CN101678080A - 苔藓抑素、苔藓抑素类似物和其它相关物质对缺血/中风引起的记忆缺陷和脑损伤的疗效 - Google Patents
苔藓抑素、苔藓抑素类似物和其它相关物质对缺血/中风引起的记忆缺陷和脑损伤的疗效 Download PDFInfo
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Abstract
本发明提供神经生长因子(NGF)、脑源性神经营养因子(BDNF)或其它神经营养因子的蛋白激酶激活剂或增强剂在治疗中风中的应用。具体说,本发明提供治疗中风的方法,所述方法包括以下步骤:鉴定患有中风的对象,给予所述对象一定量的含有蛋白激酶C(PKC)激活剂或4-甲基邻苯二酚乙酸(MCBA)和药学可接受载体的药物组合物,以治疗中风的至少一种症状。
Description
发明人:M.孙和D.L.阿尔康
本申请要求2007年2月9日提交的美国临时申请序列号60/900,339和2007年5月24日提交的美国临时申请序列号60/924,662的优先权,通过引用将其全文纳入本文。
发明领域
本发明涉及用激活蛋白激酶C(PKC)或增强神经生长因子(NGF)、脑源性神经营养因子(BDNF)或其它营养因子的化合物治疗中风。
发明背景
A.中风
中风也称为脑血管意外(CVA),是脑中某一部分供血中断的急性神经损伤。脑供血可通过数种方式中断,包括阻塞(缺血性、栓塞性或血栓性中风)或血管破裂(出血性中风)。中风包括由于脑灌注紊乱引起的神经元功能的突然丧失。这种灌注紊乱通常发生于动脉,但也可发生于静脉。
脑中灌注紊乱的部分不能再接受足够的氧气。这启动了缺血级联反应,导致脑细胞死亡或严重损伤,破坏局部的脑功能。中风是医学紧急情况,如果得不到及时的诊断和治疗可引起永久性神经损伤甚至死亡。它是美国和欧洲工业化国家的第三大死因和引起成年人残疾的最主要原因。平均来看,每45秒出现一例中风,每3分钟就有一人死于中风。每5例中风引起的死亡中,2例为男性,3例为女性。
尽管在临床前研究中可通过医学紧急处理和多种药物有效阻断脑缺血的病理过程,但目前利用rTPA进行溶栓治疗是治疗缺血性中风的唯一可选方案。设计治疗以实现时间依赖性的早期动脉再通(在时间发生后3小时内有效)。阻止梗塞发展的rTPA和其它可能药物的有效性取决于早期给药,甚至是如果可能在出现缺血事件之前给药。在缺血性中风的治疗中狭窄的治疗时间窗导致只有约5%候选患者接受有效的静脉内溶栓治疗。
缺血性中风中,缺血事件后立即发生显著的脑损伤。脑缺血/中风中“延迟的”脑损伤和细胞死亡是一个已经得到充分确认的现象,预示着治疗机会。局灶性严重中风的梗塞核心中的神经元立即死亡,无法通过药理学介入进行拯救。然而,局灶性缺血性中风中核心周围的脑组织组成的缺血半影区和全脑缺血中的敏感神经元/网络通过降低的血供得以维持。对此半影区脑组织的损伤以“延迟”方式发生,从脑缺血/中风后4-6小时的第二阶段开始,或从脑缺血/中风后数天和数周后的所谓第三阶段开始。例如,约15分钟脑缺血后,2-3天内海马CA1锥体细胞开始降解,在缺血事件发生后一周细胞死亡达到最大程度。全脑缺血和缺血半影区中的敏感神经元结构是“风险”组织。在随后数天或数周通过介入进行救助或进一步损伤决定长期残疾的显著差异。
本发明提供一种新的治疗方案,包括在缺血事件发生后数小时至数天至数周的较宽治疗窗内,向发生脑缺血/中风的对象瞬时、定期或长期给予PKC激活剂、其它化合物和其组合。
B.蛋白激酶C
PKC已被鉴定为非受体丝氨酸-苏氨酸蛋白激酶的最大基因家族之一。自从Nishizuka和同事们在80年代早期发现PKC(Kikkawa等(1982)J.Biol.Chem.257:13341),并将其鉴定为佛波酯的主要受体(Ashendel等(1983)Cancer Res.,43:4333),已发现多种生理信号传导机制与该酶有关。对PKC的强烈兴趣来源于其被钙和二酰甘油(和其佛波酯模拟物)体外激活的独特能力,它是其形成通过生长和分化因子的作用与磷脂转换相关联的效应物。
已证明,PKC的激活能提高学习能力和记忆力。(美国专利申请序列号PCT/US02/13784;PCT/US03/07102;60/287,721;60/362,081;10/172,005;和10/476,459;各自通过引用全文纳入本文)。然而,在本申请之前,PKC介导的学习能力和记忆力提高未被认作治疗中风后记忆力缺陷和脑损伤的机制。另外,不认为本文所述的PKC激活剂,特别是能提高学习能力和记忆力的化合物在脑缺血/中风后具有脑功能恢复活性。
