CN113827587A - 丹酚酸a在制备预防血栓性脑缺血的药物中的应用 - Google Patents
丹酚酸a在制备预防血栓性脑缺血的药物中的应用 Download PDFInfo
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Abstract
本发明涉及医药技术领域,具体公开了丹酚酸A在预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病的药物制备中的应用。具体涉及丹酚酸A在预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病的用途。本发明公开了丹酚酸A在预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病的体内和体外的作用机制,发现丹酚酸A预防给药可以降低急性脑缺血后神经行为学评分,降低脑出血的发生同时对于血脑屏障具有较好的保护作用。丹酚酸A可用于预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病的药物,减少不良反应,为脑缺血疾病的预防提供一种安全、有效、经济的解决办法。
Description
技术领域
本发明涉及丹酚酸A在制备药物中的新应用,主要涉及丹酚酸A在制备预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病的药物中的应用,属于医药技术领域。
背景技术
脑卒中是由于脑部血管突然破裂或因血管阻塞导致血液不能流入大脑而引起脑组织损伤的一组疾病,包括缺血性脑卒中、出血性脑卒中和短暂性脑缺血发作。缺血性脑卒中主要是由于血管栓塞和/或动脉硬化而使脑组织血液供应不足,造成脑组织损伤,约占总数的87%,严重危害人类健康。脑缺血疾病的预防是减少疾病危害的重要方向,但目前对于预防药物的研究较少,临床仍缺乏有效的药物和措施。
对于脑缺血疾病的预防主要是抑制血栓的形成,包括抑制血小板过度活化和脑血管损伤两方面。目前临床预防脑缺血疾病的策略主要是应用抗血小板的药物预防血栓形成。阿司匹林是经典的抗血小板药物,但其产生的实际效果有限,并且在应用过程中会诱发脑出血,胃肠出血等不良反应。因此,新的预防策略和新的预防药物是目前需要研究的重点任务之一。
近年来,以发展保护“血管系统”的方法来改善脑卒中疗效的观点为脑卒中的治疗另辟蹊径。对于脑血管的保护主要是保护脑血管内皮细胞。内皮细胞功能的改变导致静息血流量的减少,血管舒张反应的损伤,以及影响急性缺血性脑卒中的组织损伤程度。并且内皮功能障碍会导致血管通透性增加。
出血转化(hemorrhagic transformation,HT)是指急性脑梗死后发生的脑内出血现象,是脑卒中常见的严重并发症。HT的发生会显著增加卒中患者的致死率和致残率,是影响预后的重要因素。HT的发生既是脑卒中病理发展的结果,也与药物治疗有关,如抗血小板药、抗凝药和溶栓药物的使用。HT发生的主要机制是血脑屏障完整性的丧失和神经血管稳态的破坏。
血脑屏障是一种物理和生化屏障,精确地控制着大脑内环境的平衡,在调节中枢神经系统与血液交换物质方面起着重要作用。低氧、缺血和脑出血转化时都伴随着血脑屏障通透性的增加。血脑屏障通透性的破坏引起白蛋白以及其他高分子量化合物的外溢,导致水肿形成,颅内压升高和紧密连接蛋白的破坏。
丹参(Salvia miltiorrhiza Bge.)为唇形科鼠尾草属植物的干燥根。性味苦,微温。功能主治:祛瘀止痛、活血通经、安神宁心。近来对丹参的作用研究主要集中在改善心、脑、肝、肺等脏器的缺血再灌注损伤;治疗高血压性心脏病,冠心病心绞痛的作用;对外周血栓形成和血小板聚集的作用;调节免疫应答、抗感染和抗肿瘤等方面。
