CN114617896B - 一种连翘酯苷a在制备预防或治疗重症急性胰腺炎并发脑损伤的药物中的应用 - Google Patents
一种连翘酯苷a在制备预防或治疗重症急性胰腺炎并发脑损伤的药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种连翘酯苷A或其药用盐在制备预防或治疗重症急性胰腺炎并发脑损伤的药物中的应用。本发明不仅明确了连翘酯苷A具有抗重症急性胰腺炎并发脑损伤作用，而且为重症急性胰腺炎并发脑损伤临床治疗提供了新的手段。
Description
技术领域
本发明属于医药技术领域，具体涉及一种连翘酯苷A在制备预防或治疗重症急性胰腺炎并发脑损伤(胰性脑病)的药物中的应用。
背景技术
重症急性胰腺炎并发脑损伤(Severe acute pancreatitis-inducedbraininjury,SAP-IBI)，又称胰性脑病(Pancreatic encephalopathy,PE)，是重症急性胰腺炎(Severe acute pancreatitis,SAP)常见的并发症之一，主要表现为定向力障碍、意识模糊、幻觉等精神状态异常。国内学者近年来对PE报道逐渐增加，其发病率占同期的9％～20％，病死率达67.00％～100％[[1]Lv Y,Jing G,Zhu G,Luo H,Li B,Xie Y,Li C,WangX.Effects and mechanism of the etanercept on pancreatic encephalopathy[J].MolMed Rep 2020；21(6):2615-2623.doi:10.3892/mmr.2020.11062.[2]Albacete RódenasP,Ortiz Sánchez ML,Gajownik U,Alberca de Las Parras F,Pons JA.Pancreatic encephalopathy,a little-known complication of acutepancreatitis[J].Rev Esp Enferm Dig 2021；doi:10.17235/reed.2021.8241/2021.[3]Wang X,Chu L,Liu C,Wei R,Xue X,Xu Y,Wu M,Miao Q.Therapeutic effects ofSaussurea involucrata injection against severe acute pancreatitis-inducedbrain injury in rats[J].Biomed Pharmacother 2018；100C:564-574.doi:10.1016/j.biopha.2018.02.044.]。如何对SAP-IBI进行有效保护和治疗是近年研究的热点。
连翘是木犀科植物连翘(Forsythia suspense(Thunb.)Vahl)的干燥果实，成熟时期7-8月，主要分布于华北黄土高原，生于海拔250～2200m山坡灌丛、林下或草丛中[[4]田丁,史梦琪,王赟.连翘挥发油化学成分及其药理作用研究进展[J].天然产物研究与开发,2018,30(10):1834-1842.[5]李敬,尤颖,赵庆生,周佳欣.连翘叶成分及生物活性研究进展[J].食品工业科技,2020,41(18):344-352.]。连翘是我国传统中药，始载于《神农本草经》，为“疮家要药”，味苦，性微寒，归肺、心、小肠经[[6]冯治朋,高秀强,韩颜超,王芳芳,周盛茂,姜永新,王保琼,田清存,崔旭盛.连翘的研究进展[J].现代农业科技,2018,2018(12):61-62,64.[7]杜会枝,马红.连翘对神经系统的药理作用研究进展[J].中国药学杂志,2021,56(7):526-530.]。祖国医学认为，连翘具有疏散风热、清热解毒、消肿散结等诸多功效。现代药理学证明连翘具有解热镇痛、抗炎、抗菌、抗病毒、抗氧化、保护心脑血管系统、抗肿瘤、保肝、利胆、调节免疫、镇吐止呕、利尿降压、降血脂等广泛药理作用[[8]齐丽娜,陈炫好,金华,李晋,何俊,常艳旭.中药连翘化学成分及药理活性研究进展[J].天津中医药大学学报,2021,40(2):168-175.]。连翘的主要成份有连翘苷、连翘酯苷类、白桦脂酸、齐墩果酸、熊果酸、香豆素类等成分。其中连翘酯苷类又有连翘酯苷A、B、C、D等成份。Chen等[[9]Chen T,Li Y,Zhang L.Nine different chemical species and action mechanisms ofpancreatic lipase ligands screened out from forsythia suspensa leaves all atone time[J].Molecules 2017；22(5):795.doi:10.3390/molecules22050795.]研究发现，连翘酯苷A(Forsythoside A，FA)具有抑制胰脂肪酶活性的作用。
