRNA的表达水平。(与对照比较，##p<0.001；与LPS比较，$$p<0.001；与LPS+非诺贝特比较，**p<0.001。Scr,无义对照(scramble)，sol，用于siRNA稀释的RNAiMAX溶液)。
图4显示PPARα对于非诺贝特介导的PGC-1α的上调和抗炎作用是不需要的。将BV2细胞与不同浓度(0.25、0.5、1和2μΜ)的PPARα拮抗剂GW6471温育0.5小时，接下来用20μΜ非诺贝特再温育18小时。然后用100ng/mlLPS处理细胞4小时。图4A显示如从为RT-PCR提取的总RNA检测的PGC-1αmRNA的表达水平。图4B显示IL-ΙβmRNA的表达。(与对照比较，**p<0.01；与LPS比较，##p<0.001)。
图5显示在源自PGC-1α野生型(WT)(PGC-lα+/+)和PGC-1α敲除(PGC-lα+/-)小鼠的原代小胶质细胞中，非诺贝特抑制LPS诱导的炎症。图5A、5B和5C显示源自PGC-1α野生型(WT)(PGC-lα+/+)的原代小胶质细胞用5、10和20μΜ的非诺贝特处理过夜，接下来用LPS处理1小时的基因表达数据。图5D、5E和5F显示源自PGC-1α敲除(PGC-1α+/-)小鼠的原代小胶质细胞用5、10和20μΜ的非诺贝特处理过夜，接下来用LPS处理1小时的基因表达数据。分离总RNA，通过RT-PCR确定IL-Ιβ(图A和D)、TNFα(图B和E)和PGC-lα(图C和F)的基因表达。(***，p<0.01，LPS与DMSO比较；##，p<0.05，###，p<0.01，LPS+非诺贝特与LPS比较，使用ANOVAwithStudent-Newman-Keulsposthoc分析)。
图6显示非诺贝特增强AMP激活的蛋白激酶(AMPK)磷酸化，并且抑制AMPK减弱非诺贝特介导的抗炎作用。图6A显示来自用不同剂量的非诺贝特处理1小时的BV2细胞在Western印迹中的磷酸化的AMPK水平。图6B显示来自用AMPK抑制剂化合物C处理0.5小时，再用非诺贝特处理1小时的BV2细胞培养物的裂解物在Western印迹中的磷酸化的AMPK水平。收集细胞裂解物以用于Western印迹分析。图6C显示用化合物C处理0.5小时，再用非诺贝特处理过夜的BV2细胞的细胞培养物的IL-Ιβ水平。分离总RNA，通过RT-PCR测定IL-Ιβ的基因表达(**，p<0.01，非诺贝特和LPS相比，使用ANOVAwithStudent-Newman-Keulsposthoc分析)。
发明详述
此处提供诱导PGC-1α在神经细胞或神经细胞群体中表达的方法，治疗患有神经退行性疾病或者处于发展神经退行性疾病的风险的受试对象的方法，及筛选神经保护剂的方法。
在本发明之前，通常通过PGC-1α过表达的基因递送上调PGC-1α的活性。然而，腺病毒相关病毒(AAV)介导的PGC-1α的过表达引起多巴胺能标记物的选择性损失及纹状体多巴胺胺含量的减少。重要的是，更高的AAV介导的PGC-1α的表达导致多巴胺能神经元的明显退化。因此，超生理水平的PGC-1α引起有害作用。PGC-1α诱导的药理调节诱导PGC-1α的表达或活性，并可以被更紧密地调节。这种PGC-1α的药理调节可被滴定到适度增加或使病理性失调的PGC-1α正常化。本方法提供通过药理调节PGC-1α的表达而保持生理水平的PGC-1α的活性的方法，由此，通过药物的剂量和治疗而安全控制PGC-1α的水平。
所述诱导PGC-1α在神经细胞或神经细胞群体中表达的方法包括：使所述细胞或所述细胞群体与非诺贝特或其类似物接触。所述接触步骤可以在体内或体外进行。可选地，所述PGC-1α的诱导与过氧化物酶体增殖物激活受体α(PPAR-α)或γ(PPAR-γ)或与两者是均是独立的。
非诺贝特或其类似物可以任意数量的方法施用至神经细胞或神经细胞群体，其包括，例如，离体、体外和体内。体内施用可针对中枢或外周神经系统的神经细胞。因此，如果受试对象具有或有风险发展PGC-1α水平在中枢神经系统中减少，体内接触可以是有用的。体外接触例如在处理用于移植的细胞时可以是需要的。所述神经细胞可以从相同或不同受试对象的神经系统移出，可源自干细胞，或可源自细胞系。所述神经细胞可以源自去分化的非神经细胞，然后引起其分化为神经细胞系。这种细胞可以是诱导的多能干细胞。由于非诺贝特或其类似物穿过血脑屏障，通过对受试对象全身施用非诺贝特或其类似物，中枢神经系统中的神经细胞可以与非诺贝特或其类似物直接接触。但是，非诺贝特或其类似物可以鞘内施用，例如，通过局部注射，通过泵或通过缓慢释植入物。
在此使用的，神经细胞包括神经元(包括多巴胺能神经元)和神经胶质细胞(星形细胞、少突胶质细胞、雪旺细胞和小胶质细胞)。可选地，所述神经细胞或神经细胞群体包括中枢神经系统细胞。
