CN117018197A - 促进dock11表达的试剂作为治疗神经病理性疼痛药物的应用 - Google Patents
促进dock11表达的试剂作为治疗神经病理性疼痛药物的应用 Download PDFInfo
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- CN117018197A CN117018197A CN202310989899.3A CN202310989899A CN117018197A CN 117018197 A CN117018197 A CN 117018197A CN 202310989899 A CN202310989899 A CN 202310989899A CN 117018197 A CN117018197 A CN 117018197A
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- neuropathic pain
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Abstract
本发明公开了促进DOCK11表达的试剂作为治疗神经病理性疼痛药物的应用。本申请研究发现神经病理性疼痛小鼠存在明显的机械异常性疼痛和热痛觉过敏，而DOCK11的表达与CCI小鼠的机械痛和热痛密切相关。过表达DOCK11载体可以有效促进脊髓中DOCK11的表达，同时明显抑制神经病理性疼痛。本发明的上述研究成果为临床治疗神经病理性疼痛提供了潜在的治疗靶点。
Description
技术领域
本发明属于生物医药领域，涉及促进DOCK11表达的试剂作为治疗神经病理性疼痛药物的应用。
背景技术
神经病理性疼痛(Neupropathic pain，NP)是继发于外周或中枢神经系统损伤后的一种慢性疾病状态，不仅症状严重，而且发病率高，《Lancet Neurology》的数据显示，一般人群的神经病理性疼痛的发病率高达约8.0％，而我国是神经病理性疼痛发病率最高的国家之一，年发病率以8.7％的速率快速增长，远高于全球平均水平。以此数据推算，我国目前神经病理性疼痛患者可达9000万。有理由相信随着人口老龄化、糖尿病发病率逐年增高以及癌症患者生存时间的延长，该发病率会逐年递增。2020年10月，《Lancet》全球疾病负担(GBD)数据显示，神经病理性疼痛一直位于全球疾病负担病因的前列，每年因慢性疼痛消耗的医疗费用达1000亿美元，这还不包括病人因疼痛丧失工作能力而造成的损失。有研究显示：接近半数的神经病理性疼痛患者可伴发抑郁症，严重影响患者的生活质量。神经病理性疼痛目前尚无有效的治疗措施,即使采取循证规范治疗，也只有50％病人能够获得40％的疼痛缓解，且现有药物长期服用都有很大副作用。因此，寻找有效的神经病理性疼痛的救治措施是现代麻醉与疼痛医学面临的棘手难题之一。
发明内容
为了弥补现有技术的不足，本发明的目的在于提供一种治疗神经病理性疼痛的药物组合物及其应用。
为了实现上述目的，本发明采用如下技术方案：
本发明提供了促进DOCK11表达的试剂在制备治疗神经病理性疼痛的药物组合物中的应用。
促进DOCK11表达的试剂是指任何可增加DOCK11蛋白的活性、提高DOCK11基因或蛋白的稳定性、上调DOCK11蛋白的表达、增加DOCK11蛋白有效作用时间、或促进DOCK11基因的转录和翻译的物质，这些物质均可用于本发明，作为对于上调DOCK11有用的物质，从而可用于治疗神经病理性疼痛。例如所述的促进试剂包括核酸促进剂，蛋白促进剂。在一些实施方案中，所述试剂上调DOCK11蛋白的表达，包括但不限于过表达DOCK11的载体、DOCK11蛋白或其活性肽。
进一步，所述促进DOCK11表达的试剂为DOCK11的过表达载体或DOCK11蛋白。
进一步，所述药物组合物还包括药学上可接受的载体。
本发明还提供了一种治疗神经病理性疼痛的药物组合物，所述药物组合物包括有效量的促进DOCK11表达的试剂。