范晓彬等[[10]范晓彬,李文星,陈炳合,熊泽翼,段吉明.连翘对重症急性胰腺炎大鼠肝组织中NF-κB和Foxp3表达的影响[J].临床肝胆病杂志，2013,29(7):503-507.]研究发现核因子-κB(Nuclear factor-κB,NF-κB)的激活参与了SAP相关性肝损伤的发生，而连翘能显著降低NF-κB的活性及肝脏组织中NF-κB信使核糖核(Message ribonucleic acid,mRNA)和叉头状螺旋转录因子(Forkhead/winged helix transcription factor,Foxp3)mRNA的表达，从而减轻SAP相关性肝损伤的严重程度。但其中哪些化学成分起着防治SAP相关性肝损伤作用未见相关文献报道。
FA是从连翘中提取的最为重要的有效活性成分之一，是一种中药单体，化学分子式为C29H36O15，相对分子质量为624.59，为白色结晶粉末，易溶于水、乙醇、甲醇难溶于乙醚、氯仿[[11]Gong L,Zhou H,Wang C,He L,Guo C,Peng C,Li Y.Hepatoprotective effectof forsythiaside a against acetaminophen-induced liver injury in zebrafish:Coupling network pharmacology with biochemical pharmacology[J].JEthnopharmacol 2021；271:113890.doi:10.1016/j.jep.2021.113890.]。中药单体优势在于其不同于中药粗提物和中药复方，其具有明确的分子量及物理和化学特性，容易进行定量和定性分析，因此在其制备过程中能严格管控技术问题和质量要求，从而使得中药中的有效成分高度浓缩，提高药物在体内的吸收，发挥最佳疗效[[12]刘畅,夏士林,尚东.中药单体治疗急性胰腺炎的研究进展[J].辽宁中医杂志,2018,45(10):2232-2236.]。
马忠英等[[13]马忠英,张迪,孙金,牛静,任茜,武倩雯,王婧雯.连翘酯苷A通过TLR4/NF-κB抑制PC12细胞低氧/再复氧诱导的炎症反应[J].安徽医科大学学报,2021,56(5):730-734.]研究发现：FA可通过调控Toll样受体4(Toll Like Receptor 4,TLR4)抑制NF-κB p65核转移抑制炎症因子(IL-1β、tumor necrosis factor-α(TNF-α)及IL-6等)表达，从而减轻缺血再灌注诱导的炎症反应，发挥脑保护作用。Wang等[[14]Wang Y,Zhao H,Lin C,Ren J,Zhang S.Forsythiaside A exhibits anti-inflammatory effects inLPS-stimulated BV2 microglia cells through activation ofNrf2/HO-1signalingpathway[J].Neurochem Res 2016；41(4):659-665.doi:10.1007/s11064-015-1731-x.]研究发现FA可抑制由脂多糖(Lipopolysaccharide,LPS)刺激的BV2小胶质细胞产生TNF-α、IL-1β、前列腺素E2(Prostaglandin E2,PGE2)和一氧化氮(Nitric oxide,NO)等炎症因子。FA的抗炎机制是通过抑制NF-κB激活及激活核因子E2 p45相关因子2(Nuclear factor-erythroid 2p45-related factor 2,Nrf2)/血红素氧合酶-1(Heme oxygenase-1,HO-1)信号通路实现的。Lu等[[15]Lu C,Zheng SF,Liu J.Forsythiaside A alleviates renaldamage in adriamycin-induced nephropathy[J].Front Biosci(Landmark Ed)2020；25:526-535.doi:10.2741/4818.]