历史上,中风治疗中仅有少数疗法可供选择。例如,目前唯一可用的药物疗法由抗血栓药(溶栓治疗;如静脉内注射组织纤溶酶原激活剂)组成,它必须在缺血事件发生后3小时内给予。虽然在临床试验中检测了许多类型的潜在神经保护剂,但因为尤其是中风后使用时无效或相关毒性,没有一个被批准用于临床。在动物模型中缺血后24小时开始治疗时,已证明本发明所述化合物在人中良好耐受的剂量下(苔藓抑素-1剂量)有效。已发现靶向蛋白激酶C(PKC)的化合物,例如直接PKC激活剂苔藓抑素-1以及激活或固定神经生长因子(NGF)、脑源性神经营养因子(BDNF)或其它营养因子(它们可能是PKC靶点)的增强剂或物质甲基邻苯二酚的衍生物甲基邻苯二酚二乙酸,对大鼠(动物中风模型)中脑缺血诱导的脑损伤和记忆缺陷有治疗价值。本发明将这些物质开发为治疗中风的治疗剂。
发明概述
本发明提供治疗中风的方法,所述方法包括以下步骤:鉴定患有中风的对象,给予所述对象一定量的含有蛋白激酶C(PKC)激活剂或4-甲基邻苯二酚乙酸(MCBA)和药学可接受载体的药物组合物,所述用量能有效治疗中风的至少一种症状。
在一个实施方式中,所述PKC激活剂是FGF-18、大环内酯、苯并内酰胺(benzolactam)、吡咯烷酮或其组合。在优选实施方式中,所述大环内酯是苔藓抑素或夹竹桃抑素(neristatin)。在另一实施方式中,所述夹竹桃抑素是夹竹桃抑素-1。在另一实施方式中,所述苔藓抑素是苔藓抑素-1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18。更优选地,所述苔藓抑素是苔藓抑素-1。
在另一优选实施方式中,药物组合物包含4-甲基邻苯二酚乙酸(MCBA)、甲基邻苯二酚的其它衍生物或脑源性神经营养因子。MCBA和甲基邻苯二酚的其它衍生物能激活或上调神经生长因子(NGF)、脑源性神经营养因子(BDNF)或其它营养因子。NGF能激活、上调或增强PKC的活性,进而上调、激活或增强NGF。
在一个实施方式中,在所述中风发生后1、2、3、4、5、6、7、8、9、10、11、12、13或14天内开始给予本发明药物组合物。在另一实施方式中,在所述中风发生后1-2天、1-3天、1-4天、1-5天或1-7天开始所述给药。在另一实施方式中,在所述中风发生后1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24小时内开始给予本发明药物组合物。在又一实施方式中,在所述中风发生后1-3小时、1-5小时、1-10小时、1-24小时、3-5小时、3-10小时、3-24小时、5-10小时、5-24小时或10-24小时开始给予本发明药物组合物。在另一实施方式中,在所述中风/缺血事件发生后3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24小时开始给予本发明药物组合物。在又一实施方式中,在所述中风/缺血事件发生后1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或21天开始给予本发明药物组合物。
在一个实施方式中,包括给予本发明药物组合物的治疗连续进行约1、2、3、4、5、6、7、8、9、10、11或12周。
附图简述
图1描述训练试验中大鼠的空间水迷宫表现。数据表示为平均值±SEM。Bry,苔藓抑素-1;Isch,脑缺血;MCDA,4-甲基邻苯二酚-二乙酸。
图2描述探测试验中的目标象限比值。Bry,苔藓抑素-1;Isch,缺血;MCDA,4-甲基邻苯二酚-二乙酸。*:p<0.05。NS:p>0.05。
发明详述
定义
本文所用的组合物的″给药″包括任何给药途径,包括口服、皮下、腹膜内和肌内。
本文所用的“有效量”是足以减轻与中风有关的一种或多种症状的用量。
本文所用″蛋白激酶C激活剂″或“PKC激活剂”指通过结合蛋白激酶C提高蛋白激酶C催化的反应速率的物质。
本文所用术语“对象”指哺乳动物。
本文所用术语″药学可接受载体″指可与活性成分混合,混合后可用于将活性成分给予对象的化学组合物。本文所用术语″生理可接受的″酯或盐指,与药物组合物的任何其它其他成分相容、并且对该组合物所给对象无害的活性成分的酯或盐形式。
本文所用″药学可接受载体″也包括但不限于以下一种或多种物质:赋形剂;表面活性剂;分散剂;惰性稀释剂;成粒剂和崩解剂;粘合剂;润滑剂;甜味剂;调味剂;着色剂;防腐剂;生理可降解组合物如明胶;水性运载体和溶剂;油性运载体和溶剂;助悬剂;分散剂或湿润剂;乳化剂,缓和剂;缓冲液;盐;增稠剂;填充剂;乳化剂;抗氧化剂;抗生素;抗真菌剂;稳定剂;和药学上可接受的聚合材料或疏水性材料。本发明药物组合物可包含的其他″额外成分″是本领域已知的,参见例如Genaro编,1985,雷明顿药物科学(Remington′s Pharmaceutical Sciences),宾夕法尼亚州伊斯顿的马克出版公司(Mack Publishing Co.,Easton,Pa.),通过引用纳入本文。