本发明的药物组合物的有效量将根据期望的效果而变化。因此，本领域技术人员可容易地确定待施用的最佳剂量，并且最佳剂量将随所使用的具体药物、给药方式、制剂强度和疾病状况的进展而变化。另外，与接受治疗的具体受治疗者相关的因素，包括受治疗者年龄、体重、饮食和给药时间，将导致需要将剂量调整至适当的治疗水平。
根据具体实施方案，有效量或有效剂量是指足以实现下列效应中的一者、两者、三者、四者、或更多者的治疗量：(i)减少或改善欲被治疗的疾病、障碍、或病症的严重程度或与其相关的症状；(ii)减少所治疗疾病、障碍或病症或与之相关的症状的持续时间；(iii)预防所治疗疾病、障碍或病症或与之相关的症状发展；(iv)引起所治疗疾病、障碍或病症或与之相关的症状消退；(v)防止所治疗疾病、障碍或病症或与之相关的症状发展或发作；(vi)防止所治疗疾病、障碍或病症或与之相关的症状复发；(vii)减少患有所治疗疾病、障碍或病症或与之相关的症状的受试者的住院治疗；(viii)减少患有所治疗疾病、障碍或病症或与之相关的症状的受试者的住院时间；(ix)提高患有所治疗疾病、障碍或病症或与之相关的症状的受试者的存活；(xi)抑制或减少受试者中所治疗疾病、障碍或病症或与之相关的症状；和/或(xii)增强或改善另一种疗法的预防或治疗效果。
进一步，所述促进DOCK11表达的试剂为DOCK11的过表达载体或DOCK11蛋白。
所述药物组合物还包括药学上可接受的载体。
在本发明中，术语“药学上可接受的载体”是指任何赋形剂、稀释剂、填充剂、盐、缓冲剂、稳定剂、增溶剂、油、类脂、含脂质囊泡、微球体、脂质体包囊或本领域公知的用于药物制剂的其他材料。应当理解，载体特征将取决于具体应用的施用途径。如本发明所使用，术语“药学上可接受的载体”是指不干扰根据本发明的药物组合物的效果或根据本发明的药物组合物的生物活性的非毒性材料。用药学上可接受的载体配制药物活性成分是本领域已知的，例如Remington：《药学的科学和实践》(The Science and Practice ofPharmacy)(例如第21版(2005年)，以及任何以后的版本)。药学上可接受的载体的非限制性实例包括：盐(例如酸式盐/阴离子盐、碱盐/阳离子盐)、赋形剂、缓冲剂、稀释剂、增溶剂、张度调节剂、表面活性剂、防腐剂、等渗剂、稳定剂和螯合剂。一种或多种药学上可接受的载体可用于配制本发明的药物组合物。
在本发明的一个实施方案中，药学上可接受的载体包括酸式盐/阴离子盐。酸式盐/阴离子盐的非限制性实例包括但不限于乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、酒石酸氢盐、溴化物、依地酸钙、樟脑磺酸盐、碳酸盐、氯化物、柠檬酸盐、二盐酸盐、依地酸盐、乙二磺酸盐、依托酸盐、乙磺酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、对羟乙酰氨基苯胂酸盐、己基间苯二酚盐、海巴明、氢溴酸盐、盐酸盐、羟萘酸盐、碘化物、羟乙基磺酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、粘液酸盐、萘磺酸盐、硝酸盐、双羟萘酸盐、泛酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、次乙酸盐、琥珀酸盐、硫酸盐、鞣酸盐、酒石酸盐、茶氯酸盐、甲苯磺酸盐和三乙碘化物。
在本发明的一个实施方案中，药学上可接受的载体包括碱盐/阳离子盐。碱盐/阳离子盐的非限制性实例包括但不限于铝、2-氨基-2-羟甲基-丙烷-1,3-二醇(也已知为三(羟甲基)氨基甲烷、氨基丁三醇或“TRIS”)、氨、苄星青霉素、叔丁胺、氯普鲁卡因、胆碱、环己胺、二乙醇胺、乙二胺、锂、L-赖氨酸、镁、葡甲胺、N-甲基-D-葡糖胺、哌啶、钾、普鲁卡因、奎宁、钠、三乙醇胺或锌。
在本发明的一个实施方案中，药学上可接受的载体包括缓冲剂。缓冲剂的非限制性实例包括但不限于精氨酸、天冬氨酸、二羟乙基甘氨酸、柠檬酸盐、磷酸氢二钠、富马酸、甘氨酸、双甘氨肽、组氨酸、赖氨酸、马来酸、苹果酸、乙酸钠、碳酸钠、磷酸二氢钠、磷酸钠、琥珀酸盐、酒石酸、三嗪和三(羟甲基)氨基甲烷以及它们的混合物。
