CN114788867A - Map2k1作为化疗后神经痛的治疗靶点的应用 - Google Patents
Map2k1作为化疗后神经痛的治疗靶点的应用 Download PDFInfo
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Abstract
本发明公开了Map2k1作为化疗后神经痛的治疗靶点的应用。本发明实验证明，发现Map2k1参与紫杉醇诱导的化疗后疼痛；Map2k1抑制剂可以明显的减轻紫杉醇诱导的机械痛敏和热痛敏；提示Map2k1抑制剂可能是紫杉醇相关化疗痛的一种新型治疗途径。
Description
技术领域
本发明属于生物医药领域，涉及Map2k1作为化疗后神经痛的治疗靶点的应用。
背景技术
近年来，随着我国恶性肿瘤的发病率不断上升，大量癌症患者使用抗肿瘤化疗药物大幅度增加，部分抗肿瘤化疗药物如长春生物碱类、紫杉醇类、铂类等对周围神经产生毒性损伤作用也明显增多，化疗药物的这种效应被称为化疗药物相关性周围神经病变(Chemotherapy-induced peripheral neuropathy，CIPN)，常常导致感觉、运动、自主等一系列神经损伤，表现为肢体疼痛、麻木等感觉异常，尤以神经痛为其最常见症状。这种病变严重影响了癌症患者的生活质量，近年来相关报道越来越多并受到广泛关注。目前，最新循证医学证据表明接触化疗的患者第1个月发生CIPN的患病率68.1％，第3个月的患病率为60.0％和6个月以上的患病率为30.0％，患者因为严重的周围神经病变不能耐受最佳化疗方案被迫改变治疗方案，不仅增加住院时间、医疗费用、占用医疗资源，最关键的是增加了患者的身心创伤，加重了患者的痛苦，严重影响了患者的生活质量。目前，临床无有效的治疗措施，主要是因为其发生机制目前尚不清楚，因此，深入阐明CIPN的发病机制和寻找有效防治策略是当务之急。
发明内容
本发明提供了抑制Map2k1的试剂在制备预防或治疗化疗后疼痛的药物中的应用。
进一步，所述化疗使用的药物是紫杉醇。
进一步，所述化疗后疼痛是化疗后神经痛。
进一步，所述化疗后疼痛是化疗后机械性痛觉过敏、热痛觉过敏。
进一步，抑制Map2k1的试剂包括抑制Map2k1表达的试剂、抑制Map2k1蛋白活性的试剂。
进一步，抑制Map2k1表达的试剂包括抑制Map2k1基因mRNA表达的试剂、抑制Map2k1蛋白表达的试剂。
进一步，抑制Map2k1基因mRNA表达的试剂包括反义核酸、dsRNA、核酶、适体。
进一步，抑制Map2k1蛋白表达的试剂包括与Map2k1蛋白特异性结合的抗体。
进一步，抑制Map2k1蛋白活性的试剂包括Map2k1选择性抑制剂。
进一步，Map2k1选择性抑制剂包括TAK-733。
附图说明
图1显示化疗后神经痛模型构建成功的结果图，其中A：通过缩足频率评估机械性异位痛；B：通过缩足潜伏期评估热痛；n＝10，two-wayANOVA，同一时间点***P<0.001组；
图2显示ELISA检测紫杉醇注射后Map2k1水平变化的结果图；n＝10，two-wayANOVA，同一时间点***P<0.001组；
图3显示Map2k1选择性抑制剂TAK-733联合注射降低紫杉醇诱导的小鼠神经性疼痛的结果图，其中A：缩足频率；B：缩足潜伏期；，n＝10，two-wayANOVA，与DMSO组相比，***P<0.001；与紫杉醇组相比，$$$P<0.001；
图4显示Map2k1抑制剂TAK733对DRG神经炎症影响的结果图，其中A：CXCL1；B：CXCL12；C：IL-1β；D：TNF-α；与DMSO组相比，***P<0.01；***P<0.001；与紫杉醇组相比，$$$P<0.001；n＝10，one-way ANOVA。
具体实施方式
本发明的抑制Pak3的试剂不受限制，只要所述试剂能够抑制Pak3或涉及Pak3的上游或下游途径的物质的表达或活性即可。
本发明的药物中还可以包含传统的药用赋形剂和/或添加剂。合适的药用赋形剂包括稳定化剂、抗氧化剂、浸透压调节剂、缓冲剂、和pH调节剂。合适的添加剂包括：生理学生物相容性的缓冲剂(例如氨基丁三醇盐酸盐)、补加螯合剂(例如DTPA或DTPA-双酰胺等)，或钙螯合剂复合物(例如、钙DTPA、CaNaDTPA-双酰胺)，或者，任选地，补加钙或钠盐(例如氯化钙、抗坏血酸酸钙、葡糖酸钙或乳酸钙)。本发明的药物组合物可以进行包装以便作为液体使用，或者也可以加以冷冻干燥。