本文所述药物组合物的制剂可通过药理学领域已知或随后开发的任何方法制备。通常,这些制备方法包括将活性成分与载体或一种或多种其他辅助成分混合的步骤,然后,如果必要或需要,使所述产品形成或包装成所需的单剂量单元或多剂量单元。
虽然有关本文所述药物组合物的描述主要涉及在伦理上适合给予人的药物组合物,但本领域技术人员应理解这类组合物通常也适合给予所有种类的动物。改变适合给予人的药物组合物以使该组合物适合给予各种动物的方法是众所周知的,兽医药理学领域的普通技术人员可通过常规实验(如果需要)设计并进行这种改变。给予本发明药物组合物的对象包括但不限于:人和其他灵长动物,以及其他哺乳动物。
尽管新治疗剂的开发和几种动物模型的实用性已有进展,但仍然迫切地需要改进的用于筛选的动物模型。
B.蛋白激酶C(PKC)
PKC基因家族目前由11种基因组成,它们分成以下4个亚组:1)经典PKCα、β1、β2(β1和β2是同一基因的另路剪接形式)和γ,2)新的PKCδ、ε、η和θ,3)非典型PKCζ、λ、η和i和4)PKCμ。PKCμ类似于新的PKC同种型,但不同之处是具有推定的跨膜域(综述见Blohe等(1994)CancerMetast.Rev.13:411;Ilug等(1993)Biochem J.291:329;Kikkawa等(1989)Ann.Rev.Biochem.58:31)。α、β1、β2和γ同种型是Ca2+、磷脂和二酰甘油依赖性的,它们代表PKC的经典同种型,而其他同种型能被磷脂和二酰甘油激活,但不依赖Ca2+。所有同种型均包括5可变区(V1-V5),α、β和γ同种型含有高度保守的四个(C1-C4)结构域。除PKCα、β和γ外,所有同种型均缺少C2结构域,和η同种型还缺少二酰甘油结合的C1中两个富半胱氨酸锌指结构域中的九个。C1结构域也含有所有同种型中高度保守的假底物序列,它通过阻断底物结合位点产生该酶的无活性构象而起到自身调节功能(House等(1987)Science 238,1726)。
由于这些结构特征,认为各种PKC同种型在响应生理刺激的信号传导(Nishizuka(1989)Cancer 10:1892)以及肿瘤转化和分化(Glazer(1994)蛋白激酶C(Protein Kinase C),J.F.Kuo编,牛津大学出版社(Oxford U.Press),第171-198页)中具有高度特化的功能。已知PKC调节剂的讨论参见PCT/US97/08141,美国专利5,652,232;6,080,784;5,891,906;5,962,498;5,955,501;5,891,870和5,962,504(各自通过引用全文纳入本文)。
有越来越多的证据表明,单独的PKC同工酶在提供药理学探索基础的生物过程中起到重要作用。一个是设计PKC的特异性(优选同工酶特异性)激活剂。由于催化域不是主要负责PKC同工酶特异性的结构域,所以这种方法比较复杂。它们可提供规避具有相反生物学作用的其他信号传导通路的影响的方式。或者,通过在迅速激活后诱导PKC下调,PKC激活剂可引起长期拮抗作用。目前,苔藓抑素作为抗癌剂已进入临床试验。已知苔藓抑素能结合PKC的调节结构域,并激活该酶。苔藓抑素是PKC的同工酶选择性激活剂的例子。(参见例如WO 97/43268;通过引用全文纳入本文)。已知PKC调节剂的讨论参见PCT/US97/08141,美国专利5,652,232;6,043,270;6,080,784;5,891,906;5,962,498;5,955,501;5,891,870和5,962,504(各自通过引用全文纳入本文)。
已经鉴定到几种类型的PKC激活剂。然而,佛波酯不适合最终开发成药物,因为它具有促肿瘤活性(Ibarreta等(1999)Neuro Report 10(5和6):1035-40)。特别感兴趣的是用于刺激PKC的大环内酯(即苔藓抑素类型和夹竹桃抑素类型)。苔藓抑素类型的化合物中,已证明苔藓抑素-1能激活PKC,并且不具有促肿瘤活性。作为PKC激活剂的苔藓抑素-1也特别有用,因为苔藓抑素-1的剂量反应曲线具有两相性。此外,苔藓抑素-1能差异调节PKC同工酶,包括PKCα、PKCδ和PKCε。已在动物和人中对苔藓抑素-1进行了毒性和安全性研究,并被积极评价为抗癌剂。苔藓抑素-1在这些研究中的应用确定,在人体内的主要副反应是肌痛。有效剂量的一个例子是每周静脉内注射40μg/m2。
