CN114767666B - 柽柳黄素在制备预防或治疗缺血性脑病药物中的应用 - Google Patents
柽柳黄素在制备预防或治疗缺血性脑病药物中的应用 Download PDFInfo
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Abstract
本发明属于天然药物领域，具体涉及柽柳黄素在制备预防或治疗缺血性脑病药物中应用。具体地，本发明涉及柽柳黄素在制备预防或治疗缺血性脑卒中药物中的应用。药理学实验表明，柽柳黄素对中动脉缺血再灌注所致的局灶性缺血性脑卒中模型大鼠的运动障碍和神经功能损伤具有明显的治疗作用；对该模型大鼠的学习和记忆认知障碍亦具有显著的改善作用，因而可以将其用于制备预防或治疗相关缺血性脑病的药物。
Description
技术领域
本发明属于天然药物领域，具体涉及柽柳黄素在制备预防或治疗缺血性脑病药物中应用。
背景技术
缺血性脑病是一类因脑部供血动脉狭窄或者闭塞导致的脑部供血不足进而导致脑组织坏死的常见老年疾病。其临床常见的病症有意识不清、言语困难、面瘫、肢体麻木、力弱、感知障碍、眩晕、共济障碍等。缺血性脑病的发病率高，目前我国每年新增缺血性脑病患者约160万人。此外，该类疾病的致死和致残率也较高。研究表明75％的患者会死亡或者遗留不同程度的残疾。因该类疾病具有致病因素多，病理进程缓慢，病程长，治疗费用高等特点，给社会和家庭带来了沉重的负担，已经发展成为中国乃至世界亟需解决的公共卫生健康难题之一。
目前针对缺血性脑病的治疗是以预防(控制血压、血糖、抽烟、肥胖、教育等危险因素)为主，治疗(针对症状治疗)为辅。在临床上治疗缺血性脑病的手段有静脉注射溶栓药物、机械除栓术、抗血小板聚集药、降脂药、神经保护剂等。但由于缺血性脑病的病理机制的复杂多样，患者的个体差异性较大等多重因素使得这些临床药物的疗效是十分有限的。我国中药资源丰富，从天然产物中筛选和开发疗效确切、安全、无毒的防治缺血性脑病的单味中药、中药有效成分及复方制剂等具有独特优势。
柽柳黄素(Tamarixetin)是一种黄酮类化合物，作为槲皮素的衍生物,广泛存在于蔬菜，水果中，同时也是旋覆花、多花柽柳、三桠苦、银边南洋参、银杏叶中的活性成分。其分子量为316.24，分子式为C16H12O6，分子结构式如式(I)所示。
柽柳黄素具有较强的生物活性，现有研究已有报道柽柳黄素具有保护心脏，保肝，护胃的作用(参见，例如，Hayamizu K,Morimoto S,Nonaka M,Hoka S,SasaguriT.Cardiotonic actions of quercetin and its metabolite tamarixetin through adigitalis-like enhancement of Ca2+transients.Arch BiochemBiophys 2018；637:40-7)。近期研究表明柽柳黄素通过上调白细胞介素10表达，改善脓毒血症模型小鼠的损伤(参见，例如，Park HJ,Lee SJ,Cho J,Gharbi A,Han HD,Kang TH,et al.Tamarixetinexhibits anti-inflammatory activity and prevents bacterial sepsis byincreasing IL-10production.J Nat Prod 2018；81:1435-43.19)；同时体外实验证明柽柳黄素能够促进肿瘤细胞的凋亡，抑制肿瘤迁移(参见，例如，Xu J,Cai XH,Teng SS,LuJH,Wang XF,et al.The pro-apoptotic activity of tamarixetin on liver cancercells via regulation mitochondrial apoptotic pathway.Appl BiochemBiotechnol2019；189:647-60)。