不旨在受理论限制，PGC-1α的诱导与减少的炎症、线粒体生物生成、AMPK磷酸化、增加的细胞活力和降低的氧化应激有关。据认为炎症、线粒体功能障碍和氧化应激增加受试对象发展神经退行性疾病的可能性(例如，通过增加对环境中有毒化合物的易感性)并且会加速所述疾病的进展。因此，所述接触步骤可促进神经细胞在体内或体外的神经保护。
还提供治疗患有神经退行性疾病或者处于发展神经退行性疾病风险的受试对象的方法。此处提供的治疗或预防神经退行性疾病的方法包括对受试对象施用非诺贝特或其类似物。可选地，所述方法包括选择患有中枢神经系统神经退行性疾病或者处于发展中枢神经系统神经退行性疾病风险的受试对象。本发明方法的优点之一在于，所述方法即使在治疗所述疾病早期阶段的患者仍然是有用的。早期阶段可以通过震颤的第一征兆或精细运动技能或肌肉张力的微妙变化被注意到。帕金森氏病的另一个征兆包括，例如，嗅觉障碍、睡眠紊乱、情绪变化、自主神经功能障碍、异常脑成像、血液和CSF标记物，和/或harborPD相关基因突变(即LRR2和SNCA)。处于患神经退行性疾病风险的受试对象包括那些具有家族史、基因突变或标记物或暴露于致病试剂的职业或环境。因此，那些暴露于例如某些有毒化合物或反复震荡的受试对象将处于患神经退行性疾病的风险。
神经退行性疾病一般通过细胞死亡和功能损失的潜伏性发作和进展标记。例如，所述疾病，包括但不限于，帕金森氏病、帕金森叠加综合征、家族性痴呆、阿尔茨海默病、亨廷顿氏病、多发性硬化症、路易体痴呆、轻度认知损伤、皮克氏病、路易体疾病、多系统萎缩症、进行性核上性麻痹(progressivesupranuclearpalsy，PSP)、肌萎缩侧索硬化症和视网膜神经退行性病变。帕金森叠加综合征选自由下述疾病组成的组：多系统萎缩症(multiplesystematrophy，MSA)、进行性核上性麻痹及皮质基底节变性(corticobasaldegeneration，CBD)。
非诺贝特是贝特化合物，先前用于治疗内源性高脂血症、高胆固醇血症和高甘油三酯血症。非诺贝特的制备在美国专利No.4,058,552公开。非诺贝酸是非诺贝特的活性代谢物。非诺贝特不溶于水，这限制了其在胃肠(GI)道的吸收。替代制剂和策略已被使用以解决这一问题。参见美国专利No.4,800,079和No.4,895,726(微粒化的非诺贝特)；美国专利No.6,277,405(微粒化的非诺贝特片剂或以颗粒形式在胶囊内部)；美国专利No.6,074,670(固体状态的微粒化的非诺贝特的即时释放)；美国专利No.5,880,148(非诺贝特和维生素E的组合)；美国专利No.5,827,536(二乙二醇单乙基醚(DGME)作为非诺贝特增溶剂)；以及美国专利No.5,545,628(非诺贝特与一种或多种聚乙二醇化(polyglycolyzed)甘油酯的组合物)，所有这些在此通过参考并入其全部内容。许多其它的衍生物、类似物和制剂对于本领域技术人员是已知的。例如，可以使用如美国专利No.4,058,552描述的p-羰基苯氧基异丁酸的其它酯，在此通过参考并入其全部内容。非诺贝特类似物包括美国专利No.4,800,079中定义的那些。例如，吉非罗齐可用于此处公开的方法中。
可选地，将非诺贝特溶于适合的溶剂或增溶剂中。已知非诺贝特在许多不同的增溶剂是可溶的，包括，例如，阴离子(例如SDS)和非离子(例如TritonX-100)表面活性剂、配位剂(N-甲基吡咯烷酮)。用于口服施用非诺贝特或非诺贝特衍生物的具有改进的生物利用度的液体和半固体制剂在国际专利申请公开No.WO2004002458中描述，在此通过参考并入其全部内容。
以300-400mg/天的速率使用非诺贝特的长期治疗已被使用，但考虑到受试对象的状况或期望的PGC-1α的水平，更高或更低的浓度是必要的。非诺贝特常用的成人剂量为每天3个明胶胶囊，每个胶囊包含100mg非诺贝特。本领域技术人员可以通过选择有效量的非诺贝特或其类似物选择剂量或给药方案。这种有效量包括引起PGC-1α在神经细胞中表达的量，具有抗炎性质的量，减少一种或多种氧化应激作用的量。另外，所述非诺贝特或其类似物的有效量增加磷酸化AMPK的水平、增加线粒体数量，并增加细胞活力。
可选地，每天施用所述非诺贝特或其类似物。
用非诺贝特或其类似物进行治疗的方法可进一步包括对受试对象施用第二治疗剂。所述第二治疗剂，例如，选自由下述物质组成的组：左旋多巴、多巴胺激动剂、抗胆碱能试剂、单胺氧化酶抑制剂、COMT抑制剂、金刚烷胺、卡巴拉汀、NMDA拮抗剂、胆碱酯酶抑制剂、利鲁唑、抗精神病试剂、抗抑郁药和丁苯那嗪。
治疗患有神经退行性疾病或者处于发展神经退行性疾病风险的受试对象的方法可选地还包括，在非诺贝特或其类似物施用之前，施用中和/或施用后任意数量的多种测试。例如，可以对所述受试对象进行测试，以确定与对照水平相比，其是否具有减少的PGC-1α的表达水平或活性。减少水平的PGC-1可以表明应该对客户施用非诺贝特或其类似物，可表明需要增加的剂量或增加的给药频率，或可表明非诺贝特或其类似物不是充分的治疗，应该与非诺贝特或其类似物组合施用另外的试剂或治疗。
