CN108354941A - 一种天然产物小分子α-熊果苷(Arb)在防治帕金森疾病药物中的应用 - Google Patents
一种天然产物小分子α-熊果苷(Arb)在防治帕金森疾病药物中的应用 Download PDFInfo
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Abstract
本发明提供了一种天然产物小分子α‑熊果苷(Arb)在防治帕金森疾病药物中的应用。本发明研究结果表明该化合物在神经细胞体系中能够降低氧化应激水平，保护神经元细胞。本发明进而通过蛋白检测考察Arb对AMPK及其下游蛋白p62的影响，首次发现Arb通过抑制AMPK激活及p62表达，来保护神经元细胞免于氧化应激的损害，从而发挥防治帕金森疾病的作用。Arb作为来源于天然产物的新型的自噬激活剂，具有良好的市场应用前景。
Description
技术领域
本发明涉及一种天然产物有效成分Arb的药用用途，尤其涉及Arb在防治帕金森疾病中的应用，属于中药领域。
背景技术
帕金森病(PD)是一种多发于中老年人的中枢神经系统退变性疾病。目前PD已经成为导致老年人生活水平下降的主要疾病之一，同时也是社会医疗卫生领域亟需攻克的难题。PD的早期干预和治疗已经成为了社会关注的热点，具有十分重大的现实意义，也符合我国目前人口老龄化日益加剧这一国情。
PD的主要病理特征为中脑黑质致密部的多巴胺(DA)能神经元的进行性丢失,导致纹状体多巴胺(DA)含量的减少,从而造成运动机能障碍。近来研究发现氧化应激在DA神经元死亡中发挥了非常重要的作用。另外自噬作为氧化应激的下游途径在能量代谢平衡中也起着重要作用。其中p-AMPK及p62的上调是导致细胞内氧化应激及自噬受阻的关键因素。因此AMPK及p62可能是治疗PD的新靶标，自噬激活剂将成为治疗PD的候选药物。
基于其复杂的发病机制，目前能够有效治疗帕金森病的方法几乎没有。天然产物因其具有活性好且毒副作用小等特点，正日益成为药物研发的重要研究领域。抗氧化小分子(Arb)，作为一种天然的酪氨酸酶抑制剂，被广泛添加于化妆品中，但至今未有报道将其应用于帕金森病的治疗中。
发明内容
本发明解决的技术问题是：提出一种天然产物有效成分α-熊果苷(Arb)在防治帕金森疾病药物中的应用。
为了解决上述技术问题，本发明提出的技术方案是：通过药物活性筛选，筛选出一种天然产物有效成分Arb(可市购)，可以用来防治帕金森疾病，结构如下所示：
本发明通过细胞活性检测，共聚焦显微成像及蛋白检测考察Arb对神经细胞的保护作用以及其保护作用下的机制。结果发现Arb可以降低神经元细胞内氧化应激(即降低活性氧水平，提高ATP和GSH水平)。共聚焦成像显示Arb能缓解氧化应激导致的线粒体膜电位降低的现象。蛋白检测发现Arb可以抑制p-AMPK及p62的上调，即通过促进自噬途径来发挥保护神经细胞的作用。
本发明的有益效果:Arb对鱼藤酮(Rot)诱导的氧化应激产生的细胞损伤可产生较好的保护作用，降低细胞内活性氧水平，提高ATP及GSH的量。进一步机制研究表明该分子的保护作用是通过促进细胞内自噬途径而产生的。说明该化合物可以作为一种较好的干预PD治疗的潜在药物。
附图说明
图1：XTT法检测Arb对细胞存活力的影响示意图；A.不同浓度Rot在不同时间下对SH-SY5Y细胞毒性；B.不同浓度Arb对细胞的保护作用。
图2：Arb对Rot诱导的SH-SY5Y细胞内活性氧水平ROS的影响；
A.100uM Arb降低细胞内ROS水平；B.荧光强度定量图。
图3：Arb对Rot诱导的SH-SY5Y细胞内线粒体膜电位MMP的影响；A.100uM Arb缓解线粒体MMP降低现象；B.荧光强度定量图。
图4：Arb对Rot诱导的SH-SY5Y细胞内ATP及GSH水平的影响；A.不同浓度Arb对细胞内ATP水平的影响；B.不同浓度Arb对细胞内GSH水平的影响。
图5：Rot诱导SH-SY5Y细胞内AMPK及p62的表达水平情况(浓度及时间曲线图)；A.不同浓度Rot诱导SH-SY5Y细胞内AMPK及p62表达情况；B.灰度分析定量图；C.0.001uM Rot在不同时间下诱导SH-SY5Y细胞内AMPK及p62表达情况；D.灰度分析定量图。
图6：Arb对Rot诱导的SH-SY5Y细胞内AMPK及p62表达情况的影响。A.不同浓度Arb降低p-AMPK和p62过度表达情况；D.灰度分析定量图。
