CN113980068B - 一种老鹳草素及其在制备防治脑缺血再灌注损伤药物中的应用 - Google Patents
一种老鹳草素及其在制备防治脑缺血再灌注损伤药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种老鹳草素及其在制备防治脑缺血再灌注损伤药物中的应用。老鹳草素具有抗神经功能损伤作用，可抗氧化损伤、降低脑组织、血清及PC12细胞株培养液上清中MDA、LDH、NO、nNOS水平，升高SOD活性，从而达到防治脑缺血再灌注损伤的效果，可以用于制备治疗或/和预防脑缺血再灌注损伤的药物，较于目前临床上常用的同类药物和治疗手段，老鹳草素来源广泛、价格低廉、疗效显著，为脑缺血再灌注损伤的防治提供了新途径。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种老鹳草素及其在制备防治脑缺血再灌注损伤药物中的应用。
背景技术
缺血性脑卒中，又称脑梗死，是世界范围内高发病率和高死亡率的主要原因之一。每年有近620万人死于中风，据估计，中风的终生风险为8％至10％，缺血性中风占所有中风的85％。脑缺血再灌注损伤(cerebral ischemia reperfusion injury,CIRI)是缺血性脑卒中的重要病理生理过程，涉及兴奋性毒性、氧化应激、炎症反应和细胞凋亡等多个环节。
脑缺血再灌注损伤发生时产生大量氧自由基，脑组织内超氧化物歧化酶(superoxide dismutase,SOD)活性下调，乳酸脱氢酶(lactate dehydrogenase,LDH)、丙二醛(malondialdehyde,MDA)含量增加，导致脂质过氧化，进一步破坏神经细胞功能，引起脑损伤。此时，神经元型一氧化氮合酶(neuronal nitric oxide synthase，nNOS)大量增加，催化一氧化氮(nitric oxide,NO)合成，加剧神经元损伤，降低nNOS的表达，可保护神经元。因此，检测SOD、LDH、MDA、NO、nNOS的含量可反映机体抗氧化损伤能力。
目前对缺血性脑血管病的治疗研究主要从溶栓和神经保护两个方面着手，溶栓药物多使用重组组织型纤溶酶激活剂，但要保证其疗效对于发病时间窗有着严格要求。许多脑细胞保护剂包括钙离子拮抗剂、自由基清除剂、兴奋性氨基酸NMDA受体拮抗剂和其它脑细胞代谢赋活剂等有一定疗效，但多数药物治疗仍有许多缺陷，疗效不能令人满意。因此，研究植物来源、安全有效、作用机制明确的抗脑缺血再灌注损伤新型药物刻不容缓，意义深远。
老鹳草素是从云南特色药用植物苦味叶下珠(amarus Linn.)提取分离的多酚类活性化合物，分子式为C41H28O27，淡黄色柱状结晶，属于可水解鞣质中的鞣花鞣质，易溶于水及甲醇、乙醇等极性大的有机溶媒，具有抗骨质疏松、抗炎、祛风湿、通经络及抗肿瘤等多种功效。老鹳草素是一种重要的医药中间体，迄今尚未有关于老鹳草素具有防治脑缺血再灌注损伤药理作用的公开报道。
发明内容
本发明所要解决的技术问题是提供了一种老鹳草素及其在制备防治脑缺血再灌注损伤药物中的应用。
为了实现上述目的，本发明通过如下技术方案实现：本发明的一种老鹳草素，具有通式(I)所示结构：
本发明所述的老鹳草素用于制备治疗或/和预防脑缺血再灌注损伤的药物中的应用。
本发明含所述的老鹳草素的植物提取物在防治脑缺血再灌注损伤药物制备中的应用。
进一步地，所述的脑缺血再灌注损伤为脑缺血、脑梗塞、脑血栓或脑缺氧中的一种或几种的组合。
