CN113509460A - 高丽槐素在制备用于抗神经炎症药物中的应用 - Google Patents
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Abstract
本发明属于医药技术领域，涉及高丽槐素的应用。本发明提供了高丽槐素的应用，实验结果表明，高丽槐素能够安全有效控制神经炎症反应，从而改善脑组织的认知功能、记忆障碍和运动协调能力，可用于预防和治疗阿尔茨海默症、帕金森症等。高丽槐素应用于制备预防和治疗神经炎症药物或保健品，具有很好的应用价值和开发前景。
Description
技术领域
本发明属于医药技术领域，涉及高丽槐素的应用。
背景技术
炎症反应是机体抵御感染和损伤的复杂的级联过程，其病理变化表现为炎症因子的过度产生、炎症细胞的广泛浸润和组织的坏死崩解，而神经炎症是发生在神经系统的特殊免疫应答。在正常情况下，小胶质细胞和星形胶质细胞处于不活跃状态，具有维持中枢神经系统正常组织稳态的作用。在脑部感染或损伤时，这些细胞被激活，发动免疫反应及组织修复过程，一旦感染或损伤恢复，这些细胞回到静息状态。一般情况下，炎症很快就会消失，但是若炎症慢性持续性地进行，会引起神经退行性疾病(Neurodegenerativediseases，NDDs)，比如阿尔茨海默症(Alzheimer disease，AD)、帕金森症(Parkinson’s disease，PD)、多发性硬化症(Multiple sclerosis，MS)和肌萎缩侧索硬化症(Amyotrophic lateralsclerosis，ALS)等。
目前有许多治疗神经炎症的化合药物，但这些药只能改善症状，很少能有效逆转病情，甚至还有副作用，故寻找新的治疗神经炎症的药物及方法显得尤为重要。
临床和实验证实，中草药有着良好的抗炎效果，而我国运用中草药治疗炎症的历史悠久，且中草药资源丰富，因此从天然产物中筛选和开发疗效确切、安全无毒药物具有得天独厚的优势。关于牛大力可治疗风湿性关节炎、慢性支气管炎和慢性肝炎早已有报道，所以可以利用牛大力抗炎功效的特点，开发防治阿尔茨海默症等神经炎症的药物。本发明从牛大力中分离出的主要成分高丽槐素(Maackiain，MAA)属于二氢异黄酮类化合物，研究表明，其具有抗氧化、抗过敏、抗炎、抗菌、抗肿瘤等多种药理作用。本发明主要研究高丽槐素抗神经炎症的效果及其作用机制。
发明内容
本发明的目的在于提供一种高丽槐素在抑制神经炎症方面的应用。对小鼠进行造模和给药治疗后，进行水迷宫实验，检测小鼠的记忆力和运动协调能力。之后对各组别小鼠的脑组织进行转录组测序，研究高丽槐素在抗神经炎症方面作用的途径。结果显示，高丽槐素能够控制神经炎症，改善记忆障碍和运动协调能力，且不会产生明显的副作用。
本发明的具体技术方案如下：
高丽槐素在制备抑制神经炎症药物中的应用。
本发明对实验后所有组别的小鼠进行水迷宫实验，记录它们在水迷宫定位航行和空间探索实验中的行动轨迹，目的是检测它们在被高丽槐素治疗前后记忆力所发生的变化。本发明将实验动物随机分为5组，分别是：正常对照组(Control)、LPS组(LPS，250μg/kg/d)、阳性药物组(LPS+阳性药物，TTP488，5mg/kg/day)、低剂量高丽槐素组(LPS+低剂量高丽槐素，MAA-L，25mg/kg/day)和高剂量高丽槐素组(LPS+高剂量高丽槐素，MAA-H，50mg/kg/day)，每组7只。第1周各实验组分别先按浓度给药，然后注射LPS。第2周，各实验组每天按浓度给药。2周后，采用水迷宫实验考察小鼠的记忆功能，实验数据以Mean±SD表示，所有实验数据均采用GraphPad Prism 8软件进行统计分析，各组小鼠的组间参数用ANOVA进行检验，P＜0.05被认为有统计学意义。
按说明书方法提取高丽槐素治疗LPS诱导的小鼠神经炎症前后的总RNA，将质检合格的总RNA样本(包含生物学重复)送至华大基因进行转录组测序(RNA-seq)分析。测序原始数据经过预处理后，得到高丽槐素治疗LPS诱导的小鼠神经炎症前后各样本的有效转录组数据，数据分析中采用Q值，即校正后的P值，Q＜0.05认为有显著差异。
本发明还提供了高丽槐素在制备预防和治疗退行性神经疾病药物、保健品中的应用。
本发明中，神经退行性疾病为神经炎症相关的疾病，高丽槐素用于预防和治疗神经退行性疾病时，给药剂量优选为25mg/kg/d～50mg/kg/d。
