CN113499329A - 异甘草素在制备用于抗神经炎症药物中的应用 - Google Patents
异甘草素在制备用于抗神经炎症药物中的应用 Download PDFInfo
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Abstract
本发明属于医药技术领域,涉及异甘草素的应用。本发明提供了异甘草素的应用,实验结果表明,异甘草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。异甘草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,涉及异甘草素的应用。
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(Neurodegenerative diseases,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异甘草素(Isoliquiritigenin,ISL)属于查尔酮类化合物,研究表明,其具有抗炎、抗氧化、抗肿瘤等多种药理作用。本发明主要研究异甘草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异甘草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,研究异甘草素在抗神经炎症方面作用的途径。结果显示,异甘草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:
异甘草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异甘草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)、低剂量异甘草素组(LPS+低剂量异甘草素,ISL-L,25mg/kg/day)和高剂量异甘草素组(LPS+高剂量异甘草素,ISL-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 250μg/kg/d。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。
按说明书方法提取异甘草素治疗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,得到异甘草素治疗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。
本发明还提供了异甘草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,异甘草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,包括异甘草素,异甘草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小鼠海马区小胶质细胞Iba-1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 水迷宫实验测试异甘草素对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)、低剂量异甘草素组(LPS+低剂量异甘草素,ISL-L,25mg/kg/day)和高剂量异甘草素组(LPS+高剂量异甘草素,ISL-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异甘草素对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异甘草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,高剂量异甘草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,低剂量和高剂量异甘草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,表明异甘草素能够减缓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 异甘草素对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,对切片进行免疫荧光,结果请参阅图3,再通过免疫荧光染色来测定海马区中炎症因子Iba-1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→自来水冲洗掉多余同定液→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荧光试验,检测异甘草素对LPS诱导的小胶质细胞活化程度的抑制作用。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(组织切片置于盛满柠檬酸pH 6.0抗原修复液的修复盒中,于微波炉内进行抗原修复)→防止荧光淬灭(切片稍干后用组化笔在组织周围画圈)→血清封闭(3%BSA孵育30min)→一抗孵育4度过夜(滴加一抗Iba-1,1∶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→DAPI复染细胞核(滴加DAPI染液,避光室温孵育10min)→洗涤封片(摇床洗涤3次后,晾干,用抗荧光淬灭封片剂封片)→镜检拍照(片于尼康到置荧光显微镜下观察并采集图像,DAPI紫外激发波长330-380nm,发射波长420nm,发蓝光;CY3激发波长510-560nm,发射波长590nm,发红光),结果请参阅图3。
正常情况下,小胶质细胞处于静止状态,产生抗炎因子和神经营养因子,保护大脑组织。而病理状态下,小胶质细胞被广泛激活,产生大量的炎症因子损伤神经元,甚至引起脑组织认知和代谢障碍。图3为实施例2小鼠海马区小胶质细胞Iba-1蛋白表达图,其中,(A)免疫荧光图,第一行为Iba-1/DAPI荧光图,第二行为Iba-1荧光图,(B)采用Image-Pro plus8软件对大脑海马体图像进行Iba-1蛋白荧光量表达定量分析。图3表明,LPS注射后,引起小胶质细胞的广泛活化。相对于正常对照组,LPS组中大量的小胶质细胞被激活,红色荧光明显增多,注射LPS引起了神经炎症反应。再给予异甘草素后,小胶质细胞的活化水平被抑制,红色荧光标记的细胞明显减少。与LPS模型组相比,给予高剂量异甘草素可以显著降低海马中的Iba-1蛋白表达水平,表明异甘草素能够有效抑制小胶质细胞的活化。
以上结果显示,异甘草素能够有效抑制小胶质细胞的活化,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)分析异甘草素治疗LPS诱导的小鼠神经炎症前后基因表达的差异
按说明书方法提取异甘草素治疗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,得到异甘草素治疗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、ISL组组间基因表达量Venn图,RNA-seq数据分析显示,Control组、LPS组、ISL组共同表达的基因数为21497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ISL组中检测到的基因数量有23007个。为了进一步研究ISL干预影响了哪些基因的表达,对LPS组和Control组、LPS组和ISL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ISL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130个,说明ISL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ISL组不同比较组差异基因表达水平,从LPS组和Control组、LPS组和ISL组的组间差异基因数量上可以看出,ISL组较LPS组有120个基因表达上调,有360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 ISL上调基因的KEGG富集气泡图中,可以看出,相比较LPS组的样本,ISL组样本中上调基因主要富集到过氧化物酶体(Peroxisome)、人巨细胞病毒感染(Human cytomegalovirus infection)中。从(G)LPS vs ISL下调基因的KEGG富集气泡图中,可以看出,相比较LPS组的样本,ISL组样本中下调基因主要富集到丙氨酸、天冬氨酸和谷氨酸的代谢(Alanine,aspartate andglutamate metabolism)、β-丙氨酸代谢(beta-Alanine metabolism)、丁酸代谢(Butanoate metabolism)、酪氨酸代谢(Tyrosine metabolism)、丙酸代谢(Propanoatemetabolism)、缬氨酸、亮氨酸和异亮氨酸的降解(Valine,leucine and isoleucinedegradation)中。由此可以看出,异甘草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.异甘草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,包括异甘草素。
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CN115337294A (zh) * | 2022-08-22 | 2022-11-15 | 暨南大学 | 异甘草素在制备防治精神类疾病药物中的应用 |
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