大环内酯,具体是苔藓抑素-1可参见美国专利4,560,774(通过引用全文纳入本文)。大环内酯和其衍生物的描述参见美国专利6,187,568、美国专利6,043,270、美国专利5,393,897、美国专利5,072,004、美国专利5,196,447、美国专利4,833,257和美国专利4,611,066(通过引用全文纳入本文)。上述专利描述了大环内酯的各种化合物和各种应用,包括其作为抗炎剂或抗肿瘤剂的应用。(Szallasi等(1994)Journal of Biological Chemistry 269(3):2118-24;Zhang等(1996)Caner Research 56:802-808;Hennings 等(1987)Carcinogenesis 8(9):1343-1346;Varterasian等(2000)Clinical CancerResearch 6:825-828;Mutter等(2000)Bioorganic & Medicinal Chemistry8:1841-1860)(各自通过引用全文纳入本文)。
本领域普通技术人员也应理解,大环内酯化合物和其衍生物,特别是苔藓抑素类型的化合物可用组合合成技术合成,因此可产生化合物文库,以优化药理参数,包括但不限于该组合物的效能和安全性。此外,可测定这些文库,以确定优先调节α-胰泌素和/或PKC的那些成员。
对天然产物和发酵肉汤进行组合文库高通量筛选能够发现几种新的药物。目前,产生和筛选大量化合物被广泛用作发现先导化合物的主要技术,这肯定是药物发现领域主要的基础性进步。此外,即使在鉴定到“先导”化合物之后,组合技术也能作为优化所需生物学活性的有价值的工具。应理解,主题反应能够产生筛选药物,或其他生物学或医学相关活性或者材料相关品质所需的组合化合物文库。用于本发明目的的组合文库是多种化学相关化合物的混合物,可对其中的所需特性进行筛选;所述文库可以是溶液形式或者共价偶联于固体支持物。在单一反应中制备许多相关化合物大大降低和简化了需要进行的筛选过程的数量。可通过常规方法筛选合适的生物学特性。因此,本发明也提供测定一种或多种本发明化合物结合并有效调节α-胰泌素和/或PKC的能力的方法。
可从本领域获得产生组合文库的各种技术,如下所述,但应理解,本发明不仅限于上述例子和描述。(参见例如,Blondelle等(1995)Trends Anal.Chem.14:83;美国专利5,359,115;5,362,899;U.S.5,288,514;PCT公开WO 94/08051;Chen等(1994)JACCS 16:2661:Kerr等(1993)JACCS I 15:252;PCT公开W092/10092,W093/09668;W091/07087;和W093/20242;各自通过引用纳入本文)。因此,可合成约16至1,000,000或更多多样异构体(diversomer)数量级的各种文库,并筛选特定的活性或特性。
苔藓抑素的类似物通常称为苔藓抑素类似物,它们是适用于本发明方法的一种特定类型的PKC激活剂。下表总结了几种苔藓抑素类似物的结构特征,证明苔藓抑素类似物与PKC的亲和力变化很大(从0.25nM至10μM)。它们在结构上相似。虽然苔藓抑素-1具有两个吡喃环和一个六元环状缩醛,但在大部分苔藓抑素类似物中,苔藓抑素-1的一个吡喃被第二个六元缩醛环取代。与苔藓抑素-1相比,这种改变降低了苔藓抑素类似物在强酸或强碱中的稳定性,但在生理pH下影响很小。与苔藓抑素-1(988)相比,苔藓抑素类似物还具有较低的分子量(约600至755),该特性有利于其通过血脑屏障转运。
名称 | PKC亲和力(nM) | MW | 说明 |
苔藓抑素1类似物1类似物2类似物7a类似物7b类似物7c类似物7d类似物8类似物9 | 1.350.256.50-2973.4100008.310000 | 988737723642711726745754599 | 2吡喃+1环状缩醛+大环1吡喃+2环状缩醛+大环1吡喃+2环状缩醛+大环1吡喃+2环状缩醛+大环1吡喃+2环状缩醛+大环1吡喃+2环状缩醛+大环1吡喃+2环状缩醛+大环,乙酰化2环状缩醛+大环2环状缩醛 |
类似物1(Wender等(2004)Curr Drug Discov Technol.1;Wender等(1998)Proc Natl Acad Sci USA 95:6624;Wender等(2002)Am Chem Soc.124:13648(各自通过引用全文纳入本文))与PKC亲和力最高。这种苔藓抑素类似物的强度是苔藓抑素-1的约100倍。只有类似物1与PKC的亲和力高于苔藓抑素。缺少苔藓抑素-1的A环的类似物2是最简单的类似物,其保留了与PKC的高亲和力。除了活性苔藓抑素类似物以外,26位乙酰化的类似物7d与PKC基本上没有亲和力。