优选的，所述神经退行性疾病选自阿尔茨海默症、帕金森症、抑郁症、脑中风、术后神经系统并发症、肌萎缩侧索硬化症或多发性硬化症。
优选的，所述药物还包括药学上可接受的辅料。
优选的，所述药物的剂型为口服制剂或注射剂。
本发明中，所述口服制剂选自胶囊剂、微囊剂、丸剂、片剂、汤剂、颗粒剂、膏剂、分散粉末、露剂口服剂、滴丸剂或脂质体；
所述注射剂为粉针剂或注射液。
本发明还提供了一种抑制神经炎症的产品，包括高丽槐素，高丽槐素为抑制神经炎症的产品的有效成分。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1为实施例1小鼠水迷宫定位航行实验结果图；
图2为实施例1小鼠水迷宫空间探索实验结果图；
图3为实施例2小鼠脑组织COX-2蛋白表达图；
图4为实施例3小鼠脑组织转录组测序结果图。
具体实施例
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
具体实施例中，使用的原料及试剂均可由市场购得。实验动物采用体重20～22g的SPF级8周龄雄性C57小鼠，购自中山大学实验动物中心，许可证号SCXK(粤)2016-0112。小鼠饲料购自广州中医药大学实验动物中心。实验动物在清洁级层流架中饲养，饲养环境温度空调控制为23±2℃，相对湿度为75±10％，照明时间12h/d(7：00-19：00)。
实施例1 水迷宫实验测试高丽槐素对LPS诱导的小鼠神经炎症记忆障碍的改善作用
本实施例将实验动物随机分为5组，分别是：正常对照组(Control)、LPS组(LPS，250μg/kg/d)、阳性药物组(LPS+阳性药物，TTP488，5mg/kg/day)、低剂量高丽槐素组(LPS+低剂量高丽槐素，MAA-L，25mg/kg/day)和高剂量高丽槐素组(LPS+高剂量高丽槐素，MAA-H，50mg/kg/day)，每组7只。第1周各实验组分别先按浓度给药，然后注射LPS。第2周，各实验组每天按浓度给药。2周后，采用水迷宫实验考察小鼠的记忆功能，实验数据以Mean±SD表示，所有实验数据均采用GraphPad Prism 8软件进行统计分析，各组小鼠的组间参数用ANOVA进行检验，P＜0.05被认为有统计学意义。水迷宫定位航行实验结果请参阅图1，水迷宫空间探索实验结果请参阅图2。
长期腹腔注射LPS会导致脑组织发炎，导致大脑神经损伤，从而降低学习和记忆能力。因此，本实施例通过水迷宫实验考察高丽槐素对LPS诱导的小鼠记忆和认知损伤是否有改善作用。在水迷宫定位航行实验中，每只小鼠必须从一、二、三、四象限开始寻找隐藏的平台。图1为实施例1小鼠水迷宫定位航行实验结果图，(A)定位航行实验小鼠运动轨迹图(隐藏平台)，(B)定位航行实验小鼠在各象限的逃避潜伏期(隐藏平台)。图2为实施例1小鼠水迷宫空间探索实验结果图，(A)空间探索实验小鼠的运动轨迹图(撤除平台)，(B)空间探索实验小鼠跨越原平台区域的次数(撤除平台)，(C)空间探索实验小鼠在原平台目标象限所花时间百分比(撤除平台)。本实施例记录了潜伏时间，可见在定位航行实验的4个象限中，相比Control组，LPS组中小鼠腹腔注射LPS后明显延长了小鼠在水迷宫定位航行实验中的潜伏期，小鼠运动轨迹结果与潜伏期结果一致(图1A和1B)。同时减少了小鼠在空间探索实验中进入目标象限的次数及时间比例(图2B和2C)，这表明连续腹腔注射LPS导致小鼠的学习记忆功能受损。而连续灌胃给予低剂量和高剂量高丽槐素的实验组小鼠记忆功能得到不同程度的改善，相比LPS组，可见4个象限中潜伏期缩短，小鼠运动轨迹结果与潜伏期结果一致，高剂量高丽槐素组小鼠找到平台所用的游泳距离更短(图1A和1B)。在空间探索实验中，低剂量和高剂量高丽槐素组小鼠进入目标平台的次数和时间比例均增加(图2B和2C)，小鼠运动轨迹结果如图2A所示，表明高丽槐素能够减缓LPS诱导的神经炎症对小鼠学习和记忆功能的影响。
实施例2 高丽槐素对LPS诱导的神经炎症小鼠脑组织中炎症反应的影响
本实施例实验分组和给药方案同实施例1，给药结束后对小鼠处死，将完整的脑组织取出制作石蜡切片，对切片进行免疫组化，结果请参阅图3，再通过免疫组化染色来测定皮层区中炎症因子COX-2的表达量，实验数据以Mean±SD表示，所有实验数据均采用GraphPad Prism 8软件进行统计分析，各组小鼠的组间参数用ANOVA进行检验，P＜0.05被认为有统计学差异。