研究发现，FA以剂量依赖性方式降低肾脏中NF-κB p65/巨噬细胞炎症蛋白-2(Macrophage inflammatory protein-2,MIP-2)的水平，降低促炎细胞因子(IL-6、IL-1β及TNF-α)的血清水平，并提高了阿霉素处理小鼠的存活率。FA减轻了阿霉素诱导的肾病小鼠的肾功能障碍。Zhang等[[16]Zhang J,ZhangY,Huang H,Zhang H,Lu W,FuG,ZhuY.Forsythoside A inhibited S.aureus stimulated inflammatory response inprimary bovine mammary epithelial cells[J].Microb Pathog 2018；116:158-163.doi:10.1016/j.micpath.2018.01.002.]研究发现，FA抑制了金黄色葡萄球菌(Staphylococcus aureus,S.aureus)刺激的牛乳腺上皮细胞中TNF-α、IL-1β及IL-6的表达。FA可以通过抑制S.aureus诱导的丝裂原活化蛋白激酶(Mitogen-activated proteinkinase,MAPK)和NF-κB信号通路的激活来减轻炎症反应。Tong等[[17]Tong C,Chen T,ChenZ,Wang H,Wang X,Liu F,Dai H,Wang X,Li X.Forsythiaside A plays an anti-inflammatory role in LPS-induced mastitis in a mouse model by modulating theMAPK and NF-κB signalingpathways[J].Res Vet Sci 2021；136:390-395.doi:10.1016/j.rvsc.2021.03.020.]研究发现，FA减轻了LPS刺激的乳腺炎的炎症反应。此外，FA抑制了LPS上调的促炎症介质(TNF-α,IL-6及IL-1β)的产生。FA通过抑制p38 MAPK/NF-κB信号通路抑制促炎介质的产生，从而减轻LPS在小鼠乳腺中诱导的炎症反应，保护小鼠乳腺组织。
发明内容
本发明的目的是提供一种连翘酯苷A在制备预防或治疗重症急性胰腺炎并发脑损伤(胰性脑病)的药物中的应用。
为了实现上述目的，本发明采用的技术方案如下：
本发明的第一方面提供了一种连翘酯苷A或其药用盐在制备预防或治疗重症急性胰腺炎并发脑损伤(胰性脑病)的药物中的应用。
所述连翘酯苷A的结构[[18]Ma T,Shi YL,Wang YL.Forsythiaside Aprotectsagainst focal cerebral ischemic injury by mediating the activation ofthe Nrf2and endoplasmic reticulum stress pathways[J].Mol Med Rep 2019；20(2):1313-1320.doi:10.3892/mmr.2019.10312.]如下所示：
所述预防或治疗重症急性胰腺炎并发脑损伤(胰性脑病)的药物是指连翘酯苷A或其药用盐作为单一活性成分。
所述连翘酯苷A作为单一活性成分的重量含量为0.1％～99.9％。
所述药物的剂型为注射剂、胶囊剂、片剂、颗粒剂、丸剂、微囊微球制剂。
所述药物的给药方式为口服、注射。
所述重症急性胰腺炎并发脑损伤(胰性脑病)是重症急性胰腺炎的严重并发症之一，临床表现为急剧上腹痛等急腹症表现合并定向力障碍、激动、妄想、意识模糊及幻觉等异常精神状态，神经表现为痉挛、震颤、失语等。重症急性胰腺炎并发脑损伤其病死率明显增加。其发病机制目前较为公认的理论是胰酶激活、细胞因子作用学说。重症急性胰腺炎发作时，大量胰蛋白酶、脂肪酶、弹力蛋白酶和磷脂酶A等激活释放入血，其中磷脂酶A2(PLA2)在其发病中的作用最为关键。PLA2进入脑组织可引起脑膜血管扩张出血、脑内微血管充血、脑实质炎性细胞浸润以及脑组织水肿、出血及软化。重症急性胰腺炎发作时大量炎性细胞因子如TNF-α、IL等释放入血，进而通过瀑布样炎症级联反应引起全身炎症反应综合征，导致多脏器功能损伤，其中TNF-α、IL等破坏血脑屏障、增加血脑屏障通透性、损伤脑组织。目前该病仍缺乏有效治疗方法，治疗方法多为对重症急性胰腺炎原发病的治疗及对神经系统症状的对症处理，缺乏标本兼治手段。