B-环苔藓抑素类似物也适用于本发明方法。这些合成的苔藓抑素类似物的亲和力在低纳摩尔范围(Wender等(2006)Org Lett.5299(通过引用全文纳入本文))。B-环苔藓抑素类似物具有全合成的优点,不需要由天然来源纯化。
第三类合适的苔藓抑素类似物是A-环苔藓抑素类似物。这类苔藓抑素类似物与PKC的亲和力略低于苔藓抑素I(苔藓抑素类似物3、4和5的亲和力分别为6.5、2.3和1.9nM),但分子量较低。
许多二酰甘油(DAG)的衍生物能结合和激活蛋白激酶C(Niedel等(1983)Proc.Natl.Acad.Sci.USA 80:36;Mori等(1982)J.Biochem(Tokyo)91:427;Kaibuchi等(1983)J.Biol.Chem.258:6701)。然而,DAG和DAG衍生物的药用价值有限。二酰甘油对PKC的激活作用是瞬时的,因为它们被二酰甘油激酶和脂酶迅速代谢(Bishop等(1986)J.Biol.Chem.261:6993;Chung等(1993)Am.J.Physiol.265:C927;通过引用将其全文纳入本文)。脂肪酸取代决定激活的强度。具有不饱和脂肪酸的二酰甘油活性最高。立体异构构型也至关重要。具有1,2-sn构型的脂肪酸具有活性,而2,3-sn-二酰甘油和1,3-二酰甘油不结合PKC。顺式-不饱和脂肪酸与二酰甘油有协同作用。在本发明的一个实施方式中,术语“PKC激活剂”明确排除DAG或DAG衍生物,如佛波酯。
类异戊二烯是适用于本发明方法的PKC激活剂。例如,法呢基硫代三唑是以Kd 2.5μM激活PKC的合成类异戊二烯。例如,法呢基硫代三唑的强度与二油酰甘油相等(Gilbert等(1995)Biochemistry 34:3916;通过引用全文纳入本文),但不具有可水解的脂肪酸酯。法呢基硫代三唑和相关化合物是稳定的持续性PKC激活剂。由于其低MW(305.5)和不带电,法呢基硫代三唑易于通过血脑屏障。
辛基吲哚内酰胺V(Octylindolactam V)是与杀鱼菌素有关的非佛波醇蛋白激酶C激活剂。辛基吲哚内酰胺V,特别是(-)-对映异构体的优点包括较高的代谢稳定性、高强度(Fujiki等(1987)Adv.Cancer Res.223;Collins等(1982)Biochem.Biophys.Res.Commun.104:1159;各自通过引用全文纳入本文)(EC50=29nM)和有利于跨血脑屏障转运的低分子量。
格尼迪木灵是瑞香烷型二萜,它在0.1-1nM的浓度下对鼠白血病和实体瘤具有强效抗肿瘤活性。在K562细胞中,浓度约为3nM时它用作PKC激活剂,并通过抑制Cdc25A和随后抑制细胞周期蛋白依赖性激酶2(Cdk2)(5ng/ml时实现100%抑制)而将细胞周期进展调节在G1/S期。格尼迪木灵是类似于苔藓抑素、但分子量略低(MW=774.9)的杂环天然产物。
伊利帕利达(Iripallidal)是由白鸢尾(Iris pallida)分离的双环三萜类化合物。伊利帕利达在NCI 60种细胞系筛选中显示出抗增殖活性,GI50(抑制50%生长所需的浓度)值在微摩尔至纳摩尔范围。它以高亲和力结合PKCα(Ki=75.6nM)。它以RasGRP3-依赖方式诱导ERK1/2磷酸化。M.W.486.7。伊利帕利达的大小大约只有苔藓抑素的一半,且不带电。
巨大戟二萜醇是与佛波醇有关、但毒性小得多的双萜类化合物。它衍生自乳草属植物南欧大戟(Euphorbia peplus)。例如,巨大戟二萜醇3,20-二苯甲酸酯与[3H]佛波醇二丁酸酯竞争结合PKC(结合的Ki=240nM)(Winkler等(1995)J.Org.Chem.60:1381;通过引用纳入本文)。巨大戟二萜醇-3-当归酸酯外用时,对鳞状细胞癌和黑素瘤具有抗肿瘤活性(Ogbourne等(2007)Anticancer Drugs.357;通过引用纳入本文)。
萘磺酰胺,包括N-(正庚基)-5-氯-1-萘磺酰胺(SC-10)和N-(6-苯基己基)-5-氯-1-萘磺酰胺,是另一类型的PKC激活剂的成员。SC-10以钙依赖方式,采用类似于磷脂酰丝氨酸的机制激活PKC(Ito等(1986)Biochemistry25:4179;通过引用纳入本文)。萘磺酰胺通过不同于苔藓抑素的机制起作用,预计它与苔藓抑素有协同作用,或者是另一类型的PKC激活剂的成员。萘磺酰胺的结构类似于钙调蛋白(CaM)拮抗剂W-7,但据报道对CaM激酶没有作用。
