CN113332271A - 盐酸甲氯芬酯在制备预防或治疗帕金森病的药物中的应用 - Google Patents
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Abstract
本发明涉及生物制药领域，尤其涉及一种盐酸甲氯芬酯(meclofenoxate‑hydrochloride，MH)在制备预防或治疗帕金森病的药物中的应用。本发明通过整合多组学数据进行基因共表达网络的探索，应用细胞和动物实验验证，发现盐酸甲氯芬酯可明显预防帕金森病中因线粒体功能下降引起的突触损伤，可有效减低线粒体膜损伤，降低线粒体水肿情况，并有效升高突触特异性蛋白表达，表明其可以预防以神经元突触病变为特征的帕金森病，提升多巴胺的活性，预防帕金森病病变，并改善帕金森病的行为症状。
Description
技术领域
本发明涉及生物制药领域，尤其涉及一种盐酸甲氯芬酯在制备预防或治疗帕金森病的药物中的应用。
背景技术
帕金森氏病(PD)是世界上第二大最常见的神经退行性疾病，是一种以中脑黑质多巴胺神经元变性坏死为特点的中枢神经系统变性疾病。目前，该病无论是药物治疗还是手术治疗都只能改善其症状，不能阻止疾病的发展，更无法治愈。
盐酸甲氯芬酯(MH)是中枢兴奋药，一般应用在脑外伤昏迷、新生儿缺氧和精神错乱的患者。
发明内容
本发明的目的在于克服现有技术的不足，提供一种盐酸甲氯芬酯在制备预防或治疗帕金森病的药物中的应用。
为实现上述目的，本发明采取的技术方案为：提供一种盐酸甲氯芬酯在制备预防和/或治疗帕金森病的药物中的应用。
本发明应用加权基因共表达网络分析和识别与生物相关差异共表达模块的生物信息学方法，借用统计学检验，将277个和帕金森病密切相关的基因匹配到基因网络模块中，得到与帕金森疾病相关的基因共表达模块，并通过关联性图谱数据库和来自于帕金森病人与正常对照组中脑黑质脑区样本间的差异基因表达谱数据，得到可以明显逆转模块中异常表达基因的药物。通过实时定量聚合酶链反应(qt-PCR)实验证实MH逆转异常基因表达的能力。进一步的细胞实验表明，在帕金森病模型原代神经中，MH药物可以增加线粒体膜电位正常的原代神经元的数量，恢复神经元活性。动物实验表明，该药物可改善动物的行为，防止帕金森病的发展，并表明MH具有恢复多巴胺神经元活力的能力。
作为本发明所述的应用的优选实施方式，所述预防和/或治疗帕金森病的药物剂型为胶囊剂、片剂、口服制剂、微囊制剂、注射剂、栓剂、喷雾剂或软膏剂。
作为本发明所述的应用的优选实施方式，所述药物还包括药学上可接受的载体。
本发明还提供一种用于预防和/或治疗帕金森病的药物组合物，所述药物组合物包括盐酸甲氯芬酯和药学上可接受的载体。
作为本发明所述的药物组合物的优选实施方式，所述药物组合物用于皮下注射、静脉注射、肌肉注射或经鼻给药。
本发明还提供所述的药物组合物在制备用于预防和/或治疗帕金森病的药物中的应用。
本发明的有益效果：
本发明发现盐酸甲氯芬酯可明显预防帕金森病中因线粒体功能下降引起的突触损伤，可有效减低线粒体膜损伤，降低线粒体水肿情况，并有效升高突触特异性蛋白表达，表明其可以预防以神经元突触病变为特征的帕金森病，提升多巴胺的活性，预防帕金森病病变，并改善帕金森病的行为症状。基于此，本发明提供一种防治帕金森病的药物组合物，所述药物组合物包括盐酸甲氯芬酯和药学上可接受的载体，该药物生产可靠、质量稳定、疗效确切。
附图说明
图1：给予MH处理每个视野细胞存活数。*：p＜0.05，**：p＜0.01。
图2：给予MH处理对小鼠体重的影响；其中NC：处理前的对照组；ROT：处理前的ROT组；MH：处理前的MH组；NC2：处理后的对照组；ROT2：处理后的ROT组；MH2：处理后的MH组；*：p＜0.05。
图3：给药对小鼠行为学的影响。
具体实施方式
为更清楚地表述本发明的技术方案，下面结合具体实施例进一步说明，但不能用于限制本发明，此仅是本发明的部分实施例。
为了便于公众更好地理解本发明，下面通过药效实验、对比试验等具体实施方式来进一步说明本发明的有益效果。动物实验证明，盐酸甲氯芬酯有效预防帕金森病的行为学改变。细胞实验证明，该药物可减低线粒体膜损伤，降低线粒体水肿情况，并有效升高突触特异性蛋白表达，可以预防以神经元突触病变为特征的帕金森病。
为验证本发明药物在治疗帕金森病的药理作用，为其临床应用提供科学依据，特进行如下药效学实验。本实验采用帕金森病小鼠模型，检测行为学、细胞形态学以及影像学的相关指标。
实施例1细胞原代突触形态测定
购买0天C57乳鼠提取皮层神经元细胞，待神经元细胞长出神经突触后给予MH(1μM)处理2h后加入ROT(400μM)构建PD细胞模型，24h后观察细胞突触形态，应用tubulin对神经突触微管蛋白进行显影，利用Neu N对神经元细胞进行胞体显影，利用BX86观察。