可选地，所述方法包括选择患有神经退行性疾病或者处于发展神经退行性疾病风险的受试对象。本领域技术人员知晓如何诊断患有或者处于发展神经退行性疾病风险的受试对象。例如，可以使用一种或多种下述测试：遗传测试(例如，鉴定TDP-43基因中的突变)或家族性的分析(例如，家族史)、中枢神经系统成像(例如，磁共振成像和正电子发射断层成像)、临床或行为学试验(例如，肌无力、震颤、肌紧张、运动技能或记忆力的评估)，或实验室测试。
用于测量PGC-1α的诱导和活性的方法是本领域已知的并且在下面的实施例中提供。例如参见，Ruiz等(2012)Acardiac-specificrobotizedcellularassayidentifiedfamiliesofhumanligandsasinducersofPGC-1αexpressionandmitochondrialbiogenesis.PLoSOne:7:e46753.doi:10.1371/journal.pone.0046753.3。PGC-1α水平可以使用例如针对PGC-1α的抗体或其它检测手段直接评估。PGC-1α活性可以例如通过评估线粒体功能的调节(例如，氧化代谢)进行检测，并可通过检测线粒体基因(例如，LDH-2、ATP5j或类似物)的活性或表达对其进行评估。
全文使用的术语“有效量”，被定义为对于产生期望的生理响应而言必要且充分的任意量。举例而言，全身剂量的非诺贝特或其类似物可以是每日1-1000mg，包括例如，每日300-400mg(例如每天施用1-5剂)。本领域技术人员会基于下述调整下述剂量：抑制剂的具体特点、接收其的受试对象、施用方式、待治疗或预防的疾病的类型和严重性等。此外，治疗的持续时间可以是日、周、月、年或者受试对象的寿命。例如，对患有或者处于发展神经退行性疾病风险的受试对象进行的施用至少为每日(例如，每日一次、两次、三次)持续数周、数月、数年，只要效果是持续的，副作用都是可控的。
施用非诺贝特或其类似物的有效量和时间表可以通过经验确定，进行这样的确定是在本领域的技术人员的经验范围内。施用的剂量范围是大到足以产生期望的效果的剂量，所述效果中疾病或失调的一种或多种症状受影响(例如，减少或延迟)。该剂量也不应过大而导致大量实质性的副作用，例如不希望的交叉反应和细胞死亡等。通常，所述剂量将随神经退行性疾病的类型，受试对象的物种、年龄、体重、总体健康、性别和膳食，施用模式和时间，排泄率，药物组合和具体病症的严重性而变化，所述物质，患者的年龄，体重，总的健康状况而变化，并可由本领域技术人员决定。在任何禁忌的事件中剂量可由个体医生调节。剂量可以变化，并且可以每日一个或多个剂量进行施用。
本发明还提供药物包或试剂盒，其包含包装和/或一个或多个填充有一种或多种药物组合物成分的容器。可选地，所述药物包或试剂盒包括如上所述的第二治疗剂(例如，左旋多巴)。还可以包括所述组合物的使用说明书。
此处提供药物组合物，其包含在药学上可接受的载体中的有效量的非诺贝特或其类似物。术语载体是指下述化合物、组合物、物质或结构，当与化合物或组合物组合时，所述化合物、组合物、物质或结构帮助或促进制备、储存、施用、递送、有效性、选择性，或化合物或组合物的用于其指定用途或目的的任何其它特征。例如，可以选择载体以将活性成分的任何降解降到最低程度，将受试对象中任何不良副作用最小化。此类药学上可接受的载体包括无菌生物相容性药物载体，其包括但不限于，盐水、缓冲盐水、人工脑脊液、右旋糖和水。
根据指定的施用方式，药物组合物可以为固体、半固体或液体剂型的形式，例如，片剂、栓剂、丸剂、胶囊、粉末、液体、气溶胶或悬浮液，优选地，以适合单次施用精确剂量的单位剂型。所述组合物包括与药学上可接受的载体组合的治疗有效量的本文所述的化合物或其衍生物与，此外，可包括其他医学试剂、药学试剂、载体或稀释剂。药学上可接受是指不是生物学上的或其它不期望的材料，其可以伴随选定的化合物对个体施用而不引起不可接受的生物学效应或与所述药物组合物包含的其他成分以有害的方式相互作用。
此处使用的术语载体包括任何赋形剂、稀释剂、填充剂、盐、缓冲液、稳定剂、增溶剂、脂类或用于药物制剂中的本领域公知的其它材料。用于组合物的载体的选择将取决于所述组合物的指定施用途径。药学上可接受的载体和包含所述材料的制剂的制备描述在，例如Remington'sPharmaceuticalSciences,21stEdition,ed.UniversityoftheSciencesinPhiladelphia,Lippincott,Williams&Wilkins,PhiladelphiaPa.,2005。生理学上可接受的载体的例子包括缓冲液，如磷酸盐缓冲液、柠檬酸盐缓冲液及使用其它有机酸的缓冲液；抗氧化剂，包括抗坏血酸；低分子量(少于约10个残基)多肽；蛋白质，例如血清白蛋白、明胶或免疫球蛋白；亲水性聚合物，如聚乙烯吡咯烷酮；氨基酸，如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸；单糖、二糖和包括葡萄糖、甘露糖或糊精的其它碳水化合物；螯合剂，如EDTA；糖醇，如甘露醇或山梨糖醇；成盐反离子(counterion)，如钠；和/或非离子表面活性剂，如(ICI,Inc.；Bridgewater,NewJersey)、聚乙二醇(PEG)和PLURONICSTM(BASF；FlorhamPark,NJ)。