丹酚酸A(Salvianolic acid A)是丹参的干燥根及根茎中所含的一种水溶性酚酸类化合物,最早是由中国医学科学院药物研究所黎莲娘教授于丹参中分离得到。其化学结构式如下:
经过长期研究,已经发现丹酚酸A显著的抗氧化、心肌缺血保护、抗血栓、神经保护、抗肝纤维化、抗血小板聚集和防治糖尿病及并发症等多方面的生物活性和药理活性,相关文章已经发表。在治疗脑缺血性疾病相关研究中发现,在脑缺血再灌注(ischemiareperfusion,I/R)损伤中,丹酚酸A通过抗炎、抗细胞凋亡、抗氧化应激、保护血脑屏障等多方面机制促进神经功能恢复,减少梗死体积和脑水肿,降低相关脑区的神经功能损伤程度,发挥有效的脑保护作用。关于丹酚酸A抗血栓的作用,有文献报道丹酚酸A具有抗大鼠肠系膜动脉血栓形成及颈动脉-颈静脉短路血栓模型血栓形成的作用;抗血小板聚集,抑制微血栓形成的作用。进一步的研究发现,丹酚酸A通过MAPK通路抑制神经细胞凋亡;通过激活Nrf2/HO-1通路发挥抗氧化作用;通过抑制损伤区域内NF-κB和Cdk5的活性来减少炎症和凋亡达到对BBB的保护作用;通过调节血液流变学及抑制PI3K通路发挥抗血栓,抗血小板的作用。这些研究是在长期研究工作积累的基础上,不断丰富和完善的结果,对丹酚酸A的临床应用提供了实验基础。
本发明是在对丹酚酸A进行长期研究的过程中,探索丹酚酸A可能的作用和作用机制,并通过大量实验进行证明。我们的研究发现,目前研究的结果虽然证明丹酚酸A的多种药理作用,但并不能代表丹酚酸A的全部作用。本发明的核心创新内容在于丹酚酸A可以用于制备预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病,这是迄今为止研究尚未证明的新用途。
迄今为止,关于丹酚酸A现有的技术主要集中在其提取方法、制备纯化方法等方面,大量专利报道了制备丹酚酸的技术方法,如本实验室的“一种制备丹酚酸A原料药的方法”(CN102731308A),介绍了丹酚酸A原料药的制备方法。“丹酚酸A的α晶型物质、制法以及药物组合物与用途”(CN102976943A),介绍了新发现的丹酚酸A的晶型状态和制备方法。
本实验室已申请有关丹酚酸A用途的专利如“丹酚酸A在预防和\或治疗糖尿病及并发症中的应用”(CN101347422A),“丹酚酸A预防和\或治疗脑微血管血栓栓塞性疾病的应用”(CN102784133A),“丹酚酸A预防和/或治疗糖尿病所致肝脏病变的用途”(CN102247349A)等;其他实验室关于丹酚酸A对于血管内皮保护作用的专利如,“丹酚酸A冻干粉针用于制备保护脑血管内皮细胞药物的用途”(CN103142576A),“丹酚酸A组合物用于制备脑血管内皮细胞药物的用途”(CN103083300A)等,从多方面证明了丹酚酸A的作用。然而,上述对于丹酚酸A的作用研究均为对于脑缺血后的治疗作用,未见丹酚酸A单纯预防脑缺血疾病和关注于预防脑缺血的同时预防脑出血疾病的相关研究报道。因此,本发明所述的丹酚酸A在制备预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病的药物中的应用是新发现的丹酚酸A的新用途。
发明内容
本发明解决的技术问题在于提供丹酚酸A在制备预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病的药物,,从而为预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病发生提供一种不良反应轻微的解决办法。
为此,本发明提供了如下技术方案:
本发明技术方案的一方面是提供了如式Ⅰ所示的丹酚酸A在制备预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病的药物中的应用,
所述预防血栓性脑缺血是指预防性给予丹酚酸A可以减少脑血栓的形成,降低急性脑缺血性卒中的发生率和慢性脑缺血的危害。