由于采用上述技术方案，本发明具有以下优点和有益效果：
本发明提供了连翘酯苷A在制备预防或治疗重症急性胰腺炎并发脑损伤(胰性脑病)的药物中的应用，研究发现连翘酯苷A具有显著的抗重症急性胰腺炎并发脑损伤(胰性脑病)的作用。本发明经动物实验证明：采用3.5％牛磺胆酸钠逆行胰胆管注射诱发重症急性胰腺炎并发脑损伤(胰性脑病)小鼠模型实验，发现连翘酯苷A可显著降低小鼠血清中PLA2、TNF-α及IL-6含量，而显著升高IL-10含量，改善胰腺和脑组织病理损伤、降低脑组织含水量，降低小鼠神经功能评分，具有良好的抗重症急性胰腺炎并发脑损伤(胰性脑病)作用，因此连翘酯苷A对重症急性胰腺炎并发脑损伤(胰性脑病)可以起防治或治疗作用。
本发明不仅明确了连翘酯苷A具有抗重症急性胰腺炎并发脑损伤(胰性脑病)作用，而且为重症急性胰腺炎并发脑损伤(胰性脑病)临床治疗提供了新的手段。
附图说明
图1是3.5％牛磺胆酸钠造模给药后24h胰腺组织HE(HE×200)假手术组(SO组)的染色图。
图2是3.5％牛磺胆酸钠造模给药后24h胰腺组织HE(HE×200)重症急性胰腺炎并发脑损伤(胰性脑病)模型组(SAP-IBI组)的染色图。
图3是3.5％牛磺胆酸钠造模给药后24h胰腺组织HE(HE×200)小剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAL+SI组)的染色图。
图4是3.5％牛磺胆酸钠造模给药后24h胰腺组织HE(HE×200)中剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAM+SI组)的染色图。
图5是3.5％牛磺胆酸钠造模给药后24h胰腺组织HE(HE×200)大剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAH+SI组)的染色图。
图6是3.5％牛磺胆酸钠造模给药后24h脑组织HE(HE×200)假手术组(SO组)染色图。
图7是3.5％牛磺胆酸钠造模给药后24h脑组织HE(HE×200)重症急性胰腺炎并发脑损伤(胰性脑病)模型组(SAP-IBI组)染色图。
图8是3.5％牛磺胆酸钠造模给药后24h脑组织HE(HE×200)小剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAL+SI组)染色图。
图9是3.5％牛磺胆酸钠造模给药后24h脑组织HE(HE×200)中剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAM+SI组)染色图。
图10是3.5％牛磺胆酸钠造模给药后24h脑组织HE(HE×200)大剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAH+SI组)染色图。
图11是3.5％牛磺胆酸钠造模给药后24h脑组织假手术组(SO组)透射电镜图。
图12是3.5％牛磺胆酸钠造模给药后24h脑组织重症急性胰腺炎并发脑损伤(胰性脑病)模型组(SAP-IBI组)透射电镜图。
图13是3.5％牛磺胆酸钠造模给药后24h脑组织小剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAL+SI组)透射电镜图。
图14是3.5％牛磺胆酸钠造模给药后24h脑组织中剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAM+SI组)透射电镜图。
图15是3.5％牛磺胆酸钠造模给药后24h脑组织大剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAH+SI组)透射电镜图。
图16是胰腺组织病理学评分结果的柱状图。
图17是脑组织病理学评分结果的柱状图。
图18是脑组织含水量结果的柱状图。
图19是各组血清TNF-α含量结果的柱状图。
图20是各组血清IL-6含量结果的柱状图。
图21是各组血清IL-10含量结果的柱状图。
图22是各组血清磷脂酶A2(PLA2)结果的柱状图。
图23是各组神经功能评分结果的柱状图。
具体实施方式
为了更清楚地说明本发明，下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
实施例1
连翘酯苷A对3.5％牛磺胆酸钠逆行胰胆管注射诱发重症急性胰腺炎并发脑损伤(胰性脑病)模型小鼠的治疗作用