进一步地，所述药物可改善脑缺血再灌注损伤所致神经功能缺失，降低神经学评分，增强运动能力，降低血清及脑组织内MDA、LDH、NO、nNOS含量，升高SOD活性的药物。
更进一步地，所述的药物为降低缺血再灌注损伤神经元MDA、LDH、NO、nNOS含量，升高SOD活性的药物。
本发明的一种治疗或/和预防脑缺血再灌注损伤的药物，所述药物的主要活性成分为老鹳草素。
进一步地，以老鹳草素为活性成分，加上药学上可接受的辅料制备而成的制剂。
进一步地，所述的制剂为注射制剂。
进一步地，所述的注射制剂为溶液型注射剂、乳剂型注射液或混悬液。
与现有技术相比，本发明具有如下优点：本发明提供了老鹳草素用于制备治疗或/和预防脑缺血再灌注损伤的药物的用途。药效实验表明，该化合物具有显著的抗神经功能损伤、抗氧化损伤作用，改善神经学评分、运动能力，降低血清、脑组织以及MDA、LDH、NO、nNOS含量，升高SOD活性。老鹳草素具有抗神经功能损伤作用，可抗氧化损伤、降低脑组织、血清及PC12细胞株培养液上清中MDA、LDH、NO、nNOS水平，升高SOD活性，从而达到防治脑缺血再灌注损伤的效果，可以用于制备治疗或/和预防脑缺血再灌注损伤的药物，较于目前临床上常用的同类药物和治疗手段，老鹳草素来源广泛、价格低廉、疗效显著，为脑缺血再灌注损伤的防治提供了新途径。
附图说明
图1为本发明的老鹳草素对MCAO/R大鼠神经病学评分、运动能力的影响图。注：(与假手术组比较：▲▲P<0.01,与模型组比较：*P<0.05,**P<0.01)。
图2为本发明的老鹳草素对MCAO/R大鼠梗死面积的影响图。注：(与假手术组比较：▲▲P<0.01,与模型组比较：**P<0.01)。
图3为本发明的老鹳草素对MCAO/R大鼠脑组织病理结构改变的影响图。
图4为本发明的老鹳草素对MCAO/R大鼠血清、脑组织LDH、、SOD、MDA、NO、nNOS含量的影响图。(与假手术组比较：▲▲P<0.01,与模型组比较：*P<0.05，**P<0.01)。
图5为本发明的老鹳草素对OGD/R PC12细胞存活率的影响图。注：(与正常组比较：▲▲P<0.01,与模型组比较：*P<0.05，**P<0.01)。
图6为本发明的老鹳草素对OGD/R PC12细胞LDH、SOD、MDA、NO、nNOS含量的影响图。注：(与正常组比较：▲▲P<0.01,与模型组比较：*P<0.05，**P<0.01)。
具体实施方式
以下结合附图及实施例对本发明作进一步说明，但不以任何方式对本发明加以限制，基于本发明教导所作的任何变换或改进，均落入本发明的保护范围。
本发明具体实施方式中使用的原料、试剂及设备均为已知产品，通过购买市售产品获得。以下通过实验案例证明本发明的有益效果。
实施例1
本发明的一种老鹳草素，具有通式(I)所示结构：
本发明所述的老鹳草素用于制备治疗或/和预防脑缺血再灌注损伤的药物中的应用。
本发明含所述的老鹳草素的植物提取物在防治脑缺血再灌注损伤药物制备中的应用。
所述的脑缺血再灌注损伤为脑缺血、脑梗塞、脑血栓或脑缺氧中的一种或几种的组合。
所述药物可改善脑缺血再灌注损伤所致神经功能缺失，降低神经学评分，增强运动能力，降低血清及脑组织内MDA、LDH、NO、nNOS含量，升高SOD活性的药物。
所述的药物为降低缺血再灌注损伤神经元MDA、LDH、NO、nNOS含量，升高SOD活性的药物。
本发明的一种治疗或/和预防脑缺血再灌注损伤的药物，所述药物的主要活性成分为老鹳草素。