所述减少脑血栓形成是丹酚酸A预防给药通过保护脑血管,发挥对动脉血栓和静脉血栓形成的抑制作用,从而实现在制备预防血栓性疾病的药物中的应用。
所述保护脑血管是指丹酚酸A预防给药后对于血管内皮细胞和平滑肌功能和血脑屏障的完整性发挥保护作用。
所述的预防血栓性脑缺血合并脑出血相关疾病是包括预防脑栓塞发病后的出血性转化或由于血管功能破坏引起的脑血管出血。
所述的脑栓塞发病后的出血性转化是指在发病期间,缺血区及周边区域由于缺血后的血管损伤导致的梗死区的出血。
所述的脑出血包括单纯性脑出血性卒中、因脑缺血后自发性出血性转化或者使用预防脑血栓药物后引发的出血。所述的单纯性脑出血性卒中是指原发性非脑外伤性脑实质内血管破裂引起的出血。所述的使用预防脑血栓药物后引发的出血是指使用预防脑血栓药物后,引发的出血,如使用阿司匹林药物后引发的脑出血。
本发明技术方案的第二方面是提供了一种药物组合物在制备预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病的药物中的应用,其特征在于,所述的药物组合物包括式I所示的丹酚酸A和药学上可接受的载体或赋形剂,
所述预防血栓性脑缺血是指预防性给予丹酚酸A组合物可以减少脑血栓的形成,降低急性脑缺血性卒中的发生率和慢性脑缺血的危害。
所述减少脑血栓形成是丹酚酸A组合物预防给药通过保护脑血管,发挥对动脉血栓和静脉血栓形成的抑制作用,从而实现在制备预防血栓性疾病的药物中的应用。
所述预防血栓性脑缺血合并脑出血相关疾病是包括预防脑栓塞发病后的出血性转化或由于血管功能破坏引起的脑血管出血。
所述的药物组合物包括口服制剂,注射给药剂型,皮肤黏膜途经给药剂型。
所述的口服制剂包括片剂、缓释剂、胶囊剂、控释剂、滴丸剂、液体制剂;所述的注射给药剂型包括肌肉注射、静脉注射、静脉滴注。
进一步,所述丹酚酸A可与药学上可接受的辅料按常规制剂方法制成各种剂型的预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病的药物。
该组合物可根据本领域公知的方法制备。可通过发明所述丹酚酸A与一种或多种制药上可接受的固体或液体赋形剂和/或辅料组合,制成与人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-99%。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也可制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明化合物与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。本发明化合物药物组合物的给药剂量依照所要预防疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。一般来讲,本发明化合物每天的合适剂量范围为0.001-250mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
本发明的有益效果在于:采用大鼠电凝自身血栓移位法急性脑卒中模型,对丹酚酸A预防脑出血,脑血栓形成等作用,特别是脑缺血急性期防止脑栓塞发病后的出血性转化,保护脑血管内皮功能,血脑屏障的作用进行了考察,结果显示,在大鼠电凝自身血栓移位法急性脑卒中模型中,丹酚酸A预防给药能够改善神经功能,发挥神经保护作用,与阿司匹林相比降低脑出血的发生,减少血红蛋白在缺血脑组织中的渗出量,减少伊文思蓝在缺血脑组织中的渗出量,对于血脑屏障具有保护作用。可以预防脑缺血疾病的过程中预防出血转化发生或缓解出血程度,预防脑血栓的形成。所以为预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病提供了一种安全、有效、经济的解决办法。