对于固体组合物，可以使用常规的无毒固态载体；例如，药物级的甘露醇、乳酸、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、葡萄糖、蔗糖、碳酸镁等。
例如，用于口服施用的固体药物组合物中可以包含上述列举的任意载体和赋形剂，以及10-95％，优选25-75％的本发明的抑制Map2k1的试剂。用于气雾剂(吸入)施用的药物组合物可以包含0.01-20wt％、优选1-10wt％的包被于上述脂质体中的一种或多种本发明的抑制Map2k1的试剂，以及推进剂。还可以根据需要包含载体，例如用于鼻内投递的卵磷脂等。
除上述之外，本申请的药物中还可以包含其它药学活性成分，只要它们不抑制本申请抑制Map2k1的试剂的体内功能。
术语“表达的水平”或“表达水平”一般指生物学样品中生物标志物的量。“表达”一般指信息转化成细胞中存在并运行的结构的过程。因此，如本文中使用的，“表达”可以指转录成多核苷酸，翻译成多肽，或甚至多核苷酸和/或多肽修饰(例如多肽的翻译后修饰)。转录的多核苷酸的，翻译的多肽的，或多核苷酸和/或多肽修饰(例如多肽的翻译后修饰)的片段也应视为表达的，无论它们是源自通过可变剪接生成的转录物或经过降解的转录物，或者是源自多肽的翻译后加工(例如通过蛋白水解)。“表达的基因”包括转录成多核苷酸(如mRNA)，然后翻译成多肽的基因，还有转录成RNA但不翻译成多肽的基因(例如转运和核糖体RNA、miRNA、lncRNA、circRNA)。在本发明的特定的实施方式中，“表达的基因”是指转录成RNA但不翻译成多肽的基因。
“反义核酸”指含有与编码Map2k1的mRNA互补的序列的核酸。反义核酸可以由DNA、RNA或二者组成。反义核酸不需要与靶基因的mRNA 100％互补。反义核酸可含有非互补碱基，只要它能够在严格条件下特异性杂交即可。当将反义核酸引入细胞时，它结合靶多核苷酸并抑制转录、RNA加工、翻译或稳定性。除反义多核苷酸之外，反义核酸还包括多核苷酸模拟物，它含有经过修饰的主链、和3′和5′端部分。这样的反义核酸可以根据HCK序列信息来恰当设计并使用本领域技术人员公知的方法来生成。
“dsRNA”指含有双链RNA结构，通过RNA干扰(RNAi)来抑制基因表达的RNA，包括siRNA(短干扰RNA)和shRNA(短发夹RNA)。dsRNA不需要与靶基因序列具有100％的同源性，只要它可抑制靶基因表达即可。为了稳定化或其它目的，可以将dsRNA的一部分用DNA替代。优选的是，siRNA是21-23个碱基的双链RNA。siRNA可以通过本领域技术人员公知的方法来制备，例如通过化学合成或作为天然存在RNA的类似物。shRNA是具有发夹转角(hairpinturn)结构的短链RNA。shRNA可以通过本领域技术人员公知的方法来制备，例如通过化学合成或通过将编码shRNA的DNA引入细胞并表达DNA。
“核酶”指具有催化活性的RNA，它能够切割、粘贴、插入、和转移RNA。核酶的结构可以包括锤头、发夹等。
“适体”指结合某物质诸如蛋白质的核酸。适体可以是RNA或DNA。核酸的形式可以是双链或单链。适体的长度无限制，只要它能够特异性结合靶分子即可，可以由例如10至200个核苷酸、优选10至100个核苷酸、更优选15至80个核苷酸、进一步更优选15至50个核苷酸组成。适体可以使用本领域技术人员公知的方法来选择。例如，可以采用SELEX(通过指数式富集进行的配体的系统进化)。
现参照下列意在举例说明本发明(而非限定本发明)的实施例来描述本发明。
除非特别指明，否则基本上按照本领域内熟知的以及在各种参考文献中描述的常规方法进行实施例中描述的实验和方法。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。本领域技术人员知晓，实施例以举例方式描述本发明，且不意欲限制本发明所要求保护的范围。本文中提及的全部公开案和其他参考资料以其全文通过引用合并入本文。
实施例TAK-733与紫杉醇诱发的神经痛相关性研究
一、实验步骤
1)实验分组：