适用于肠胃外注射的含有此处描述的化合物或其或其药学上可接受的盐或前体药物的组合物，可包括生理学上可接受的无菌水性或非水溶液、分散液、悬浮液或乳剂，及重建(reconstitution)为无菌注射溶液或分散剂的无菌粉末。合适的水性和非水载体、稀释剂、溶剂或载剂的例子包括水、醇、多元醇(丙二醇、聚乙二醇和甘油等)、它们的合适混合物、植物油(如橄榄油)及可注射的有机酯，如油酸乙酯。适当的流动性可以通过下述维持：例如通过使用包衣(如卵磷脂)，在分散剂的情况下通过保持必需的颗粒大小和通过使用表面活性剂。
所述组合物也可包含佐剂，例如防腐剂、润湿剂、乳化剂和分散剂。预防微生物作用可通过各种抗细菌剂和抗真菌剂而促进，例如，对羟基苯甲酸酯、氯丁醇、苯酚和山梨酸等。也可以包括等渗剂，例如，糖和氯化钠等。可注射药物形式的延长吸收可通过使用延迟吸收的试剂带来，例如，单硬脂酸铝和明胶。
此处所述的化合物或其药学上可接受的盐或前体药物的用于口服施用的固体剂型，包括胶囊、片剂、丸剂、粉末和颗粒。在此类固体剂型中，此处所述化合物或其衍生物混合至少一种惰性常规赋形剂(或载体)，例如柠檬酸钠或磷酸二钙，或(a)填充剂或膨胀剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸，(b)粘合剂，例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶，(c)保湿剂，例如甘油，(d)崩解剂，例如琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸，某些复合硅酸盐和碳酸钠，(e)溶液缓凝剂，例如石蜡，(f)吸收加速剂，例如季铵类化合物，(g)润湿剂，例如十六烷醇和单硬脂酸甘油酯，(h)吸附剂，例如高岭土和膨润土，及(i)润滑剂，例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠或它们的混合物。在胶囊、片剂和丸剂的情况下，剂型也可以包括缓冲剂。
类似形式的固体组合物也可在软和硬填充的明胶胶囊中用作填充剂，所述胶囊使用如乳糖或奶糖和高分子量的聚乙二醇等赋形剂。
固体剂型如片剂、糖衣丸、胶囊、丸剂和颗粒剂可以用包衣和壳制备，如肠溶包衣和其它本领域已知的。它们可包含遮光剂的试剂，也可以是以延迟的方式在肠道的特定部分释放活性化合物的组合物。使用的包埋组合物的例子可以是聚合物质和蜡。所述活性化合物还可以是微囊形式，如果合适，与一种或多种上述赋形剂。
此处描述的化合物或其药学上可接受的盐或前体药物的用于口服给药的液体剂型，包括乳液、溶液、悬浮液、糖浆和酏剂。除了活性化合物，所述液体剂型可以包含本领域常用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油、芝麻油、甘油、四氢呋喃醇、聚乙二醇，和去水山梨糖醇的脂肪酸酯，或这些物质的混合物，等等。
除了这些惰性稀释剂外，所述组合物可还包括另外的试剂，如润湿剂、乳化剂、助悬剂、甜味剂、调味剂或增香剂。
悬浮剂，除了活性化合物之外，可以包含另外的试剂，例如，乙氧基化异硬脂醇、聚氧乙烯山梨糖醇和去水山梨糖醇酯、微晶纤维素、氢氧化铝氧化物(aluminummetahydroxide)、膨润土、琼脂-琼脂和黄蓍胶，或这些物质的混合物，等等。
用于直肠施用的此处描述的化合物或其药学上可接受的盐或前体药物的的组合物，可选地，为栓剂，其可以通过将所述化合物与适当的无刺激性的赋形剂或载体(如可可脂、聚乙二醇或栓剂用蜡)混合而制备，其在常温下是固体但在体温下是液体，因此，在直肠或阴道腔中融化并释放活性成分。
此处还提供筛选促进神经保护的试剂的方法，所述方法包括使细胞与待筛选的试剂接触并检测细胞中的PGC-1α水平或活性，PGC-1α水平或活性的增加说明所述试剂促进神经保护。可选地，所述细胞是神经元、神经胶质细胞或单核血细胞。
全文使用的对照是指来自缺少神经退行性疾病的受试对象的值或缺少神经退行性疾病的受试对象群体的已知典型对照值示例。在如上所述的一些情况下，对照值可来自神经退行性疾病发病前的或者对其进行治疗开始前的同一受试对象。