附图说明
图1.丹酚酸A(10mg/kg)预防给药对大鼠体重及对脑缺血后大鼠的神经保护功能的影响。A—丹酚酸A预防给药对于大鼠体重的影响。B-脑缺血24h后,丹酚酸A对于mNSS评分的影响;C—脑缺血24h后,丹酚酸A对于Longa评分的影响;D—脑缺血24h后,丹酚酸A对于抓握能力的影响。###P<0.001和####P<0.0001与假手术组相比,*P<0.05和**P<0.01与模型组相比,n=10。
图2.丹酚酸A(10mg/kg)预防给药对急性脑卒中大鼠脑出血的影响。A—丹酚酸A对脑出血转化的影响;B—丹酚酸A对脑血红蛋白的影响;C—急性脑卒中大鼠脑组织苏木精-伊红染色。#P<0.05,##P<0.01与假手术组相比,^^P<0.05与阿司匹林组相比,n=10。
图3.丹酚酸A(10mg/kg)预防给药对急性脑卒中大鼠血管内皮功能的影响。A—脑组织中血管性血友病因子免疫组化结果(n=3);B—丹酚酸A对血清中血管性血友病因子的影响;C—丹酚酸A对血清中血管性血友病因子裂解酶的影响;D—丹酚酸A对脑组织中扣针蛋白的影响。###P<0.001和####P<0.0001与假手术组相比,*P<0.05,**P<0.01和***P<0.01vs与模型组相比,n=6。
图4.丹酚酸A(10mg/kg)预防给药对急性脑卒中大鼠血脑屏障的影响。A,B—丹酚酸A对伊文思蓝渗漏的影响;C-F—丹酚酸A对于闭锁连接蛋白-1、咬合蛋白、闭合蛋白-5蛋白表达的影响。#P<0.05,##P<0.01和###P<0.001与假手术组相比,*P<0.05,**P<0.01和***P<0.001与模型组相比,n=6。
图5.丹酚酸A对人脑微血管内皮细胞糖氧剥夺后细胞活力和紧密连接蛋白的影响。A—丹酚酸A共孵育对于糖氧剥夺后细胞活力的影响;B-E—丹酚酸A对于闭锁连接蛋白-1、咬合蛋白、闭合蛋白-5蛋白表达的影响。#P<0.05与对照组相比,*P<0.05与模型组相比,n=6。
具体实施方式
为使本发明的目的、技术方案、优点更加清楚,下面将结合附图对本发明作进一步的详细描述,其中:
实施例1.丹酚酸A(10mg/kg)预防给药对急性脑卒中大鼠的神经保护功能的影响。
实验材料:雄性SD大鼠,体重220~260g,购自维通利华(北京维通利华实验动物技术有限公司)。丹酚酸A粉末由中国医学科学院药物研究所国家药物筛选中心提供。阿司匹林购自美国Sigma公司。羧甲基纤维素钠购自国药集团化学试剂有限公司。
实验分组:SD大鼠共40只,每组10只,分别灌胃给予空白组0.5%羧甲基纤维素钠,阿司匹林100mg·kg-1和丹酚酸A 10mg·kg-1,早晚各1次,连续5天,第6天制备电凝自身血栓移位法脑缺血模型。
模型制备方法:大鼠用水合氯醛麻醉,取仰卧位固定。剪开颈部皮肤,钝性分离颈总动脉,颈内动脉与颈外动脉,用动脉夹夹闭颈外动脉。剥离颈总动脉,将其放入YLS-14B小动物血栓生成仪的血管电刺激夹的沟槽内,调整好高度和方向,使用1.00mA电流强度,预刺激1min,再持续电刺激4min。电刺激结束后,取下电击夹,使用动脉夹夹闭颈总动脉的远心端,使用长度为1cm的软质镊子夹动血栓,使其变为小块血栓,并见动脉恢复搏动并冲击碎栓,放开动脉夹,见到血栓进入颈内动脉后立即夹闭颈总动脉近心端15min,然后打开所有动脉夹,缝合大鼠颈部皮肤。模型组和预防给药组造模,假手术组只分离不电凝,其余步骤同手术组。脑缺血24h后,mNSS评分和Longa评分检测神经功能,抓握实验检测前肢肌力。
结果如图1所示,丹酚酸A预防给药期间并没有影响动物的体重增长。脑缺血后,丹酚酸A预防给药组显著降低脑缺血大鼠mNSS评分和Longa评分,并且前肢肌力也有所恢复。
实施例2.丹酚酸A(10mg/kg)预防给药对急性脑卒中大鼠脑出血的影响。