以老鹳草素为活性成分，加上药学上可接受的辅料制备而成的制剂。
所述的制剂为注射制剂。
所述的注射制剂为溶液型注射剂、乳剂型注射液或混悬液。
试验例1
老鹳草素由中国科学院昆明植物研究所植物化学与西部植物资源持续利用国家重点实验室提供。药物以50mg/ml的浓度用二甲基亚砜(Dimethyl sulfoxide,DMSO)溶解后加入10％的吐温80充分混匀，用生理盐水稀释至20mg/kg的剂量。
试验例2
应用试验例1老鹳草素对大鼠脑缺血再灌注损伤的保护作用
选取成年健康雄性SD大鼠，体重250-300g，SPF级，由昆明医科大学实验动物中心提供，生产许可证号：SCXK(滇)K2020-0004。将大鼠随机分为假手术组、模型组、老鹳草素低剂量组(Geraniin，5mg/kg)，老鹳草素中剂量组(Geraniin，10mg/kg)和老鹳草素高剂量组(Geraniin，20mg/kg)，尼莫地平组(Nimodipine,1mg/kg)，每组19只大鼠，每只大鼠按1mL/100g体重腹腔注射给药，假手术组和模型组给予等体积蒸馏水。采用线栓法复制大鼠MCAO/R模型，复制方法如下：将大鼠用2％异氟烷吸入麻醉麻醉，颈部剃毛并进行常规消毒后颈正中偏右0.5cm处切口约1.5cm，用玻璃分针分离大鼠右侧颈总动脉(CCA)和迷走神经至分叉处，结扎CCA近心端，CCA远心端用1个动脉夹夹闭，在CCA上用缝合线打一活结，眼科剪在距分叉1cm处剪一“V”形缺口，将线栓经缺口插入。松开CCA上动脉夹，向右牵拉CCA近心端上的结扎线，向左侧调整进线角度使栓线成功进入ICA，并轻拉CCA，使栓线进入大脑，线栓插入深度为18-20mm，此时即完成一侧大脑中动脉阻塞。MCAO后2h，再灌注时缓慢的轻拉尼龙线使其头端回到颈总动脉内，即可实现大脑中动脉再灌注。在缺血及再灌注期间保持室温在25℃-30℃。大鼠清醒后，观察其神经功能缺失症状，在再灌注72h后参照Zea Longa评分标准进行神经行为学评分，评分标准：0分：无神经功能缺损症状；1分：轻度局灶性神经功能缺损，即提尾悬空不能伸展左侧前爪；2分：中度局灶性神经功能缺损，即行走向左侧转圈；3分：中度局灶性神经功能缺损，即行走困难，并向左侧倾倒；4分：不能自发行走，意识水平下降。评分完成后，进行旷场实验，评价动物运动能力。旷场实验结束，各组随机选大鼠2％异氟烷吸入麻醉后，立即断头取脑，沿脑桥上界面切断，去除嗅球，称全脑重，立即放入-20℃冰箱，5min后取出。由前向后做连续冠状切片，共5片，将脑切片置入0.2％ TTC溶液中，放入恒温振荡器中，37℃避光染色30min。将脑切片取出后放入4％中性多聚甲醛中固定24h，取出脑片，用数码相机拍照，用Images J图象分析系统计算梗塞面积。实验结果见表1、图1、2。老鹳草素对MCAO/R大鼠神经病学评分、运动能力及TTC染色脑梗死面积比例的影响(n＝8)如表1所示：
表1
注：(与假手术组比较：▲▲P<0.01,与模型组比较：*P<0.05,**P<0.01)
实验结果表明：老鹳草素高剂量组(20mg/kg)能显著降低模型大鼠神经病学评分，增加其运动路程，提高运动速度，降低脑梗死面积比例(P<0.05,P<0.01)。上述结果表明，老鹳草素对脑缺血再灌注损伤大鼠有较强的神经保护作用。
试验例3
老鹳草素对MCAO/R大鼠脑组织病理结构改变的影响