在全文中，治疗(treat)、治疗(treating)和治疗(treatment)是指一种用于减少或延迟一种或多种神经退行性疾病的效果或症状的方法。受试对象可以被诊断为患有该疾病。治疗也可以指一种用于减少潜在病变而不仅仅是症状的方法。对所述受试对象施用的效果可以具有，但不限于，减少神经退行性疾病或病症待一种或多种症状，降低神经疾病或损伤的严重性，神经病学疾病或损伤的完全消除，或一种或多种症状发作或恶化的延迟的作用。例如，当与治疗前的受试对象时或与对照受试对象或对照值比较时，如果受试对象中的所述疾病的一种或多种症状具有约10％的减少，所公开的方法被认为是治疗。因此，所述减少可以为约10％、20％、30％、40％、50％、60％、70％、80％、90％、100％，或它们之间任何的减小量。
此处使用的预防(prevent)、预防(preventing)或预防(prevention)是指阻止、延迟、避免、排除、预防、停止或阻碍神经退行性疾病或所述神经退行性疾病的一种或多种症状的发生、发病率、严重性或复发。例如，如果与易患神经退行性疾病的而没有接受非诺贝特或其类似物的受试对象对照相比，在易患神经退行性疾病的受试对象中具有神经退行性疾病或神经退行性疾病的一种或多种症状(震颤、虚弱、记忆丧失、僵硬、痉挛、萎缩)的发生、发病率、严重性或复发的减少或延迟，则所公开的方法被认为是预防。如果与接受治疗前的受试对象进展相比，在易患神经退行性疾病的受试对象接受非诺贝特或其类似物后，具有神经退行性疾病或神经退行性疾病的一种或多种症状的发生、发病率、严重性或复发的减少或延迟，则所公开的方法被认为是预防。因此，神经退行性疾病的发生、发病率、严重性或复发的减少或延迟可以为约10％、20％、30％、40％、50％、60％、70％、80％、90％、100％，或它们之间任何的减小量。
全文使用的受试对象指个体。优选地，所述受试对象是哺乳动物，例如灵长类动物，更优选为，人类。非人类的灵长类也可以作为受试对象。术语受试对象包括驯养动物，例如猫、狗等，家畜(例如，牛、马、猪、绵羊、山羊等)和实验动物(例如，雪貂、灰鼠(chinchilla)、小鼠、兔、大鼠、沙鼠、豚鼠等)。因此，兽医应用和医疗制剂均在此处考虑。
本文公开了可以用于、可以结合使用、可用于制备，或者是所公开的方法和组合物的材料、组合物和组分。这些和其它材料在此处公开，同时可以理解这些材料的组合、子集、相互作用、组等被公开，可能未明确公开的每种不同的个体或集合的组合及所述化合物的排列的具体参考，每一个作为具体设想方法并在此处公开。例如，如果了一种方法被公开、讨论和多个修改，其可以产生包括公开的方法的多个分子，除非特别指出是相对的，所述方法的每种或每个组合物和排列是具体考虑的。同样，所述材料的任何子集或组合物也是具体考虑和公开的。这个概念适用于本发明的所有方面，包括但不限于，本使用公开的组合物的方法的步骤中。因此，如果可以进行多个附加步骤，可以理解，每一个所述附加步骤可以用任何特定的方法步骤或公开方法的方法步骤的组合进行，并且每个这样的组合或组合子集被具体考虑并且应该被考虑公开。
此处所引用的的出版物和引用的材料，以其全部作为参考具体并入本文。进行了多个实施方式的描述。然而，进行多种修改将是可以理解的。因此，其它的实施方式也包含在下面权利要求保护的范围内。
实施例
实施例1
非诺贝特是通过FDA批准用于降低血液胆固醇水平的药物，用作可诱导PGC-1α基因表达的分子。在多巴胺能神经元细胞系的MN9D中，非诺贝特以剂量依赖性方式增加PGC-1α(图1A上左侧)并促进线粒体含量的较小增加(图1B)。另外，非诺贝特强烈保护MN9D细胞免受6-羟基多巴胺(6-hydroxydopamine，6-OHDA)诱导的氧化应激介导的细胞死亡(图1C)。类似地，在小胶质细胞系BV2中，非诺贝特也以剂量依赖性方式诱导PGC-1α的基因表达(图2A)并且显著抑制LPS诱导的IL-Ιβ上调(图2B)。此外，使用siRNA敲弱PGC-1α，非诺贝特在BV2细胞中介导的抗炎作用显示要求PGC-1α，其通过PGC-1α基因表达(图3A)和II-1β基因表达(图3B)的减少显示。PPARα拮抗剂GW6471不能在BV2细胞中抑制非诺贝特介导的PGC-1α上调和抗炎作用(图4)，这表明在BV2细胞中，非诺贝特作用是PPARα非依赖性的。
试剂
非诺贝特购自Sigma(Cat#F6020)。PPARα拮抗剂购自Sigma(Cat#G5045)。IL-Ιβ(Mm00434228-ml)和PGC-1αRT-PCR检验购自LifeTechnologies(Carlsbad，CA)。细胞培养试剂也购自LifeTechnologies。
细胞培养