制作石蜡切片的主要步骤包括将组织洗净后置4％多聚甲醛中固定1周→自来水冲洗掉多余固定液→用不同浓度梯度(70％、80％、90％、95％和100％)的酒精进行梯度脱水→脱水之后浸泡于梯度二甲苯(50％和100％)中透明→将已透明的样品于熔化状态的石蜡中浸蜡4h→包埋(倒入包埋的石蜡至凝固)→切片(以5μm的厚度切片)→展片→烤片→脱蜡复水。
对组织切片进行免疫组化染色，检测炎症因子COX-2的表达水平。将切好的石蜡切片进行烤片(置于温度62～65℃的烘箱中烤片1h后，二甲苯乙醇溶液中脱蜡水化)→抗原修复(组织切片置于盛EDTA抗原修复缓冲液pH8.0的修复盒中，于微波炉内进行抗原修复)→阻断内源性过氧化物酶(使用3％过氧化氢溶液室温避光孵育25min，再PBS洗涤)→血清封闭(3％BSA孵育30min)→一抗孵育4℃过夜(滴加一抗TNF-α，1∶100，1×PBS稀释)→一抗洗涤→二抗孵育室温50min(滴加与一抗相应种属的二抗，1∶100，1×PBS稀释)→二抗洗涤→DAB显色(显微镜下控制显色时间，阳性为棕黄色，自来水冲洗切片终止显色)→苏木素复染细胞核→酒精脱水封片(摇床洗涤3次后，晾干，中性树胶封片)→二甲苯脱水透明→镜检拍照(切片于显微镜下观察并采集图像)，结果请参阅图3。
正常情况下，COX-2在正常组织细胞内的活性极低，当细胞受到炎症等刺激时，其在炎症细胞中的表达水平可升高至正常水平的10-80倍，导致炎症反应和组织损伤。图3为实施例2小鼠脑组织COX-2的表达图，其中(A)为免疫组化图，第一行为小鼠脑组织横断图，第二行为大脑皮层区，(B)为采用Image-Pro plus 8软件对大脑皮层区域图像进行织COX-2表达定量分析，图3表明，结合免疫组化切片表征皮层中COX-2的表达水平(图3A)和图像分析量化皮层中COX-2的表达水平(图3B)，LPS注射后，引起炎症因子COX-2的过度表达，在给予高丽槐素后，炎症因子COX-2浓度均显著减少。
以上结果显示，高丽槐素能够有效抑制炎症因子COX-2的分泌，控制神经炎症反应，从而缓解后续所致的神经元损伤，改善记忆障碍和运动协调能力。
实施例3 转录组测序(RNA-seq)分析高丽槐素治疗LPS诱导的小鼠神经炎症前后基因表达的差异
按说明书方法提取高丽槐素治疗LPS诱导的小鼠神经炎症前后的总RNA，将质检合格的总RNA样本(包含生物学重复)送至华大基因进行转录组测序(RNA-seq)分析。测序原始数据经过预处理后，得到高丽槐素治疗LPS诱导的小鼠神经炎症前后各样本的有效转录组数据。
图4为实施例3小鼠脑组织转录组测序结果图，其中(A)为Control组、LPS组、MAA组组间基因表达量Venn图，RNA-seq数据分析显示，Control组、LPS组、MAA组共同表达的基因数为21365个，在Control组中检测到的基因数量有23698个，在LPS组中检测到的基因数量有24056个，在MAA组中检测到的基因数量有22933个。为了进一步研究MAA干预影响了哪些基因的表达，对LPS组和Control组、LPS组和MAA组之间的差异表达基因进行交集并分析，从(B)LPS组和Control组、LPS组和MAA组不同比较组的差异表达基因Venn图，发现两者共同表达的差异基因有161个，说明MAA主要影响了这部分基因的表达，从而改善神经炎症。(C)为LPS组和Control组、LPS组和MAA组不同比较组差异基因表达水平，从LPS组和Control组、LPS组和MAA组的组间差异基因数量上可以看出，MAA组较LPS组有723个基因表达上调，有468个基因表达量下调。KEGG通路富集分析可以为基因功能及其相互作用提供进一步信息，因此对LPS组和Control组、LPS组和MAA组的上调和下调基因进行KEGG富集分析。从(D)LPSvs Control上调基因的KEGG富集气泡图中，可以看出，相比较LPS组的样本，Control组样本中上调基因主要富集到内质网中的蛋白质加工(Protein processing in endoplasmicreticulum)、过氧化物酶体(Peroxisome)、嘧啶代谢(Pyrimidine metabolism)、胞吞作用(Endocytosis)、药物代谢-其他酶(Drug metabolism-other enzymes)中。