亚油酸衍生物DCP-LA(2-[(2-戊基环丙基)甲基]环丙基辛酸)是少数已知的同种型特异性PKC激活剂之一。DCP-LA选择性激活PKCε,在100nM时达到最大作用。(Kanno等(2006)J.Lipid Res.47:1146)。类似于SC-10,DCP-LA与PKC的磷脂酰丝氨酸结合位点,而不是二酰甘油结合位点相互作用。
另一种直接激活PKC的方法是提高内源性激活剂二酰甘油的水平。二酰甘油激酶抑制剂如6-(2-(4-[(4-氟苯基)苯基亚甲基]-1-哌啶基)乙基)-7-甲基-5H-噻唑并[3,2-a]嘧啶-5-酮(R59022)和[3-[2-[4-(双(4-氟苯基)亚甲基]哌啶-1-基)乙基]-2,3-二氢-2-硫代-4(1H)-喹唑酮(R59949)能提高内源性配体二酰甘油的水平,从而激活PKC(Meinhardt等(2002)Anti-Cancer Drugs 13:725)。
各种生长因子,如成纤维细胞生长因子18(FGF-18)和胰岛素生长因子均通过PKC途径起作用。在学习过程中,FGF-18表达上调,胰岛素生长因子受体也与学习有关。这些或其他生长因子激活PKC信号传导途径提供了另一种激活蛋白激酶C的可能方式。
刺激生长因子如NGF和BDNF的合成和/或激活的生长因子激活剂,如4-邻苯二酚衍生物,如4-甲基邻苯二酚乙酸(MCBA)也激活PKC以及负责突触发生和/或神经分枝(neuritic branching)的会聚途径。
可通过各种途径、以各种剂型给予本发明化合物,包括适合口服、直肠、胃肠外(如皮下、肌内和静脉内)、硬膜外、鞘内、关节内、局部和含服给药的途径和剂型。成人的剂量范围取决于多种因素,包括患者的年龄、体重和身体状况以及给药途径。
本文中述及的所有书籍、文章、专利和其他发表物均通过引用全文纳入本文。本文提到的任何化合物均包括外消旋物以及单个对映异构体。
实施例
以下实施例用于进一步说明本发明,但不应理解为以任何方式限制本发明的范围。
实施例1:中风的全脑缺血模型
将大鼠(雄性,维斯达大鼠(Wistar),200-225g)随机分成6组(每组8只),饲养1周后进行实验。瞬时或永久性限制脑血流和氧供导致缺血性中风。用于诱导血管记忆缺陷的全脑缺血模型是合并出现短期全身缺氧的双侧血管闭塞。在麻醉(戊巴比妥,60mg/kg,i.p.)下结扎双侧颈总动脉。术后恢复一周后,使大鼠暴露于缺氧条件14分钟(在玻璃罐中5%氧气条件下)。对照大鼠(假操作和运载体对照)也进行相同的切开术,以分离双侧颈总动脉,并暴露于空气条件14分钟(玻璃罐中)。在手术过程中用热光源将体温保持在37-37.5℃,直到动物完全苏醒。
实施例2:苔藓抑素和MCDA处理
从缺氧处理结束后24小时开始,给予20μg/m2苔藓抑素-1(尾静脉注射,2个剂量/周,共给10个剂量)。在另一组大鼠中,给予1.0mg/kg 4-甲基邻苯二酚-二乙酸(MCDA,可能的NGF和BDNF增强剂)(每天腹膜内给药,同样持续5周)。
最后一次苔藓抑素-1、MCDA或运载体给药后1周,用水迷宫空间学习任务训练大鼠(每天进行2次训练试验,持续4天),然后进行探测试验。在探测试验后进行可见的平台试验。结果见图1。
总之,6组之间存在显著的学习差异(图1;F5,383=27.480,p<0.001;ANOVA)。详细分析揭示,缺血组未学会空间迷宫任务,因为试验中的逃离潜伏期没有显著差异(F7,63=0.102,p>0.05),与对照大鼠(组差异:F1,127=79.751,p<0.001)相比学习能力明显受损,而其他5组大鼠均学会该任务(试验中,用MCDA治疗的缺血大鼠:p<0.05,其他4组:p<0.001)。苔藓抑素-1治疗显著提高其表现(用苔藓抑素-1治疗的缺血组相对于缺血大鼠:F1,127=72.782,p<0.001),提高至与对照大鼠无统计学差异的表现水平(用苔藓抑素-1治疗的缺血组相对于对照大鼠:F1,127=0.001,p>0.05)。MCDA治疗也提高了缺血大鼠的学习能力(NCDA治疗的缺血组相对于缺血大鼠:F1,127=15.584,p<0.001),但在治疗5周后用MCDA治疗的缺血组和对照大鼠之间仍然有显著性差异(用NCDA治疗的缺血组相对于对照大鼠:F1,127=16.618,p<0.001)。对照和仅用苔藓抑素-1之间没有差异(苔藓抑素-1相对于对照:F1,127=0.010,p>0.05),且对照和仅用MCDA之间没有差异(MCDA相对于对照:F1,127=0.272,p>0.05)。