在本发明的一个实施方案中，药学上可接受的载体包括防腐剂。防腐剂的非限制性实例包括但不限于苄索氯铵、苯甲酸、苄醇、溴代硝基丙二醇、4-羟基苯甲酸丁酯、氯丁醇、氯甲酚、氯己啶、氯苯甘油醚、邻甲酚、间甲酚、对甲酚、4-羟基苯甲酸乙酯、咪脲、4-羟基苯甲酸甲酯、苯酚、2-苯氧基乙醇、2-苯基乙醇、4-羟基苯甲酸丙酯、脱氢乙酸钠、硫柳汞以及它们的混合物。
在本发明的一个实施方案中，药学上可接受的载体包括等渗剂。等渗剂的非限制性实例包括但不限于氨基酸(诸如甘氨酸、组氨酸、精氨酸、赖氨酸、异亮氨酸、天冬氨酸、色氨酸和苏氨酸)、糖醇(诸如甘油、1,2-丙二醇、丙二醇)、1,3-丙二醇和1,3-丁二醇)、聚乙二醇(例如，PEG400)以及它们的混合物。等渗剂的另一个实例包括糖。糖的非限制性实例可以是单糖、二糖或多糖，或水溶性葡聚糖，包括例如果糖、葡萄糖、甘露糖、山梨糖、木糖、麦芽糖、乳糖、蔗糖、海藻糖、葡聚糖、支链淀粉、糊精、环糊精、α和β-HPCD、可溶性淀粉、羟乙基淀粉和羧甲基纤维素钠。等渗剂的另一个实例是糖醇，其中术语“糖醇”被定义为具有至少一个-OH基团的C(4-8)烃。糖醇的非限制性实例包括甘露糖醇、山梨醇、肌醇、半乳糖醇、己六醇、木糖醇和阿拉伯糖醇。包含本段中列出的每种等渗剂的药物构成本发明的可供选择的实施方案。
在本发明的一个实施方案中，药学上可接受的载体包括螯合剂。螯合剂的非限制性实例包括但不限于柠檬酸、天冬氨酸、乙二胺四乙酸(EDTA)的盐以及它们的混合物。
在本发明的一个实施方案中，药学上可接受的载体包括稳定剂。稳定剂的非限制性实例包括羧基-/羟基纤维素及其衍生物(诸如HPC、HPC-SL、HPC-L和HPMC)、环糊精、2-甲基硫基乙醇、聚乙二醇(诸如PEG 3350)、聚乙烯醇(PVA)、聚乙烯基吡咯烷酮、盐(诸如氯化钠)、含硫的物质，诸如硫代甘油或巯基乙酸。
在本发明的一个实施方案中，药学上可接受的载体包括一种或多种表面活性剂，优选一种表面活性剂、至少一种表面活性剂或两种不同的表面活性剂。术语“表面活性剂”是指任何由水溶性部分(亲水性)和脂溶性和部分(亲脂性)组成的分子或离子。例如，表面活性剂选自：阴离子表面活性剂、阳离子表面活性剂、非离子表面活性剂和/或两性离子表面活性剂。
在本发明的一个实施方案中，药物为液体制剂。液体制剂的一个优选实例为水性制剂，即包含水的制剂。液体制剂包括但不限于溶液、悬浮液、乳液、微乳液或凝胶。水性制剂通常包含至少50％w/w的水，或至少60％w/w、70％w/w、75％w/w、80％w/w、85％w/w、90％w/w或至少95％w/w的水。
在一个实施方案中，可将药物配制为可注射的，其可例如经由注射装置(例如，注射器或输液泵)注射。注射可例如皮下、肌内、腹膜内或静脉内递送。
在另一个实施方案中，药物为固体制剂，例如冷冻干燥或喷雾干燥的药物，其可按原样使用，或在使用前由医师或患者添加溶剂和/或稀释剂。固体剂型可包括片剂，诸如压片和/或包衣片，以及胶囊剂(例如硬明胶胶囊或软明胶胶囊)。药物组合物也可为例如用于重构的小药囊、糖衣丸、粉末、颗粒剂、锭剂或粉末的形式。
本发明还提供了一种治疗神经病理性疼痛的药盒，所述药盒包括前面所述的药物组合物、任选地容器和说明书。
本发明的药盒包含药物和信息材料的单独容器、分隔件或隔室。例如，药物可以包含在瓶子、小瓶或注射器中，并且信息材料可以与容器结合而被包含。在一些实施方案中，药盒的单独元件包含在一个单一的、未分开的容器中。例如，药物包含在瓶子、小瓶或注射器中(以标签形式附有信息材料)。在一些实施方案中，药盒包括多个(例如，一包)单独的容器，每个容器包含一个或多个单位剂型(例如，本文所述的剂型)的活性物质。
本发明还提供了DOCK11在筛选治疗神经病理性疼痛的候选药物中的应用。
进一步，所述筛选治疗神经病理性疼痛的候选药物的方法如下：用待筛选物质处理表达或含有DOCK11基因或其编码的蛋白的培养体系；和检测所述体系中DOCK11基因或其编码的蛋白的表达或活性；其中，
当所述待筛选物质促进DOCK11基因或其编码的蛋白的表达水平或活性时，该待筛选物质是治疗神经病理性疼痛的候选药物。
本发明还提供了一种筛选治疗神经病理性疼痛的候选药物的方法，所述方法如下：用待筛选物质处理表达或含有DOCK11基因或其编码的蛋白的培养体系；和检测所述体系中DOCK11基因或其编码的蛋白的表达或活性；其中，当所述待筛选物质促进DOCK11基因或其编码的蛋白的表达水平或活性时，该待筛选物质是治疗神经病理性疼痛的候选药物。