动物造模及给药方法同实施例1。脑缺血24h后,灌流取脑,冠状切片、拍照,取灌流后的脑组织匀浆,按血红蛋白检测试剂盒(DIHB-250,美国博世生物技术有限公司)说明书操作,在400nm处检测吸光度,计算脑组织内的血红蛋白含量。苏木素-伊红染色的组织储存在4%多聚甲醛溶液中,进行苏木素-伊红染色。
结果如图2所示,缺血后脑组织发生出血转化现象,阿司匹林预防给药组脑出血严重,而丹酚酸A预防给药组与阿司匹林组、模型组相比减少脑出血的发生并降低脑血红蛋白的含量。提示丹酚酸A预防给药可以预防脑出血的发生。
实施例3.丹酚酸A(10mg/kg)预防给药对急性脑卒中大鼠血管内皮功能的影响。
动物造模及给药方法同实施例1。脑缺血24h后,腹主动脉取血,室温静置2h后,1,000×g离心10min,利用ELISA的方法检测血清中血管性血友病因子(血管性血友病因子试剂盒购自Elabscience公司)和血管性血友病因子裂解酶(血管性血友病因子裂解酶试剂盒购自Novus公司)指标。
取缺血区脑组织蛋白,加入Ripa裂解液充分研磨裂解后,12000rpm,4℃离心15min,BCA法蛋白定量。将样品处理成等浓度等质量的样品。100℃变性10min放入-20℃冰箱待用。SDS-PAGE凝胶电泳,80v电压恒压电泳,至样品压齐,改为120v至marker分开。200mA恒流转膜,依据不同蛋白设定转膜时间。室温5%BSA封闭2h后孵育一抗。3%BSA配制一抗(扣针蛋白-5购自Abcam公司),4℃孵育一晚,TBST洗膜10min*3次,二抗(1:5000配制),室温孵育2h,TBST洗膜10min*3次,ECL(1:1配置)发光液检测。
结果如图3所示,丹酚酸A预防给药组与模型组相比降低脑组织和血清中血管性血友病因子的含量,增加血清中血管性血友病因子裂解酶的含量,同时降低脑组织中扣针蛋白表达,说明丹酚酸A预防给药对于血管内皮具有保护作用。
实施例4.丹酚酸A(10mg/kg)预防给药对急性脑卒中大鼠血脑屏障的影响。
动物造模及给药方法同实施例1。本实验以伊文思蓝(EB)在脑组织中的渗漏作为血脑屏障(BBB)损伤的指标。大鼠处死前2h尾静脉注射4%伊文思蓝(2ml/kg),灌流后取脑。按1:3加入50%三氯乙酸匀浆,离心后取上清测定其在620nm处的吸光度。Western Blot检测方法同实施例3(咬合蛋白抗体购自Abcam公司,闭合蛋白-5抗体购自Immunoway公司,闭锁连接蛋白-1抗体购自proteintech公司)。
结果如图4所示,各组中未缺血侧脑组织中EB的含量没有明显变化。脑缺血后EB含量显著增加,阿司匹林组与模型组相比EB含量无明显改变,而丹酚酸A预防给药组则明显降低EB含量。Western Blot检测紧密连接蛋白闭锁连接蛋白-1、咬合蛋白和闭合蛋白-5得到的结果与EB结果相一致。说明丹酚酸A预防给药对于血脑屏障具有保护作用。
实施例5.丹酚酸A对人脑微血管内皮细胞糖氧剥夺后细胞活力和紧密连接蛋白的影响。
实验材料:人脑微血管内皮细胞购自中国医学科学院基础医学研究所细胞中心,细胞培养基及其他溶液:RPMI Medium 1640(Gibco,USA),牛血清(Gibco,USA),无糖RPMIMedium 1640(Gibco,USA),胰蛋白酶/EDTA溶液(T/E,Cat.#0103)。
本实验采用人脑微血管内皮细胞,利用三气孵箱(O2 1%,CO2 5%,N2 94%)制备糖氧剥夺模型,缺氧时间为6h。
利用CCK8法检测细胞活力。在96孔板中每孔种100μL密度为5000个CELL/孔的细胞悬液。将培养板在培养箱预培养24h(在37℃,5%CO2的条件下)后向培养板加入10μL不同浓度的待测物质。将培养板在培养箱孵育6h,向每孔加入10μL CCK8溶液。将培养板继续在培养箱内孵育2h。用酶标仪测定在450nm处的吸光度。细胞存活率=【(实验孔吸光度-空白孔吸光度)/(对照孔吸光度-空白孔吸光度)】*100%。