使用小鼠中脑细胞系MN9D，评估非诺贝特的神经保护作用。MN9D细胞在补充有10％的胎牛血清，3.7g/L碳酸氢钠的达尔伯克改良伊格尔培养基(DMEM)的培养基中，在37℃，5％二氧化碳中培养。BV-2细胞(鼠类小胶质细胞)保持在补充有10％胎牛血清和抗生素(青霉素，100U/mL，链霉素100μg/mL)的DMEM培养基中。为了进行非诺贝特评价研究省略抗生素。
实施例2
非诺贝特穿过血-脑屏障且对受帕金森氏病(PD)影响的中脑多巴胺能神经元发挥神经保护作用。断定非诺贝特介导的PGC-lα上调在干预与PGC-1α缺乏和线粒体功能障碍相关的神经退行性疾病(比如PD)是安全和有效的。
对非诺贝特在介导PGC-1α上调中的神经保护作用在MPTP毒物小鼠PD模型中进行评价。MPTP是广泛用于PD模型的有效的神经毒物。MPTP抑制线粒体复合物I，诱导ROS并引起细胞死亡。主要有三种类型的MPTP中毒方案：急性、亚急性、慢性。有力的证据表明14天慢性MPTP腹膜内输注方案更准确地再现PD早期阶段的病理特征。因此小分子PGC-1α活化剂在慢性MPTP毒物模型中的临床前评价对于开发用于PD中的早期干预的线粒体策略而言是关键的。使用转基因小鼠，所述转基因小鼠是PGC-1α基因的野生型或杂合型(PGC-1α+/-)的，并且还携带转基因，该转基因报告Nrfla,b/Nrf2介导的转录响应(抗氧化剂响应元件驱动的人胎盘碱性磷酸酶的表达；AREhPLAP)(33)。nrfl/Nrf2的转录位于PGC-1α的下游并介导II型抗氧化剂响应。将具有正常PGC-1α的表达的AREhPLAP转基因小鼠(C57BL6背景)，或具有缺陷性PGC-1α表达的唯一化合物转基因小鼠(AREhPLAP::PGC-la+/-；C57BL6背景)用于MPTP毒物模型。通过测量hPLAP，AREhPLAP小鼠允许容易地监控在受影响的脑区中的氧化应激作用。在设置一半的内源性PGC-1α的遗传互补体时，AREhPLAP::PGC-1α+/-小鼠的使用允许研究非诺贝特恢复生理水平的PGC-1α的表达。预防和保护在慢性MPTP中毒PD小鼠模型中评价。为了测试预防性干预，转基因AREhPLAP或AREhPLAP::PGC-1α+/-小鼠(所有都是C57BL/6)接受不同剂量(0、1、10和100mg/kg)的口服非诺贝特或对照灌胃持续28天的治疗。开始非诺贝特治疗后的第10天，所述小鼠腹膜内注射植入14天的渗透微泵(盐溶液对照：n＝16；MPTP，46mg/kg/每日：n＝16)。运动协调性在加速旋转杆跑步机上测试，通过AccuScanDigiscan系统监测小鼠运动以检测MPTP输注开始前的1天前和开始后18天的水平和垂直移动。一天后，处死动物，收获其大脑以用于组织病理学评估。将脑的一个子集(n＝8只/组)固定，并且切片以用于免疫化学分析。为了确定多巴胺(DA)神经元的数目和末梢，对含有SN和STR区的脑切片进行酪氨酸羟化酶(tyrosinehydroxylase，TH)染色，接下来用计算机辅助图象分析系统与体视学软件，立体逻辑计数在SN中待DA神经元并测量在STR中的TH的密度。进行TUNEL染色以确定凋亡的神经元细胞死亡。为表征胶质细胞激活特征，对于SN中小胶质细胞(IbalIHC)和星形胶质细胞(GFAPIHC)使用免疫染色。氧化应激反应通过hPLAPIHC来确定。(II).使脑的其它子集(n＝8/组)进行STR和SN的显微切割，进行DA(和代谢物)含量的生化和神经化学分析(在STR和SN中进行HPLC测定；PGC-1α表达(western印迹)；凋亡蛋白的水平(经切割半胱天冬酶-3、PARP、Bcl-2、Bax的western印迹)；应激响应/存活基因(PKC、LRG-12、gadd45-β、TGF-β、NGF、BDNF、GDNF和VIP)；氧化和抗氧化基因(SOD、Cat、NQO1、GST、Nrf2)；及促炎或抗炎基因(IL-1β、IL-6、TNF-α、NOS-II、COX-2、CCL2、Notchl、CCR2、精氨酸酶、Mmr和IL10)表达(TaqManqRT-PCR阵列；384孔微流体卡)。hPLAP通过western和qRTPCR定量。来自western印迹的免疫反应信号通过凝胶文件成像系统(BioRad)定量。
对于保护干预，使动物接受14天的MPTP输注(盐水溶液对照：n＝16；MPTP，46mg/kg/天：n＝16)，然后开始施用口服药物(0、1、10和100mg/kg)治疗28天。治疗的功能性结果通过比较MPTP注入开始前1天和开始后41天的旋转表现和运动活动评估。一天后处死动物并收获脑用于死后的神经病理学分析，包括PGC-1α、II相脱毒基因、线粒体功能和促/抗炎基因分析、PGC-lα和hPLAP蛋白表达及如上述的SN酪氨酸羟化酶(TH)阳性神经元计数和STRTH密度。
旋转杆表现
运动协调性在加速旋转杆跑步机(ColumbusInstruments,Columbus,OH)上测试。小鼠以5rpm恒定速率测试30秒，然后所述速度将以0.1转/秒加速。自动记录每只小鼠落下杆的时间。