但是，到目前为止关于柽柳黄素对缺血性脑病的预防或治疗作用尚未见到相关的报道。有鉴于此，本发明人开发了柽柳黄素用于预防或治疗缺血性脑卒中的新的医药用途。
发明内容
本发明的目的是为了解决现有技术的不足，实现采用现代药物研究方法对天然产物进行开发利用，结合药效学实验，提供柽柳黄素的新医药用途，即柽柳黄素预防或治疗缺血性脑病的应用。
具体地，本发明提供了柽柳黄素在制备预防或治疗缺血性脑病的药物中的应用。
作为可选的方式，在上述用途中，所述柽柳黄素是从旋覆花(Inula japonica)、多花柽柳(TamarixhohenackeriBunge)、三桠苦(Melicopepteleifolia)、银边南洋参(Polysciasguilfoylei)或银杏(Ginkgo biloba L.)叶中提取得到的黄酮类有效成分。
作为可选的方式，在上述用途中，所述缺血性脑病是缺血性脑卒中。
作为可选的方式，在上述用途中，所述缺血性脑卒中选自局灶性缺血性脑卒中和弥漫性缺血性脑卒中的一种或者两种。
作为可选的方式，在上述用途中，所述缺血性脑卒中选自短暂性脑缺血(TIA)、可逆性神经功能障碍(RIND)、进展性卒中(SIE)和完全性卒中(CS)中的一种或者多种。
作为可选的方式，在上述用途中，所述TIA选自颈动脉性TIA和椎动脉性TIA中的一种或者两种。
优选地，柽柳黄素作为唯一活性成分在制备所述药物中的应用。
或者，柽柳黄素和其他活性成分一起在制备所述药物中的应用；其中其他活性成分选自：尿激酶、链激酶、重组组织型纤溶酶原激活物、瑞替普酶、卡巴拉汀、美金刚、银杏叶提取物、人参皂苷、石杉碱甲、二苯乙烯苷、左旋多巴、卡比多巴、苄丝肼、苯海萦、苯托托品、丙环定、普罗吩胺、丁苯酞、潘生丁、低分子右旋糖酐、肝素、尿激肽原酶、胞二磷胆、依达拉奉、尼莫地平或阿司匹林中的一种或者多种。
更优选地，其中其他活性成分选自：丁苯酞、依达拉奉或尼莫地平。
优选地，在所述药物中，柽柳黄素与其他活性成分的重量比为10：1-1：10。
更优选地，在所述药物中，柽柳黄素与其他活性成分的重量比选自10：1、9：1、8：1、7：1、6：1、5：1、4：1、3：1、2：1、1：1、1：2、1：3、1：4、1：5、1：6、1：7、1：8、1：9或1：10。
最优选地，在所述药物中，柽柳黄素与其他活性成分的重量比选自1：3、1：4、1：5或1：6。
其中，在所述药物中，柽柳黄素与其他活性成分(特别是，丁苯酞、依达拉奉或尼莫地平)的组合在预防或治疗缺血性脑病(特别是缺血性脑卒中)中显著的协同增效作用。
可以采用本申请具体实施方式部分中使用的实验方法验证上述柽柳黄素与其他活性成分的组合的协同增效作用，这对本领域技术人员而言是容易的。
作为可选的方式，在上述用途中，所述药物包含柽柳黄素和药学上可接受的载体。
作为可选的方式，在上述用途中，所述药物的剂型为口服剂型或注射剂。
作为可选的方式，在上述用途中，所述口服剂型选自胶囊剂、片剂、颗粒剂或口服液。
本发明相对于现有技术，具有以下有益效果：
本发明人首次发现了柽柳黄素能够用于预防或治疗缺血性脑病。通过药理学实验表明，柽柳黄素对中动脉缺血再灌注导致的缺血性脑卒中急性期的运动功能障碍和脑损伤具有很好的治疗作用，对恢复期的认知障碍具有显著的改善作用，因而可以将其用于制备预防或治疗相关缺血性脑病的药物。
附图说明
图1：柽柳黄素对MCAO/R模型大鼠脑梗塞体积的影响。利用TTC染色进行脑梗塞体积分析，深色部分表示健康正常的脑组织，白色部分表示梗死的脑组织。每组6只大鼠。
图2：柽柳黄素对MCAO/R模型大鼠神经元丢失的影响。利用免疫荧光技术分析大鼠脑组织中神经元的变化，NeuN染色标注的是正常的成熟的神经元，TUNEL染色标注的是死亡的神经元。每组6只大鼠，比例尺＝100μm。
图3：柽柳黄素对MCAO/R模型大鼠缺血侧皮层小胶质细胞活化的影响。利用免疫荧光技术分析大鼠缺血侧皮层中小胶质细胞的变化，Iba-1染色标注的是活化的小胶质细胞。每组6只大鼠，比例尺＝100μm或者10μm。
具体实施方式