结果如图1所示，MH和NC神经元细胞无明显差异。ROT构建的PD组神经元细胞发生大量细胞死亡，每个视野存活细胞数较NC组少119.33个，p＝0.037。ROT+MH组神经元细胞存活较NC组低，较ROT组高，每个视野存活细胞数较ROT组多40.33，p＝0.028，具有统计学差异。
实施例2动物实验及结果
2.1实验材料及设备
2.1.1实验对象
帕金森(PD)小鼠模型，C57BL/6J小鼠，由北京维通利华实验动物技术有限公司提供(动物许可证号：SCXK(京)2016-0011)。
2.1.2实验条件
清洁级动物房，温度为22-25℃，相对湿度40％～60％，12/12h明暗周期，自由进食饮水。实验过程中对动物的饲养及取材均遵守实验动物管理与保护的有关规定。
2.1.3主要实验仪器设备
Roche Modular-ISE9OO-P800型全自动生化分析仪；电子天平BP12lS型；LDZ5-2台式低速自动平衡离心机；Spectrumlab22PC型分光光度计；日本光电MEK-6318K全自动血球分析仪；Thermo可调式移液器；LEICARM2135切片机；BMJ-Ⅲ型生物组织包埋机；TSJ-Q型全自动封闭式组织脱水机；PHY-Ⅲ型病理组织漂烘仪；OLYMPUS-BX40光学显微镜。
2.1.4受试药品
Rotenone(ROT)，Meclofenoxate-hydrochloride(MH)均购于ApexBioTechnology，USA.
2.2实验方法
2.2.1DP小鼠模型的建立
按照文献方法：Krishna Gokul,Muralidhara.Oral supplements of aqueousextract of tomato seeds alleviate motor abnormality,oxidative impairments andneurotoxicity induced by rotenone in mice:relevance to Parkinson'sdisease.Neurochem Res.2014Jul；39(7):1382-94.doi:10.1007/s11064-014-1323-1.Epub2014May 16.。
2.2.2小鼠分组及给药方法
空白对照组：C57BL/6J小鼠给予10％DMSO处理；
帕金森模型组：C57BL/6J小鼠给予10％DMSO+ROT(1mg/kg)处理；
药物对照组：C57BL/6J小鼠给予10％DMSO+MH(50mg/kg)处理；
实验组：C57BL/6J小鼠给予10％DMSO+ROT(1mg/kg)+MH(50mg/kg)处理。
2.2.3小鼠一般状况
本实验包括4组共48只小鼠雄性8WC57小鼠参与实验。
2.2.4小鼠的体重增量
如图2所示，入选时各组间体重无差异，给予处理后ROT组体重发生下降，p＜0.05，其余各组无明显变化。
2.3小鼠行为学测定
对小鼠进行分组处理后，通过步态实验及糖偏好实验检测小鼠的行为学变化。PD步态实验改变主要表现为步态改变，足迹重复率降低。
结果如图3所示，ROT构建的PD模型出现了行动方向改变和步距差增大的现象，步距差增大12.67mm，p＝0.002，步宽差增大6.35mm，p＝0.001。而给予MH后无明显的行动方向改变、步距差增大和步宽差增大。
糖偏好实验表明ROT诱导的PD小鼠对糖偏好明显减低，给予MH处理之后恢复正常水平。
实施例3统计学分析
使用通过Matlab 2016b(美国马萨诸塞州纳蒂克的MathWorks Inc.)计算的DSC，将所有GTVPET-AS轮廓与GTVPET进行比较。还计算了每个指标的平均值和标准偏差(SD)。使用Kruskal-Wallis检验分析结果。图和文字中的所有值均表示为平均值±平均值的标准误差(SEM)。行为测试中的电机性能以绝对值表示。使用Dunnett和Tukey后测进行比较，通过一种方差分析(ANOVA)分析组之间的差异。p＜0.05被认为具有统计学意义(n＝每次分析中包括的小鼠数量)。使用SPSS 19进行统计分析。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。
Claims (6)
1.盐酸甲氯芬酯在制备预防和/或治疗帕金森病的药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述预防和/或治疗帕金森病的药物剂型为胶囊剂、片剂、口服制剂、微囊制剂、注射剂、栓剂、喷雾剂或软膏剂。
3.根据权利要求1所述的应用，其特征在于，所述药物还包括药学上可接受的载体。
4.一种用于预防和/或治疗帕金森病的药物组合物，其特征在于，所述药物组合物包括盐酸甲氯芬酯和药学上可接受的载体。
5.根据权利要求4所述的药物组合物，其特征在于，所述药物组合物用于皮下注射、静脉注射、肌肉注射或经鼻给药。
6.权利要求4所述的药物组合物在制备用于预防和/或治疗帕金森病的药物中的应用。
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