参照试验例2中的造模方法，各组随机选取3只大鼠，于脑缺血2h再灌注72h后各组大鼠用2％异氟烷吸入麻醉后打开胸腔，于右心耳部剪一小口，从左心室插入导管至主动脉，向主动脉内缓慢注入300mL的多聚甲醛，至右心房流出液体变清亮。断头取脑，将组织进行脱水处理：80％乙醇40min→90％乙醇400min→95％乙醇I 50min→95％乙醇Ⅱ50min→无水乙醇I 50min→无水乙醇Ⅱ45min。接着进行透明处理：二甲苯Ⅰ20min一二甲苯Ⅱ20min一二甲苯Ⅲ30min。随即进行浸蜡：将透明好的组织块置入在温箱内已熔化的58～60℃石蜡内，共三杯蜡，第一杯蜡1h，第二杯蜡1h 20min，第三杯1h 30min。包埋：将过滤好的新蜡倾入包埋器中，尽快将浸透蜡的组织块放到里面。切片：用石蜡切片机将石蜡块切成5μm厚的切片。贴片：切好的石蜡组织片先放入40％酒精中，再转入约40℃度的温水中。最后再用经过多聚赖氨酸包被处理的载玻片将组织切片捞起并贴附于载玻片上。烤片：将石蜡切片完毕的载玻片放置于载玻片架上，在60℃烤箱烘烤过夜。染色：蒸馏水洗涤5min，苏木素染色16min，自来水洗去浮色，1％盐酸酒精分化2s，自来水返蓝，伊红室温染色15s，自来水终止显色，梯度酒精脱水，75％→80％→85％→90％→100％→100％。各10min，二甲苯透明，30min，中性树胶封片，普通光学显微镜下观察显色结果并拍照。结果见图3。实验结果表明，老鹳草素高剂量组(20mg/kg)能显著改善模型大鼠受损脑组织病理结构。
试验例4
应用试验例1老鹳草素在防治脑缺血再灌注损伤所致氧化损伤中的应用
参照试验例1中的造模方法，各组随机选取8只大鼠，于脑缺血2h再灌注72h后各组大鼠用2％异氟烷吸入麻醉后打开腹腔，找到腹主动脉，取出3ml血液，3000r/min转速离心10min，取上清液于-20℃保存。随后打开胸腔，于右心耳部剪一小口，从左心室插入导管至主动脉，向主动脉内缓慢注入400mL的肝素生理盐水溶液，至右心房流出液体变清亮，整个操作于冰浴下进行。断头取脑，去除嗅球和脑桥，取缺血侧脑组织，用滤纸吸干表面水分后称重，剪成小块放入10mL预冷的离心管中，于冰浴下匀浆，每100mg组织加入1mL 1×PBS，制成匀浆，然后置于-20℃过夜。经过反复冻融2次处理破坏细胞膜后，于4℃5000r/min离心5min取上清，将上清分装保存于-80℃。各取一支上清，按BCA蛋白测定试剂盒要求测定各组血清、脑组织匀浆液中蛋白的含量，并按LDH、SOD、MDA、NO测定试剂盒要求检测含量；按ELISA试剂盒要求检测脑组织匀浆中nNOS的活性。结果见表2、3，图4、5。
老鹳草素对MCAO/R大鼠血清中LDH、SOD、MDA、NO、nNOS水平的影响(n＝8)如表2所示：
表2
老鹳草素对MCAO/R大鼠脑组织中LDH、SOD、MDA、NO、nNOS水平的影响(n＝8)如表3所示：
表3
注：(与假手术组比较：▲▲P<0.01,与模型组比较：*P<0.05,**P<0.01)
实验结果表明：老鹳草素高剂量组(20mg/kg)能显著降低LDH、MDA、NO、nNOS含量，升高SOD活性(P<0.01)。上述结果表明，老鹳草素可减轻脑缺血再灌注损伤所致的氧化损伤。
试验例5
老鹳草素对缺糖缺氧/复糖复氧损伤PC12细胞的保护作用