缺血组的大鼠在探测试验中没有表现出目标优选性(F3,31=0.096,p>0.05),而另外5组大鼠在探测试验中均表现出目标象限优选性(所有p<0.005)。用目标象限比值(用探针试验中的目标象限距离除以非目标象限值的平均值;图2)分析数据。各组之间的目标象限比值存在显著性差异(F5,47=5.081,p<0.001)。详细分析揭示出,对照和缺血大鼠之间(F1,15=9.451,p<0.01)、缺血组和用苔藓抑素-1治疗的缺血组之间(F1,15=10.328,p<0.01)以及用MCDA治疗的缺血组和缺血大鼠之间(F1,15=5.623,p<0.05)存在组间差异,但对照和用苔藓抑素-1治疗的缺血大鼠之间(F1,15=0.013,p>0.05)、用MCDA治疗的缺血大鼠和对照之间(F1,15=2.997,p>0.05)、对照和只用苔藓抑素-1治疗的大鼠之间(F1,15=0.064,p>0.05)以及对照和只用MCDA治疗的大鼠之间(F1,15=0.0392,p>0.05)没有差异。在探测试验后测定的可见平台试验证明,组间没有显著差异(F5,47=0.115,p>0.05),这表明大鼠的感觉运动能力方面没有显著的组间差异。
实施例3:苔藓抑素治疗
通过永久闭塞双侧颈总动脉,合并约14分钟的低氧(约5%)处理,在雄性维斯达大鼠(225-250g)中诱导全脑缺血/缺氧。从缺血/缺氧处理结束后约24小时开始,给予15μg/m2苔藓抑素-1(通过尾静脉注射,2个剂量/周,共给10个剂量)。在最后一次给药9天后,进行空间学习(2次试验/天,共4天)和记忆(最后一次试验后24小时进行1分钟探测试验)任务。总之,组间(F3,255=31.856,p<0.001)和组x试验间(F21,255=1.648,p<0.05)存在显著性差异。全脑缺血损伤了空间学习能力(缺血组相对于假操作组:F1,127=79.751,p>0.001)。学习能力受损被苔藓抑素-1治疗恢复(苔藓抑素-1+缺血相对于缺血:F1,127=50.233,p<0.001),而单独的苔藓抑素-1不影响学习能力(苔藓抑素-1相对于假操作组:F1,127=2.258,p>0.05;最后一次给药9天后)。
在记忆保持试验中,接受假操作的大鼠显示出目标象限优选性。但在缺血大鼠中没有观察到这种良好的记忆保持能力,表明其空间记忆受损。缺血后苔藓抑素-1治疗将记忆保持能力有效恢复至假操作大鼠的水平。与假操作对照大鼠相比,单独的苔藓抑素-1对目标象限优选性没有显著影响。各组之间的象限比值(用目标象限游泳距离除以非目标象限的平均游泳距离计算;F3,31=6.181,p<0.005)存在显著性差异。详细分析证明,缺血大鼠和假操作对照大鼠之间(F1,15=9.451,p<0.01),缺血大鼠和用苔藓抑素-1治疗的缺血大鼠之间(F1,15=10.328,p<0.01)存在显著性差异,但用苔藓抑素-1治疗的缺血大鼠和假操作对照之间(F1,15=0.0131,p>0.05)以及假操作对照大鼠和单用苔藓抑素-1治疗的大鼠之间(F1,15=0.161,p>0.05)没有显著性差异。这些结果证明,在缺血事件发生后约7周检测时,脑缺血/缺氧对空间学习能力和记忆力产生损伤。在没有适当介入的时间框中,这种损伤是持续的并且不可恢复,但经过长期苔藓抑素-1治疗可恢复,甚至在缺血事件发生后24小时开始治疗也可恢复,治疗时间窗较宽。
Claims (19)
1.一种治疗中风的方法,所述方法包括以下步骤:鉴定患有缺血病症的对象,给予所述对象一定量的含有蛋白激酶C(PKC)激活剂或4-甲基邻苯二酚乙酸(MCBA)或甲基邻苯二酚的其它衍生物和药学可接受载体的药物组合物,所述用量能有效治疗中风的至少一种症状。
2.如权利要求1所述的方法,其特征在于,所述PKC激活剂是FGF-18、大环内酯、苯并内酰胺、吡咯烷酮或其组合。
3.如权利要求2所述的方法,其特征在于,所述大环内酯是苔藓抑素或夹竹桃抑素。
4.如权利要求3所述的方法,其特征在于,所述苔藓抑素是苔藓抑素-1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18。
5.如权利要求4所述的方法,其特征在于,所述苔藓抑素是苔藓抑素-1。
6.如权利要求3所述的方法,其特征在于,所述夹竹桃抑素是夹竹桃抑素-1。
7.如权利要求1所述的方法,其特征在于,所述药物组合物包含4-甲基邻苯二酚乙酸。
8.如权利要求1所述的方法,其特征在于,所述给药是在所述中风发生后1天内开始的。
9.如权利要求1所述的方法,其特征在于,所述给药是在所述中风发生后2天内开始的。
10.如权利要求1所述的方法,其特征在于,所述给药是在所述中风发生后3天内开始的。
11.如权利要求1所述的方法,其特征在于,所述给药是在所述中风发生后1-2天内开始的。
12.如权利要求1所述的方法,其特征在于,所述给药是在所述中风发生后1-3天内开始的。