雄性C57BL6小鼠50只，1月龄，体重100～120g，购自中国人民解放军军事医学科学院实验动物中心。采用随机数字表法分为4组(n＝10)：
DMSO组(D组)，经腹腔注射与紫杉醇等容量的0.1％DMSO，隔天注射4次；
紫杉醇组(P组)，经腹腔注射紫杉醇1mg/kg/次，隔天注射4次；
紫杉醇+TAK-7331组(PT1组)，每次紫杉醇注射前10min腹腔注射Map2k1选择性抑制剂TAK-7331mg·kg-1(Selleckchem，S2617，美国)，经腹腔注射紫杉醇1mg/kg/次，隔天注射4次；
紫杉醇+TAK-7335组(PT5组)，每次紫杉醇注射前10min腹腔注射Map2k1选择性抑制剂TAK-7335mg·kg-1(Selleckchem，S2617，美国)，经腹腔注射紫杉醇1mg/kg/次，隔天注射4次；
紫杉醇+TAK-73310组(PT10组)，每次紫杉醇注射前10min腹腔注射Map2k1选择性抑制剂TAK-73310mg·kg-1(Selleckchem，S2617，美国)，经腹腔注射紫杉醇1mg/kg/次，隔天注射4次。
2)紫杉醇注射方法：将紫杉醇溶解于40％DMSO中，随后用生理盐水稀释至0.1mg/ml的浓度。每只小鼠接受4次腹腔注射。每隔一天(第1、3、5和7天)注射一次紫杉醇，每次注射1mg/kg，累积剂量为4mg/kg。前期工作表明4mg/kg的剂量既可以产生异常性疼痛，且不会对小鼠整体健康产生不利影响。
3)行为学实验：于输注瑞芬太尼前一天(-1d)为基线值、紫杉醇第一次注射为1d，于-1d，3d，5d，7d，14d，21d时测定热刺激缩足潜伏期(PWL)和机械刺激缩足频率(PWF)，实验室温度18～22℃，安静。采用红外足底测痛仪(IICT Life Science 390)测定PWL，记录从左后足接触热板至出现回缩、踮脚、挣扎、嘶叫、舐足任一反应的时间为PWL，连续测定3次，间隔5min，取平均值作为PWL(sec)。为防止烫伤鼠爪，PWL上限定设置为20s。将大鼠置于20cm×20cm×20cm的金属笼内，30min后，以BSEVF3 von Frey纤维丝0.4g(Harvard Apparatus公司，美国)刺激右后足2、3趾骨间，垂直施加压力，记录出现快速缩足反应、舔舐右足或嘶叫时压力，连续测定10次，间隔1min，取缩足频率为PWF(％)。
4)ELISA：于最后1次行为学测定结束后，处死小鼠，取L4-5背根神经节，采用ELISA法测定Map2k1、CXCL1、CXCL12、IL-1β和TNF-α蛋白的表达。背根神经节组织加入预冷的组织蛋白裂解液，研磨成组织匀浆。将匀浆液4℃离心5min，12000rpm，离心半径10cm，上清液即为脊髓组织总蛋白。用膜蛋白提取试剂盒(Thermo公司，美国)，按照说明书进行具体操作提取膜蛋白。使用Mouse MAP2K1(Custom ELISA)ELISA Kit-LS-F16002(LSBio，LS-F16002，美国)，TNF-αMouse ELISA Kit(Invitrogen，BMS607-3,美国)，IL-1beta Mouse UncoatedELISA Kit(Invitrogen，88-7013-88,美国)，Mouse CXCL12/SDF-1DuoSet ELISA(R&DSystem，DY460,美国)，KC/CXCL1 Mouse ELISA Kit(Invitrogen，EMCXCL1，美国)，按照说明书的指南进行实验测定小鼠Map2k1、CXCL1、CXCL12、IL-1β和TNF-α蛋白的表达。
5)统计学分析：采用SPSS 18.0统计学软件进行分析，正态分布的计量资料以均数±标准差(±s)表示，随机区组设计的计量资料比较采用单因素方差分析，重复测量设计的计量资料比较采用重复测量设计的方差分析，P<0.05为差异具有统计学意义。
二、实验结果
(1)紫杉醇输注导致了机械痛和热痛阈值降低
与DMSO组输注相比，紫杉醇组以4mg/kg的总剂量输注后，可导致缩足频率(PWF)和缩足潜伏期(PWL)从第3天到21天显著降低(所有P<0.001，见图1A和图1B)。这些结果表明，以紫杉醇4mg/kg可导致大鼠的外周触压刺激和热刺激的痛觉敏感性增加，且持续存在至少3周以上，提示紫杉醇相关化疗后神经痛模型的成功以及属于慢性神经病理性疼痛。