图7：Arb通过促进细胞自噬途径来保护细胞。A.自噬抑制剂(NH4Cl+leupeptin)干扰信号通路实验；B.灰度分析定量图。
图8:Arb保护神经元细胞抵抗氧化应激现象
具体实施方式
实施例1
鱼藤酮刺激细胞建立细胞水平上的PD模型及α-熊果苷活性筛选将SH-SY5Y细胞接种在96孔板，当细胞长到70％左右时，用不同浓度的鱼藤酮(0,0.125,0.25,0.5，1,and 2μM)去处理细胞12h和24h.然后加入XTT，放入37℃培养箱培养2h,酶标仪测定λmax＝450nm处吸光值，然后算出细胞存活率。
确定好PD模型后，用不同浓度α-熊果苷(1,10,100μM)预处理细胞6h,然后再用0.25uM鱼藤酮刺激细胞24h,之后同上加入XTT测定吸光值算出细胞存活率。
实施例2
α-熊果苷通过干扰细胞内与氧化应激相关生物指标(活性氧ROS,线粒体膜电位MMP,ATP,谷胱甘肽GSH)来保护SH-SY5Y细胞
1.ROS水平测定
将SH-SY5Y细胞接在10mm玻底培养皿中，待细胞长到70％左右时，α-熊果苷或鱼藤酮处理细胞.然后用PBS洗细胞三次，换含有10uM DCFH-DA探针的培养基放入培养箱孵育30min,之后用PBS洗细胞三次，共聚焦显微镜下成像。
2.MMP测定
将SH-SY5Y细胞接在6孔板中，细胞长到70％左右时，α-熊果苷或鱼藤酮处理细胞.然后换含有10μM DJ-1探针培养基放入培养箱孵育30min,之后用PBS洗细胞三次，放在多功能酶标仪上成像。
3.ATP水平测定
将SH-SY5Y细胞接在6孔板中，待细胞长到70％左右时，同上处理细胞后，加入裂解液裂解细胞10min,12000g 4℃离心5min后，取上清液，根据商业化ATP试剂盒说明书测定每个样品吸光值，之后算出ATP含量，同时测定每个品蛋白质含量用于校准每个样品ATP含量。
4.GSH含量测定
将SH-SY5Y细胞接在6孔板中，待细胞长到70％左右时，同上处理细胞后，PBS洗细胞三次，10000g 4℃离心收集细胞。将细胞沉淀用5％蛋白去除试剂重悬起来，在液氮以及37℃中反复冻融两次。然后将样品离心，上清液用于GSH及GSSG的测定。GSH总量的测定通过标准曲线所得。然后再在样品中加入GSH去除试剂和GSH补充去除试剂去除掉GSH，同上测GSH总量制得标准曲线得到GSSG含量。最后，样品中GSH量用GSH总量减去GSSG量，再测出样品蛋白量用于校准GSH实际含量。
实施例3蛋白免疫共沉淀筛选信号通路(AMPK及p62表达量)
将细胞接在10cm培养皿中，待细胞长到70％左右时，同上处理细胞后，PBS洗细胞三次，离心收集细胞。然后再加入RIPA裂解液冰上裂解细胞10min,13000g，4℃，离心15min，取上清液用于蛋白含量测定。上清液加入上样缓冲液煮沸10min，以每孔控制40ug蛋白含量上样。经过电泳，转膜，封闭之后，一抗(AMPK,P-AMPK，P62及β-actin)4℃孵育过夜，TBST洗三次,每次10min,然后二抗常温孵育1h,TBST洗三次,每次10min,最后在凝胶化学发光仪上成像，ImageJ软件进行灰度分析。
本发明的不局限于上述实施例所述的具体技术方案，凡采用等同替换形成的技术方案均为本发明要求的保护范围。
Claims (6)
1.一种天然产物小分子α-熊果苷(Arb)在防治帕金森疾病药物中的应用，其结构为：
2.根据权利要求1所述的天然产物小分子α-熊果苷(Arb)在防治帕金森疾病药物中的应用，其特征在于，所述化合物对神经保护的有效剂量为1-100uM。
3.根据权利要求2所述的天然产物小分子α-熊果苷(Arb)在防治帕金森疾病药物中的应用，其特征在于，所述化合物能够降低神经元氧化应激中活性氧水平ROS和提高ATP及GSH水平。
4.根据权利要求3所述的天然产物小分子α-熊果苷(Arb)在防治帕金森疾病药物中的应用，其特征在于，所述化合物能够缓解由于氧化应激导致的线粒体膜电位MMP降低的现象。
5.根据权利要求4所述的天然产物小分子α-熊果苷(Arb)在防治帕金森疾病药物中的应用，其特征在于，能降低p-AMPK及p62的表达。
6.根据权利要求5所述的天然产物小分子α-熊果苷(Arb)在防治帕金森疾病药物中的应用，其特征在于，通过自噬抑制剂干扰实验再次证明该化合物的确通过促进自噬途径来保护神经元细胞的。
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