13.如权利要求1所述的方法,其特征在于,所述治疗连续进行1周。
14.如权利要求1所述的方法,其特征在于,所述治疗连续进行2周。
15.如权利要求1所述的方法,其特征在于,所述治疗连续进行3周。
16.如权利要求1所述的方法,其特征在于,所述治疗连续进行4周。
17.如权利要求1所述的方法,其特征在于,所述治疗连续进行6周。
18.如权利要求1所述的方法,其特征在于,所述治疗逆转中风引起的脑损伤。
19.如权利要求1所述的方法,其特征在于,所述治疗逆转中风引起的记忆缺陷。
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- 2008-02-11 ES ES08725396.9T patent/ES2528033T3/es active Active
- 2008-02-11 US US12/068,732 patent/US20090036514A1/en not_active Abandoned
- 2008-02-11 JP JP2009549131A patent/JP5872138B2/ja not_active Expired - Fee Related
- 2008-02-11 CN CN200880001730A patent/CN101678080A/zh active Pending
- 2008-02-11 WO PCT/US2008/001756 patent/WO2008100450A2/en active Application Filing
- 2008-02-11 EP EP14000741.0A patent/EP2737904A3/en not_active Withdrawn
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2012
- 2012-07-19 US US13/553,565 patent/US20130165453A1/en not_active Abandoned
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2013
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2015
- 2015-06-16 JP JP2015121328A patent/JP2015227338A/ja active Pending
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JP2010518092A (ja) | 2010-05-27 |
KR20090120480A (ko) | 2009-11-24 |
CA2673573C (en) | 2016-06-21 |
CA2864550A1 (en) | 2008-08-21 |
WO2008100450A4 (en) | 2009-08-06 |
CA3006091A1 (en) | 2008-08-21 |
JP2017095468A (ja) | 2017-06-01 |
US20090036514A1 (en) | 2009-02-05 |
JP2015227338A (ja) | 2015-12-17 |
US20130165453A1 (en) | 2013-06-27 |
KR20140074988A (ko) | 2014-06-18 |
JP2014074037A (ja) | 2014-04-24 |
WO2008100450A2 (en) | 2008-08-21 |
EP2121001A2 (en) | 2009-11-25 |
EP2737904A2 (en) | 2014-06-04 |
JP6017405B2 (ja) | 2016-11-02 |
ES2528033T3 (es) | 2015-02-03 |
CA2673573A1 (en) | 2008-08-21 |
WO2008100450A3 (en) | 2009-05-22 |
EP2737904A3 (en) | 2014-12-17 |
JP2016166207A (ja) | 2016-09-15 |
CA2864550C (en) | 2018-07-10 |
JP5872138B2 (ja) | 2016-03-01 |
EP2121001B1 (en) | 2014-12-17 |
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