本发明还提供了一种筛选治疗神经病理性疼痛的药物的方法，所述方法如下：
1)构建神经病理性疼痛的动物模型；
2)给步骤1)的动物模型施用测试药物；当所述测试药物促进DOCK11基因或其编码的蛋白的表达水平或活性时，该测试药物是治疗神经病理性疼痛的候选药物。
附图说明
图1显示过表达DOCK11对于神经病理性疼痛影响的结果图，其中A：缩足阈值；B：缩足潜伏期；n＝6；*P<0.05，与Sham组相比；#P<0.05，与CCI组相比；two-way ANOVA；
图2显示DOCK11表达结果图，其中A：免疫印迹图；B：柱状统计图；*P<0.05，与Sham组相比；#P<0.05，与CCI组相比。
具体实施方式
下面结合附图和实施例对本发明作进一步详细的说明。以下实施例仅用于说明本发明而不用于限制本发明的范围。根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
实施例1DOCK11表达与神经病理性疼痛的相关性研究
1、实验材料
(1)实验分组：成年雄性C57BL/6J小鼠，6-8周龄，手术时体重20-25克，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＝6)：
①假手术组(Sham组)，仅暴露小鼠右侧坐骨神经而不结扎；
②CCI组(CCI组)，暴露小鼠右侧坐骨神经后用4-0羊肠线松散结扎而无神经收缩现象；
③过表达NC的腺病毒(对照腺病毒)+CCI组(N+CCI组)，在造模之前1月在L4-5背根神经节注射过表达NC的腺病毒1μl(上海吉玛基因公司)；
过表达NC的腺病毒的构建过程：分别从pET101/D-TOPO、pCMV6-LIPG和BioEase载体中扩增His-tag、FLAG-tag和Bio-tag序列，然后克隆到pcDNA3.1中，生成名为BioFLAGHis-pcDNA或HisBioFLAG-pcDNA的空载体，用作NC对照。
④过表达DOCK11的腺病毒+CCI组(D+CCI组)，在造模之前1月在L4-5背根神经节注射过表达腺病毒DOCK11 1μl(上海吉玛基因公司)。
过表达DOCK11的腺病毒构建过程：克隆DOCK11的DNA。分别从pET101/D-TOPO、pCMV6-LIPG和BioEase载体中扩增His-tag、FLAG-tag和Bio-tag序列，然后克隆到pcDNA3.1中，生成名为BioFLAGHis-pcDNA或HisBioFLAG-pcDNA的空载体。通过PCR扩增DOCK11基因的全长或1516至2073个氨基酸序列，并将其克隆到BioFLAGHis-pcDNA载体中，形成DOCK11-BioFLAGHis-pcDNA或DOCK11-DHR2-BioFLAGHis-pcDNA。
表1序列信息
(2)神经病理性疼痛模型制作：小鼠吸入2％七氟醚麻醉，俯卧位固定，从后肢上部切开皮肤，分离肌肉，暴露坐骨神经主干，使用羊肠线环绕坐骨神经，单结固定，环绕的羊肠线能够在坐骨神经主干上滑动为宜。假手术组除未结扎坐骨神经外，其余操作步骤同上。
(3)行为学实验：于造模前24h(0d)、造模后1d、3d、5d、7d、14d时测定热刺激缩足潜伏期(PWL)和机械刺激缩足阈(PWT)，实验室温度18～22℃，安静。采用YLS-6B智能热板仪(淮北正华生物仪器设备有限公司)测定PWL，设定温度52℃，记录从右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30s。将小鼠置于10cm×10cm×20cm的金属笼内，30min后，以BSEVF3 von Frey纤维丝(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3次，间隔5min，取平均值为PWT(g)。