运动活动
小鼠移动通过AccuScanDigiscan系统进行监视(AccuScanInstruments,Inc.,Columbus,OH)以检测水平和垂直移动。由计算机收集的数据包括水平活动的数量、垂直活动的数量和总的运动距离。
免疫组织化学
整个中脑的连续冰冻切片(30μm)从延髓到尾端切片，并用TH、NeuN、GFAP、CD11抗体进行免疫染色，然后用相应的第二抗体和标准ABC程序进行免疫染色。对于无偏(unbiased)细胞计数，具有立体调查操作系统(MicroBrightfieldInc.,WillistonVT)的解剖器技术被用来估计SN中TH阳性神经元的数量。
Taqman微流体qRT-PCR
用RQ1DNase(Promega,Madison,WI)处理RNA以降解任何污染的基因组DNA，然后通过酚：氯仿提取，乙醇/LiCl沉淀。RNA完整性通过使用Bioanalyze技术(LCCC；Georgetown大学医学中心)测定。使用AppliedBiosystemsHigh-CapacitycDNAArchive试剂盒将一微克总RNA在100μl反应体系中逆转录。cDNA的品质通过β-肌动蛋白的PCR进行检查。将来自每个样品的10μl等份cDNA添加到90μlTaqmanUniversalPCRmastermix，并加载到预加载有针对靶基因(PKC、LRG-12、gadd45-P、TGF-β、NGF、BDNF、GDNF和VIP、IL-Ιβ、IL-6、TNF-α、NOS-II、COX-2、CCL2、Notchl、CCR2、精氨酸酶、Mmr、和Hesl)和一个内源性对照(18sRNA)的探针和引物的TaqmanLowDensityArrayMicro-FluidicCard上。实时PCR反应在ABIPrism7900HT序列检测系统(AppliedBiosystems,FosterCity,CA)上运行。结果用相对定量△△CT方法进行分析，将样品相对于处理对照标准化。
生物化学分析
(1)STRDA水平确定通过高效液相色谱法(HPLC)进行测量。(2)使用细胞死亡检测试剂盒进行TUNEL检验。(3)RET和AKT的磷酸化、凋亡蛋白的水平(在SN组织中切割的半胱天冬酶-3(caspase-3)、PARP、Bcl-2和Bax)通过Western印记来测定。(4)BDNF、GDNF和VIP通过ELISA测定。
实施例3
非诺贝特诱导PGC-1α基因在小胶质细胞系BV2中表达并抑制LPS-介导的促炎细胞因子IL-Ιβ以剂量依赖性方式产生。另外，随着对PGC-1α进行siRNA敲弱，在BV2中非诺贝特介导的抗炎作用显示需要PGC1α。考虑到siRNA仅部分敲弱PGC-1α基因表达，使用源自纯合和杂合PGC-1α基因敲除小鼠(PGC-1α-/-和PGC-1α-/+)的原代CNS细胞将提供更明确的证据，证明PGC-1α在介导非诺贝特的作用中是不可缺少的角色。使来自Jackson实验室(B6.129-PpargclatmlBrsp/J)(BarHarbor,ME)的杂合PGC-1α敲除小鼠(PGC-1α-/+)繁殖(PGC-1α-/+xPGC-1α-/+)，且分离和培养来自杂合和野生型新生小鼠的原代小胶质细胞杂合体。所述细胞用不同浓度的非诺贝特处理过夜，接下来用0.1ng/mLLPS温育1小时。分离总RNA且通过RT-PCR确定促炎细胞因子IL-Ιβ和TNFα的基因表达。结果显示，非诺贝特在野生型(PGC-1α+/+)和杂合型(PGC-1α+/-)原代小胶质细胞中发挥类似的抗炎保护作用(图5A、5B、5D、5E)。
试剂
组织培养材料包括培养基、磷酸盐缓冲液盐水(PBS)和胎牛血清(FBS)，购自LifeTechnologies。来自大肠杆菌LPS的脂多糖(LPS)购自Sigma(Cat#L6529)。抗体购自SantaCruzBiotechnology。
细胞培养
新生小鼠(1日龄，PGC-1α+/+或PGC-1α+/-)的大脑皮层剥离脑膜，并在Hepes平衡盐溶液(Hepesbalancedsaltsolution，HBSS；MediatechInc.,Herndon,VA)中剪碎。细胞在含有Earle's盐、L-谷氨酰胺、0.01％丙酮酸盐、0.6％葡萄糖、4％胎牛血清及6％马血清的最小必需培养基(MEM；Invitrogen,Frederick,MD)(完全培养基)中分离，离心，重悬浮，并以每T75培养瓶一个脑的密度在含10ml完全培养基的瓶中铺平板。
培养物在37℃5％CO2下生长。1天后，轻轻拍打瓶以移除细胞碎片，移除培养基并更换为新鲜的完全培养基。使培养物如上生长约12天，此时通过拍打瓶并且收集富含小胶质细胞的培养基而收获小胶质细胞。小胶质细胞通过离心(1000rpm，5min)成球团，将其重悬浮在含0.01％丙酮酸盐、0.6％葡萄糖和5％胎牛血清的MEM中并且计数。