本发明采用现代药物研究方法对天然产物进行开发利用，结合药效学实验，通过大量筛选，首次发现柽柳黄素具有用于预防或治疗缺血性脑病(特别是缺血性脑卒中)的作用。在此基础上完成了本发明。
如本文所用，本发明药物制剂的剂型为片剂、胶囊剂、颗粒剂、口服液或注射剂。优选地，本发明的剂型为片剂或胶囊剂。
如本文所用，本发明的“药学上可接受的载体”是指药物制剂领域常规的药物载体，选自填充剂、粘合剂、崩解剂、润滑剂、助悬剂、润湿剂、色素、矫味剂、溶剂、表面活性剂中的一种或几种。
本发明所述填充剂包括但不限于淀粉、微晶纤维素、蔗糖、糊精、乳糖、糖粉、葡萄糖等；所述润滑剂包括但不限于硬脂酸镁、硬脂酸、氯化钠、油酸钠、月桂醇硫酸钠、泊洛沙姆等；所述粘合剂包括但不限于水、乙醇、淀粉浆、糖浆、羟丙基甲基纤维素、羧甲基纤维素钠、海藻酸钠、聚乙烯吡咯烷酮等；所述崩解剂包括但不限于淀粉泡腾混合物即碳酸氢钠和枸橼酸、酒石酸、低取代羟丙基纤维素等；所述助悬剂包括但不限于多糖如金合欢胶、琼脂、藻酸、纤维素醚和羧甲基甲壳酯等；所述溶剂包括但不限于水、平衡的盐溶液等。
优选地，可以将本发明的药物制成各种固体口服制剂、液体口服制剂等。药剂学可接受的口服剂固体制剂有：普通片剂、分散片、肠溶片、颗粒剂、胶囊剂、滴丸、散剂等，口服液体制剂有口服液、乳剂等。
另外，还可以将本发明的药物制成注射剂，包括水针剂或冻干粉针剂等。
上述各种剂型可以根据药物制剂领域的常规工艺制备而成。
如本文所用，本发明中使用的“柽柳黄素”、“槲皮素”以及其他天然产物提取物或天然产物提取物单体可以采用生物提纯方法从含有该活性成分的植物中提取分离得到，也可以直接购自市售产品。
在上文所述的医药用途中，对于“柽柳黄素”以及其他活性成分的给药时间、给药次数和给药频率等等，需要根据病情的具体诊断结果而定，这在本领域技术人员掌握的技术范围之内。例如，将对小鼠或大鼠的治疗方案应用于人体上，所有药物对人的有效剂量可以通过该药物对小鼠或大鼠的有效剂量进行换算，这对于本领域的普通技术人员而言也是容易实现的。
下面参照具体的实施例对本发明做进一步说明。应当理解，此处所描述的具体实施例仅用于解释本发明，并不用于限定本发明的范围。
实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道购买得到的常规产品。
下面实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为市售产品。
除非另外说明，否则本发明中涉及的百分比和份数均为重量百分比和重量份数。
实施例1：柽柳黄素对缺血性脑卒中急性期的改善作用
1.实验分组及方案
若无特殊说明，本发明实施例采用如下造模和分组方法：
购自辽宁长生生物技术股份有限公司的健康的SPF级雄性Sprague-Dawley(SD)大鼠随机分为6组，即对照组、模型组、模型组+柽柳黄素低剂量组(5mg/kg)、模型组+柽柳黄素中剂量组(10mg/kg)、模型组+柽柳黄素高剂量组(20mg/kg)、模型组+阳性药槲皮素组(20mg/kg)。手术前3天始灌胃给予柽柳黄素或槲皮素，对照组大鼠给予等体积的0.5％羧甲基纤维素钠混悬液，每天一次。SD大鼠麻醉后，暴露大鼠的左侧颈总动脉、颈外动脉和颈内动脉。将光滑的线栓于颈外动脉距分叉口3mm处插入，轻柔推进使栓线经颈总动脉沿颈内动脉进入到大脑中动脉起始端。用缝合线经线栓和颈外动脉结扎固定，后进行缝合。1h后，将线栓拔出1cm左右，恢复血液供应，形成再灌注损伤。假手术组大鼠未插入线栓，其余手术过程同上。24h后进行转棒实验、平衡木实验、转角试验、Zea Longa神经功能评分、脑含水量、和TTC染色实验观察大鼠的运动功能障碍、神经功能障碍和脑损伤的程度，神经元细胞数量的丢失等指标，来评价柽柳黄素对缺血性脑卒中急性期的改善作用。
数据用SPSS 22.0软件(SPSS Inc.，Chicago，USA)进行分析，数据用平均值±SEM表示。组间进行单因素方差分析，利用Fisher’least significant difference(LSD)或Dunnett’s T3进行事后分析。p<0.05表明数据间有显著性差异。