配制好含10％FBS的DMEM 1640培养基，复苏培养PC12细胞株。将PC12细胞接种于96孔板上，分为6个组，正常组，模型组，老鹳草素低浓度组(0.1μmol/L)，老鹳草素中浓度组(1μmol/L)，老鹳草素高浓度组(10μmol/L)，尼莫地平组(1μmol/L)。待细胞密度长至90％以上，换入无糖培养基，置于37℃、5％CO2、1％O2及饱和湿度条件的培养箱中进行缺糖缺氧损伤2h后取出，模型组换入完全培养基，给药组换入不同浓度含药培养基，继续培养24h后，采用CCK8法检测细胞存活率，选择450nm波长，在酶标仪上测定各孔吸光度，计算细胞相对存活率。结果见表4、图5。
老鹳草素对PC12细胞存活率的影响(n＝6)
表4
注：(与正常组比较：▲▲P<0.01,与模型组比较：*P<0.05,**P<0.01)
实验结果表明：老鹳草素剂量为1μmol/L、10μmol/L时细胞活力显著升高(P<0.01)。
试验例6
老鹳草素在防治缺糖缺氧/复糖复氧损伤所致PC12细胞氧化损伤中的应用
将PC12细胞接种于96孔板上，分为6个组，正常组，模型组，老鹳草素低浓度组(0.1μmol/L)，老鹳草素中浓度组(1μmol/L)，老鹳草素高浓度组(10μmol/L)，尼莫地平组(1μmol/L)。待细胞密度长至90％以上，换入无糖培养基，置于37℃、5％CO2、1％O2及饱和湿度条件的培养箱中进行缺糖缺氧损伤2h后取出，模型组换入完全培养基，给药组换入不同浓度含药培养基，继续培养24h后，取细胞培养上清液，按BCA蛋白测定试剂盒要求测定各组上清液中蛋白的含量，并按LDH、SOD、MDA、NO测定试剂盒要求检测含量；按ELISA试剂盒要求检测nNOS的活性。结果见表5、图6。
老鹳草素对PC12细胞LDH、SOD、MDA、NO、nNOS水平的影响(n＝6)
表5
注：(与正常组比较：▲▲P<0.01,与模型组比较：*P<0.05,**P<0.01)
实验结果表明：老鹳草素高浓度组(10μmol/L)能显著降低LDH、MDA、NO、nNOS含量，升高SOD活性(P<0.01)。上述结果表明，老鹳草素可减轻缺糖缺氧/复糖复氧损伤所致的神经元氧化损伤。
数据处理
本研究采用SPSS20.0进行统计分析，所有数据以均数±标准差表示。两组比较采用t检验分析。P<0.05为差异具有统计学意义。
以上实施方式仅用于说明本发明，而并非对本发明的限制，本领域的普通技术人员，在不脱离本发明的精神和范围的情况下，还可以做出各种变化和变型。因此，所有等同的技术方案也属于本发明的范畴，本发明的专利保护范围应由权利要求限定。
Claims (4)
1.老鹳草素用于制备治疗或/和预防脑缺血再灌注损伤的药物中的应用。
2.根据权利要求1所述的应用，其特征在于：所述的脑缺血再灌注损伤为脑缺血、脑梗塞、脑血栓或脑缺氧中的一种或几种的组合。
3.根据权利要求1所述的应用，其特征在于：所述药物可改善脑缺血再灌注损伤所致神经功能缺失，降低神经学评分，增强运动能力，降低血清及脑组织内MDA、LDH、NO、nNOS含量，升高SOD活性的药物。
4.根据权利要求1所述的应用，其特征在于：所述的药物为降低缺血再灌注损伤神经元MDA、LDH、NO、nNOS含量，升高SOD活性的药物。
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| CN113304331A (zh) * | 2021-05-27 | 2021-08-27 | 昆明医科大学 | 老鹳草素在制备用于支架涂层药物中的应用 |
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