从(E)LPS vsControl下调基因的KEGG富集气泡图中，可以看出，相比较LPS组的样本，Control组样本中下调基因主要富集到神经活性配体-受体相互作用(Neuroactive ligand-receptorinteraction)、脂肪细胞因子信号通路(Adipocytokine signaling pathway)、年轻人的成年型糖尿病(Maturity onset diabetes of the young)中。从(F)LPS vs MAA上调基因的KEGG富集气泡图中，可以看出，相比较LPS组的样本，MAA组样本中上调基因主要富集到剪接体(Spliceosome)、赖氨酸降解(Lysine degradation)、单纯疱疹感染(Herpes simplexinfection)、mRNA监测通路(mRNA surveillance pathway)、库欣综合征(Cushingsyndrome)、糖基磷脂酰肌醇(GPI)-锚定生物合成(Glycosylphosphatidylinositol(GPI)-anchor biosynthesis)、聚合酶(RNA polymerase)中。从(G)LPS vs MAA下调基因的KEGG富集气泡图中，可以看出，相比较LPS组的样本，MAA组样本中下调基因主要富集到精氨酸生物合成(Arginine biosynthesis)、丙氨酸、天冬氨酸、谷氨酸代谢(Alanine，aspartate andglutamate metabolism)、酪氨酸代谢(Tyrosine metabolism)中。由此可以看出，高丽槐素主要通过调节氨基酸来控制神经炎症。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (6)
1.高丽槐素在制备抑制神经炎症药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述药物用于制备预防和治疗神经退行性疾病药物、保健品中的应用。
3.根据权利要求2所述的应用，其特征在于，所述神经退行性疾病选自阿尔兹海默症、帕金森病、抑郁症、脑中风、术后神经系统并发症、肌萎缩侧索硬化症或多发性硬化症。
4.根据权利要求1至3任意一项所述的应用，其特征在于，所述药物还包括药学上可接受的辅料。
5.根据权利要求1至3任意一项所述的应用，其特征在于，所述药物的剂型为口服制剂或注射剂。
6.一种抑制神经炎症的产品，其特征在于，包括高丽槐素。
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR101793692B1 (ko) * | 2016-09-28 | 2017-11-03 | 순천대학교 산학협력단 | 막키아인을 유효성분으로 포함하는 신경 질환의 예방 또는 치료용 조성물 |
Non-Patent Citations (2)
| Title |
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| HYUN WOO LEE: "Potent selective monoamine oxidase B inhibition by maackiain, a pterocarpan from the roots of Sophora flavescens", vol. 26 * |
| WENJUAN XIA等: "Discovery of a New Pterocarpan-Type Antineuroinflammatory Compound from Sophora tonkinensis through Suppression of the TLR4/NFκB/MAPK Signaling Pathway with PU.1 as a Potential Target", ACS CHEM. NEUROSCI., vol. 10, pages 298 * |
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Application publication date: 20211019 |