(4)Western blot：于最后1次行为学测定结束后，处死小鼠，取L3 6背根神经节，采用Western Blot法测定蛋白的表达。L3 6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30min，15000rpm，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anti-DOCK11(A301-638A,1:1000，Bethyl)，按照说明书的指南进行实验测定DOCK11表达。
(5)统计学分析：采用SPSS18.0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。
2、实验结果
(1)CCI小鼠具有机械异常性疼痛和热痛觉过敏
与Sham组相比，CCI组小鼠的热刺激缩足潜伏期(PWL)和机械刺激缩足阈(PWT)显著降低，于术后1天出现，并且维持到术后14天。这些结果表明，神经病理性疼痛小鼠具有明显的机械异常性疼痛和热痛觉过敏(P＜0.05，图1A和1B)。
(2)神经病理性疼痛明显抑制了DOCK11的表达
造模成功后14天处死小鼠，取小鼠脊髓L3-L6节段，行Western Blot检测DOCK11的表达水平。WB结果表明，与Sham组小鼠相比，CCI组小鼠DOCK11蛋白表达量有了明显减少(P＜0.05，图2)，这表明DOCK11蛋白表达量的减少可能与神经病理性疼痛的发病有关。
(3)过表达DOCK11可以明显逆转CCI小鼠的机械异常性疼痛和热痛觉过敏
WB检测结果显示，给予DOCK11过表达载体后脊髓DOCK11的表达明显增多(P＜0.05，图2)。在此基础上造模后测行为学发现，过表达DOCK11后CCI小鼠的热刺激缩足潜伏期(PWL)和机械刺激缩足阈(PWT)明显升高(P＜0.05，图1A和1B)，这些表现于术后1天出现，并且可以持续到术后第14天。表明DOCK11具有潜在的神经病理性疼痛治疗作用。
上述实施例的说明只是用于理解本发明的方法及其核心思想。应当指出，对于本领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也将落入本发明权利要求的保护范围内。
Claims (10)
1.促进DOCK11表达的试剂在制备治疗神经病理性疼痛的药物组合物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述促进DOCK11表达的试剂为DOCK11的过表达载体或DOCK11蛋白。
3.根据权利要求1所述的应用，其特征在于，所述药物组合物还包括药学上可接受的载体。
4.一种治疗神经病理性疼痛的药物组合物，其特征在于，所述药物组合物包括有效量的促进DOCK11表达的试剂。
5.根据权利要求4所述的应用，其特征在于，所述促进DOCK11表达的试剂为DOCK11的过表达载体或DOCK11蛋白。
6.一种治疗神经病理性疼痛的药盒，其特征在于，所述药盒包括权利要求3或4所述的药物组合物、任选地容器和说明书。
7.DOCK11在筛选治疗神经病理性疼痛的候选药物中的应用。
8.根据权利要求7所述的应用，其特征在于，所述筛选治疗神经病理性疼痛的候选药物的方法如下：用待筛选物质处理表达或含有DOCK11基因或其编码的蛋白的培养体系；和检测所述体系中DOCK11基因或其编码的蛋白的表达或活性；其中，
当所述待筛选物质促进DOCK11基因或其编码的蛋白的表达水平或活性时，该待筛选物质是治疗神经病理性疼痛的候选药物。
9.一种筛选治疗神经病理性疼痛的候选药物的方法，其特征在于，所述方法如下：用待筛选物质处理表达或含有DOCK11基因或其编码的蛋白的培养体系；和检测所述体系中DOCK11基因或其编码的蛋白的表达或活性；其中，当所述待筛选物质促进DOCK11基因或其编码的蛋白的表达水平或活性时，该待筛选物质是治疗神经病理性疼痛的候选药物。
10.一种筛选治疗神经病理性疼痛的药物的方法，其特征在于，所述方法如下：
1)构建神经病理性疼痛的动物模型；
2)给步骤1)的动物模型施用测试药物；当所述测试药物促进DOCK11基因或其编码的蛋白的表达水平或活性时，该测试药物是治疗神经病理性疼痛的候选药物。
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