2.实验结果
2.1.柽柳黄素改善MCAO/R模型大鼠的运动功能障碍
利用转棒实验和转角实验评价柽柳黄素对MCAO/R模型大鼠的运动功能障碍的影响。如表1所示，MCAO/R导致大鼠在转棒实验中首次掉落时间显著缩短，掉落次数显著增加，右转比例显著增加。不同剂量的柽柳黄素均能够抑制这一变化，且高剂量组的抑制效果最为显著。槲皮素亦呈现显著的抑制效果，但是其效果不及相同剂量(20mg/kg)下的柽柳黄素。这些结果表明柽柳黄素能够显著改善MCAO/R模型大鼠的运动功能障碍。
表1柽柳黄素对MCAO/R模型大鼠运动功能障碍的影响(平均值±SEM)
注：###p<0.001表示与假手术组比较；*p<0.05，**p<0.01，***p<0.001表示与模型组比较。
2.2.柽柳黄素改善MCAO/R模型大鼠的神经功能障碍和脑损伤
利用Zea Longa5分评价体系、脑含水量和TTC染色实验评价柽柳黄素对MCAO/R模型大鼠的神经功能障碍和脑损伤的影响。如表2和图1所示，MCAO/R导致大鼠神经功能评分显著升高，脑含水量显著增加，脑梗塞体积显著增大。中、高剂量的柽柳黄素均能够抑制这一变化，且高剂量组的抑制效果最为显著。槲皮素亦呈现显著的改善效果，但是其效果不及相同剂量(20mg/kg)下的柽柳黄素。这些结果表明柽柳黄素能够显著改善MCAO/R模型大鼠的神经功能障碍和脑损伤。
表2柽柳黄素对MCAO/R模型大鼠神经功能障碍和脑损伤的影响(平均值±SEM)
注：###p<0.001表示与假手术组比较；*p<0.05，**p<0.01，***p<0.001表示与模型组比较。
2.3.柽柳黄素抑制MCAO/R模型大鼠的神经元丢失
利用NeuN和TUNEL荧光染色来评价柽柳黄素对MCAO/R模型大鼠的成熟神经元数量的变化和神经元损伤的影响。如表3和图2所示，MCAO/R导致大鼠缺血侧皮层成熟神经元的数量显著减少，死亡神经元的数量显著增加。中、高剂量的柽柳黄素均能够抑制这一变化，且高剂量组的抑制效果最为显著。槲皮素亦呈现显著的抑制效果，但是其效果不及相同剂量(20mg/kg)下的柽柳黄素。这些结果表明柽柳黄素能够显著改善MCAO/R模型大鼠的神经元的丢失。
表3柽柳黄素对MCAO/R模型大鼠神经元丢失的影响(平均值±SEM)
注：###p<0.001表示与假手术组比较；*p<0.05，**p<0.01，***p<0.001表示与模型组比较。
2.4.柽柳黄素抑制MCAO/R模型大鼠的小胶质细胞的活化
利用Western blot和Iba-1荧光染色来评价柽柳黄素对MCAO/R模型大鼠的小胶质细胞活化的影响。如表4和图3所示，MCAO/R导致大鼠缺血侧皮层Iba-1蛋白表达量显著增加，Iba-1标记的小胶质细胞的数量显著增加。中、高剂量的柽柳黄素均能够抑制这一变化，且高剂量组的抑制效果最为显著。槲皮素亦呈现显著的抑制效果，但是其效果不及相同剂量(20mg/kg)下的柽柳黄素。这些结果表明柽柳黄素能够显著抑制MCAO/R模型大鼠的小胶质细胞的活化。
表4柽柳黄素对MCAO/R模型大鼠小胶质细胞活化的影响(平均值±SEM)
注：###p<0.001表示与假手术组比较；*p<0.05，**p<0.01，***p<0.001表示与模型组比较。
2.5.柽柳黄素抑制MCAO/R模型大鼠促炎因子的表达
利用RT-PCR实验来评价柽柳黄素对MCAO/R模型大鼠缺血侧皮层促炎因子表达的影响。如表5所示，MCAO/R导致大鼠缺血侧皮层促炎因子IL-1β、IL-6、TNF-α、iNOSmRNA表达水平显著增加。中、高剂量的柽柳黄素均能够抑制这一变化，且高剂量组的抑制效果最为显著。槲皮素亦呈现显著的抑制效果，但是其效果不及相同剂量(20mg/kg)下的柽柳黄素。这些结果表明柽柳黄素能够显著抑制MCAO/R模型大鼠的促炎因子的表达。
表5柽柳黄素对MCAO/R模型大鼠促炎因子表达的影响(平均值±SEM)
注：###p<0.001表示与假手术组比较；*p<0.05，**p<0.01，***p<0.001表示与模型组比较。
3.结论