(2)紫杉醇输注升高背根神经节中Map2k1的表达
紫杉醇输注后背根神经节中与疼痛相关的蛋白质变化对化疗后神经痛的发展至关重要。在开始紫杉醇输注后的-1d，3，5，7，14，21天，在不同时点处死小鼠取L3-5背根神经节，在ELISA结果中发现Map2k1蛋白表达明显升高(P<0.001，图2)。以上结果表明，紫杉醇输注后的痛觉阈值减低与背根神经节中Map2k1表达的增加有关。
(3)Map2k1选择性抑制剂TAK-733输注可降低紫杉醇输注后引起的化疗后相关神经痛
DMSO组中的小鼠在每个时间点均未显示机械性疼痛或热痛阈值变化(P>0.05，图3A和3B)。Von Frey测试表明，与DMSO组中的小鼠相比，紫杉醇注射可以导致PWF快速下降(<3d)和连续下降(>3周)(P<0.001，图3A)，表明持久的机械性异常性疼痛。此外，热痛行为测试表明，紫杉醇注射组在手术后至少3d也导致PWL降低(P<0.001，图3B)，表明瑞芬太尼输注可引起化疗后的热痛觉阈值降低。有趣的是，我们观察到腹腔注射紫杉醇1mg/kg后即刻经腹腔注射TAK-733(分为三个浓度1mg·kg-1，5mg·kg-1，10mg·kg-1)，紫杉醇引起的机械和热痛阈值降低在TAK-7335mg·kg-1，10mg·kg-1明显减少，表现为PWF和PWL的恢复(P<0.001，图3A和3B)，但TAK-7331mg·kg-1无此作用，提示TAK-733治疗紫杉醇引起的大鼠痛觉阈值降低的最低有效剂量接近5mg·kg-1·h-1，而TAK-733具有明显的减低紫杉醇输注3天-21天后出现的机械痛和热痛增加，持续超过3周。
(4)TAK-733可能通过降低CXCL1、CXCL12、IL-1β和TNF-α表达从而减轻紫杉醇引起的神经炎症
我们前期的研究发现神经病理性诱导的痛觉过敏不仅表现出行为学实验中降低的疼痛阈值，而且还影响介导背根神经节中的炎症相关因子的表达，例如紫杉醇输注之后会显著增加CXCL1、CXCL12、IL-1β和TNF-α的表达水平。而TAK-733的输注明显降低了CXCL1、CXCL12、IL-1β和TNF-α的表达水平(图4A-D)。提示紫杉醇相关的背根神经节的紫杉醇相关炎症可疑通过Map2k1活性降低得到缓解，这可能是Map2k1参与紫杉醇化疗痛的镇痛机制。
总之，我们的发现表明，发现Map2k1参与紫杉醇诱导的化疗后疼痛；Map2k1抑制剂可以明显的减轻紫杉醇诱导的机械痛敏和热痛敏；提示Map2k1抑制剂可能是紫杉醇相关化疗痛的一种新型治疗途径。
尽管本发明的具体实施方式已经得到详细的描述，但本领域技术人员将理解：根据已经公布的所有教导，可以对细节进行各种修改和变动，并且这些改变均在本发明的保护范围之内。本发明的全部分为由所附权利要求及其任何等同物给出。
Claims (10)
1.抑制Map2k1的试剂在制备预防或治疗化疗后疼痛的药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述化疗使用的药物是紫杉醇。
3.根据权利要求1所述的应用，其特征在于，所述化疗后疼痛是化疗后神经痛。
4.根据权利要求3所述的应用，其特征在于，所述化疗后疼痛是化疗后机械性痛觉过敏、热痛觉过敏。
5.根据权利要求1所述的应用，其特征在于，抑制Map2k1的试剂包括抑制Map2k1表达的试剂、抑制Map2k1蛋白活性的试剂。
6.根据权利要求5所述的应用，其特征在于，抑制Map2k1表达的试剂包括抑制Map2k1基因mRNA表达的试剂、抑制Map2k1蛋白表达的试剂。
7.根据权利要求6所述的应用，其特征在于，抑制Map2k1基因mRNA表达的试剂包括与mRNA结合的核酸。
8.根据权利要求6所述的应用，其特征在于，抑制Map2k1蛋白表达的试剂包括与Map2k1蛋白特异性结合的抗体。
9.根据权利要求5所述的应用，其特征在于，抑制Map2k1蛋白活性的试剂包括Map2k1选择性抑制剂。
10.根据权利要求7所述的应用，其特征在于，Map2k1选择性抑制剂包括TAK-733。
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