Western Blot检测方法同实施例3,检测糖氧剥夺损伤后丹酚酸A对于紧密连接蛋白表达的影响。
结果如图5所示,糖氧剥夺6h后细胞活力及紧密连接蛋白表达量显著下降,共孵育丹酚酸A(10μmol·L-1)组细胞活力与模型组相比明显恢复,并且紧密连接蛋白表达量与模型组相比也有所回升。提示丹酚酸A对于糖氧剥夺损伤后紧密连接蛋白具有保护作用。
综上所述,本发明采用体内实验、体外实验,对丹酚酸A预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病药物的作用进行了考察。结果显示,体内实验中,在电凝自身血栓移位法制备的脑缺血大鼠模型中,丹酚酸A预防给药可以明显降低大鼠手术后mNSS评分,Longa评分,前肢肌力有所恢复,并且降低脑出血的发生,对于血脑屏障具有较好的保护作用。体外实验中,在糖氧剥夺损伤模型中通过共孵育丹酚酸A,细胞活力和紧密连接蛋白的表达量均有所恢复。说明丹酚酸A具有预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病的作用。以丹酚酸A为活性物质,单独使用或/与其他具有药理学活性的化合物和/或提取物组成复方使用,按照药学领域的常规制剂方法制成各种剂型的预防血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病的药物,或与其他预防脑出血,预防血栓形成药物等制成复方制剂,用于在保持疗效的情况下减少药物作用中的不良反应,可为血栓性脑缺血或血栓性脑缺血合并脑出血相关疾病的预防提供了一种安全、有效、经济的解决办法。
最后说明的是,以上实施例仅用于说明本发明的技术方案而非限制,尽管通过参照本发明的优选实施例已经对本发明进行了描述,但本领域普通技术人员应当理解,可以在形式上和细节上对其做出各种各样的改变,而不偏离所附权利要求书所限定的本发明的精神和范围。
Claims (12)
2.根据权利要求1的应用,其特征在于,所述预防血栓性脑缺血是指预防性给予丹酚酸A可以减少脑血栓的形成,降低急性脑缺血性卒中的发生率和慢性脑缺血的危害。
3.根据权利要求2的应用,其特征在于,丹酚酸A预防给药可以通过保护脑血管功能,发挥对动脉血栓和静脉血栓形成的抑制作用,从而实现在制备预防血栓性疾病的药物中的应用。
4.根据权利要求2的应用,其特征在于,所述保护脑血管是指丹酚酸A预防给药后对于血管内皮细胞和平滑肌功能和血脑屏障的完整性发挥保护作用。
5.根据权利要求1的应用,其特征在于,所述的预防血栓性脑缺血合并脑出血相关疾病是包括预防脑栓塞发病后的出血性转化或由于血管功能破坏引起的脑血管出血。
6.根据权利要求5的应用,其特征在于,所述的脑栓塞发病后的出血性转化是指在发病期间,缺血区及周边区域由于缺血后的血管损伤所导致的梗死区的出血。
7.根据权利要求1的应用,其特征在于,所述的脑出血包括单纯性脑出血性卒中、因脑缺血后自发性出血性转化或者使用预防脑血栓药物后引发的出血。
8.根据权利要求7的应用,其特征在于,所述的单纯性脑出血性卒中是指原发性非脑外伤性脑实质内血管破裂引起的出血。
9.根据权利要求7的应用,其特征在于,所述的使用预防脑血栓药物后引发的出血是指使用预防脑血栓药物后,引发的出血,如使用阿司匹林药物后引发的脑出血。
11.根据权利要求10应用,其特征在于,所述的药物组合物的剂型包括口服制剂,注射给药剂型,皮肤黏膜途经给药剂型。
12.根据权利要求10应用,其特征在于,所述的口服制剂包括片剂、缓释剂、胶囊剂、控释剂、滴丸剂、液体制剂,所述的注射给药剂型包括肌肉注射、静脉注射、静脉滴注。
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