上述结果表明，柽柳黄素对中动脉缺血再灌注导致的缺血性脑卒中急性期具有显著的治疗作用，能够有效的改善运动功能障碍，抑制脑损伤，减少神经元细胞的丢失，抑制神经炎症。
实施例2：柽柳黄素对缺血性脑卒中恢复期的认知障碍的改善作用
1.实验分组及方案
大鼠的分组和MCAO/R手术过程同实施例1。缺血1h后拔出线栓进行血液再灌注。手术前3d开始灌胃给予药物，对照组灌胃给予等体积的0.5％羧甲基纤维素钠混悬液，每天一次，直至实验结束。14d后开始进行Y迷宫实验，避暗实验，和Morris水迷宫实验观察大鼠的学习、记忆和认知能力来评价柽柳黄素对缺血性脑卒中恢复期的认知障碍的改善作用。
数据用SPSS 22.0软件(SPSS Inc.，Chicago，USA)进行分析，数据用平均值±SEM表示。Y迷宫、避暗实验、Morris水迷宫进行单因素方差分析，利用Fisher’leastsignificant difference(LSD)或Dunnett’s T3进行事后分析。p<0.05表明数据间有显著性差异。
2.实验结果
2.1.柽柳黄素改善MCAO/R模型大鼠的短期和长期记忆障碍
利用Y迷宫和避暗实验分别考察柽柳黄素对MCAO/R模型大鼠的短期和长期记忆障碍的影响。如表6所示，MCAO/R导致大鼠在Y迷宫实验中的自发交替反应率显著降低；在避暗实验中的逃避潜伏期显著减少，错误次数显著增加。中、高剂量的柽柳黄素均能够抑制这一变化，且高剂量组的抑制效果最为显著。表明柽柳黄素能够显著改善MCAO/R模型大鼠的短期和长期记忆障碍。
表6柽柳黄素对MCAO/R模型大鼠短期和长期记忆障碍的影响(平均值±SEM)
注：###p<0.001表示与假手术组比较；*p<0.05，**p<0.01，***p<0.001表示与模型组比较。
2.2.柽柳黄素改善MCAO/R模型大鼠的空间记忆能力障碍
利用Morris水迷宫空间探索实验评价柽柳黄素对MCAO/R模型大鼠的空间记忆能力的影响。如表7所示，MCAO/R导致大鼠穿越目标平台的次数显著减少，在目标象限停的游泳距离和停留时间显著减少，穿越目标象限的次数显著减少。中、高剂量的柽柳黄素均能够抑制这一变化，且高剂量组的抑制效果最为显著。表明柽柳黄素能够显著改善MCAO/R模型大鼠的空间记忆障碍。
表7柽柳黄素对MCAO/R模型大鼠神经功能障碍和脑损伤的影响(平均值±SEM)
注：###p<0.001表示与假手术组比较；*p<0.05，**p<0.01，***p<0.001表示与模型组比较。
3.结论
上述结果表明，柽柳黄素对中动脉缺血再灌注导致的缺血性脑卒中恢复期模型大鼠的短期和长期记忆障碍，空间学习和记忆障碍具有显著的改善作用。通过上述研究提示柽柳黄素对缺血性脑卒中恢复期的认知障碍的改善作用。
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。
Claims (6)
1.柽柳黄素在制备预防或治疗缺血性脑病的药物中的应用，其特征在于：所述缺血性脑病是缺血性脑卒中，所述柽柳黄素对中动脉缺血再灌注导致的缺血性脑卒中急性期的运动功能障碍和脑损伤具有治疗作用，对恢复期的认知障碍具有改善作用。
2.根据权利要求1所述的应用，其特征在于：所述柽柳黄素是从旋覆花Inulajaponica、多花柽柳TamarixhohenackeriBunge、三桠苦Melicopepteleifolia、银边南洋参Polysciasguilfoylei或银杏Ginkgo biloba L.叶中提取得到的黄酮类有效成分。
3.根据权利要求1所述的应用，其特征在于：所述缺血性脑卒中选自局灶性缺血性脑卒中和弥漫性缺血性脑卒中的一种或者两种。
4.根据权利要求1所述的应用，其特征在于：所述药物包含柽柳黄素和药学上可接受的载体。
5.根据权利要求1所述的应用，其特征在于：所述药物的剂型为口服剂型或注射剂。
6.根据权利要求5所述的应用，其特征在于：所述口服剂型选自胶囊剂、片剂、颗粒剂或口服液。
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