将BV-2细胞(小鼠小胶质细胞)保持在补充有10％胎牛血清和抗菌素(青霉素，100U/mL，链霉素100μg/mL)的达尔伯克改良伊格尔培养基培养基中。对于非诺贝特评价研究省略抗生素。
实施例4
AMPK是一种能量感受器并且可以磷酸化PGC-1α。AMPK磷酸化PGC-1α然后PGC-1α通过正反馈起作用，结合肌细胞增强因子(myocyteenhancerfactor，MEF)结合位点来增加其自身的基因表达是看起来合理的。因此，为确定是否AMPK信号传导参与了在CNS细胞中介导非诺贝特的作用，用不同剂量的非诺贝特处理BV2细胞1小时，然后收集细胞裂解物以用于用Western印迹分析。AMPK磷酸化响应非诺贝特的处理以剂量依赖性方式增加(图2A)。接下来，用AMPK抑制剂化合物C处理BV2细胞0.5小时，然后再用非诺贝特处理另外1小时。观察到化合物C对AMPK磷酸化的浓度依赖性的抑制作用(图2B)。测试在BV2细胞中化合物C对非诺贝特介导的抗炎的抑制作用。将化合物C添加到BV2细胞培养物中0.5小时，接着用非诺贝特处理过夜。化合物C在BV2细胞中以剂量依赖性方式减弱非诺贝特介导的抗炎作用(图2C)。这些数据表明在CNS细胞中介导非诺贝特的作用方面AMPK激活起作用。
已经描述了本发明的多个实施方式。然而，可以理解的是，可以在不脱离本发明的精神和范围内做出多种修改。因此，其它实施方式也在下列权利要求的范围内。
Claims (25)
1.一种诱导PGC-1α在神经细胞中表达的方法，所述方法包括使神经细胞或神经细胞群体与有效量的非诺贝特及其类似物接触。
2.如权利要求1所述的方法，其中所述接触步骤在体内进行。
3.如权利要求1或2所述的方法，其中所述接触步骤在体外进行。
4.如权利要求1-3中任一项所述的方法，其中所述PGC-1α的诱导是PPARα非依赖性的。
5.如权利要求1-4中任一项所述的方法，其中所述神经细胞或神经细胞群体包含一种或多种神经元。
6.如权利要求5所述的方法，其中所述神经元为多巴胺能神经元。
7.如权利要求1-4中任一项所述的方法，其中所述神经细胞或神经细胞群体包含一种或多种神经胶质细胞。
8.如权利要求1-7中任一项所述的方法，其中所述有效量减少一种或多种氧化应激的影响。
9.如权利要求1-7中任一项所述的方法，其中所述有效量增加磷酸化AMPK的水平。
10.如权利要求1-7中任一项所述的方法，其中所述有效量增加线粒体的数量。
11.如权利要求1-7中任一项所述的方法，其中所述有效量增加神经细胞活力。
12.如权利要求1-7中任一项所述的方法，其中所述有效量提供抗炎作用。
13.一种治疗和预防受试对象中的神经退行性疾病的方法，所述方法包括
选择患有神经退行性疾病或处于患神经退行性疾病风险的受试对象；及
对所述受试对象施用有效量的非诺贝特及其类似物。
14.如权利要求133所述的方法，其中所述受试对象具有早期神经退行性疾病。
15.如权利要求133或14所述的方法，其中所述神经退行性疾病由下述疾病组成的组：帕金森氏病、帕金森叠加综合征、家族性痴呆、阿尔茨海默病、亨廷顿氏病、多发性硬化症、路易体痴呆、轻度认知损伤、视网膜神经退行性病变及肌萎缩侧索硬化症。
16.如权利要求155所述的方法，其中所述帕金森叠加综合征选自由下述疾病组成的组：多系统萎缩症(MSA)、进行性核上性麻痹(PSP)及皮质基底节变性(CBD)。
17.如权利要求133-166中任一项所述的方法，其中全身施用所述非诺贝特及其类似物。
18.如权利要求177所述的方法，其中口服施用所述非诺贝特及其类似物。
19.如权利要求143-188中任一项所述的方法，其中有效量的非诺贝特及其类似物诱导PGC-1α在神经细胞中表达。
20.如权利要求143-199中任一项所述的方法，其中每日施用所述非诺贝特及其类似物。
21.如权利要求143-20中任一项所述的方法，所述方法进一步包括对所述受试对象施用第二治疗剂。
22.如权利要求21所述的方法，其中所述第二治疗剂选自由下述物质组成的组：左旋多巴、多巴胺激动剂、抗胆碱能试剂、单胺氧化酶抑制剂、COMT抑制剂、金刚烷胺、卡巴拉汀、NMDA拮抗剂、胆碱酯酶抑制剂、利鲁唑、抗精神病试剂、抗抑郁药和丁苯那嗪。
23.如权利要求13-22中任一项所述的方法，所述方法进一步包括确定与对照受试对象相比，所述受试对象具有减少水平的PGC-1α表达。
24.一种用于筛选促进神经保护的试剂的方法，所述方法包括使细胞与待筛选的试剂接触，并且检测所述细胞中PGC-1α的水平或活性，PGC-1α水平或活性的增加表明所述试剂促进神经保护。
25.如权利要求24所述的方法，其中所述细胞是神经元、神经胶质细胞或单核血细胞。
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