1材料与方法
1.1研究对象和实验试剂
选择健康雄性C57BL/6小鼠，体质量22～25g，鼠龄8-10w，购自南通大学实验动物中心，实验动物生产许可证号：SCXK(浙)2019-0001，实验动物使用许可证号为SYXK(苏)2017-0046，实验动物合格证号为20211125Abzz0619000560。实验动物饲养环境为SPF级，按照我国实验动物饲养环境要求，保持饲养环境通风良好，保持室温在21～23℃，相对湿度在45％～55％，室内明暗交替各12h，实验小鼠自由进食和饮水，3～4只/笼饲养。95％牛磺胆酸钠购自美国Sigma公司，TNF-α、IL-6及IL-10酶联免疫吸附试验(ELISA)试剂盒购自南京建成生物工程研究所。FA购自AMEKO life Sciences，编号：AB20727，规格：20mg，分析标准品，HPLC≥98％。
1.2实验分组及各组处理
本实验设置假手术组(SO)组；重症急性胰腺炎并发脑损伤(胰性脑病)模型(SAP-IBI)组；小剂量连翘酯苷A(FA)处理SAP-IBI(FAL+SI)组；中剂量FA处理SAP-IBI(FAM+SI)组；大剂量FA处理SAP-IBI(FAH+SI)组，共5组，每组10只小鼠。FA的用药剂量根据前期药物毒性试验结果得出。
A、SO组：小鼠采用与SAP-IBI组小鼠相同的麻醉和开腹操作。进腹后，翻动十二指肠并触摸胰腺数次。
B、SAP-IBI组：采用逆行胰胆管注射3.5％牛磺胆酸钠的方式建立小鼠SAP-IBI模型，参照程振兴等[[19]程振兴,唐忠明,余卫平,张南,郑曙云,欧希龙.一种小鼠胆源性重症急性胰腺炎模型建立方法的改进[J].中华危重病急救医学,2016,28(4):308-313.]的方法建立模型，具体操作如下：实验小鼠术前禁食8h，自由饮水。腹腔内注射10％水合氯醛(10mL/kg)麻醉小鼠后，于剑突下开腹0.5cm，然后用经钝化处理的眼科镊提出十二指肠降部于切口外，见到十二指肠包绕的粉色胰腺组织，肉眼观察胆总管走向及其在十二指肠降段开口位置，用8-0带针缝合线在胰头紧贴肠壁部呈“U”型穿过胆总管并打一不收紧的单结；左手食指垫在十二指肠降部下方，于胆总管开口处对侧肠壁无血管区用胰岛素注射器针头(31G)轻戳一小孔，然后将带有导管的金属针头循此孔插入肠腔，圆润的针头即可在胆总管开口大致位置无损伤地滑入胆总管内且脱空感明显。针头进入约3mm收紧单结并打3个叠结固定。导管固定后用微型动脉夹夹闭肝门处胰胆管，防止胰胆管注射液体向肝脏反流。由微量泵控制注入新鲜配制的3.5％牛磺胆酸钠1mL/kg，输注时间维持5min，输注完毕保留装置5min，可见胰腺组织逐渐出现鲜红色片状出血表现。松开微型动脉夹，拆除固定缝线并退出针头，用8-0缝线关闭肠壁穿刺孔，两层关腹。术后将小鼠放置保温毯内，同时背部皮下注射生理盐水20mL/kg复苏。此模型为经典小鼠SAP-IBI模型，研究证实，3.5％牛磺胆酸钠胰胆管注射后6h，出现脑损伤，即SAP-IBI建模成功。
C、FAL+SI组：建模方法同SAP-IBI组，建模(3.5％牛磺胆酸钠胰胆管注射后)即给予腹腔注射FA 20mg/kg。
D、FAM+SI组：建模方法同SAP-IBI组，建模(3.5％牛磺胆酸钠胰胆管注射后)即给予腹腔注射FA 40mg/kg。
E、FAH+SI组：建模方法同SAP-IBI组，建模(3.5％牛磺胆酸钠胰胆管注射后)即给予腹腔注射FA 80mg/kg。
各组分别于SAP-IBI建模(3.5％牛磺胆酸钠胰胆管注射后)24h，处死各组存活小鼠。收集各组存活小鼠的血液样本、胰腺及脑组织标本进行后续检测。
1.3各组存活率的比较
SAP-IBI建模(3.5％牛磺胆酸钠胰胆管注射后)24h，统计各组小鼠的存活只数，计算各组存活率，进行各组小鼠存活率两两比较。
1.4胰腺组织苏木素-伊红(HE)染色
取各组小鼠胰腺组织，浸入4％多聚甲醛溶液中进行固定。取出组织块用流水冲洗后，依次放入70％酒精2h、80％酒精过夜、90％酒精2h、100％酒精1h进行脱水处理。然后将组织块依次浸入二甲苯、二甲苯和石蜡混合物、石蜡中，进行石蜡包埋。用切片机将样本蜡块切成5μm的薄片，并铺展至载玻片上。烘干后取出切片，放入二甲苯中浸泡15min脱蜡。然后将切片依次放入95％、85％、75％酒精中浸泡2min。切片经蒸馏水洗涤后放入苏木素溶液中染色5min，经蒸馏水洗涤后放入1％盐酸酒精中3s。取出切片用蒸馏水洗涤，然后放入伊红染液染色3min。取出切片，擦干液体，封片后盖在盖玻片上，室温晾干。显微镜下观察并拍照。
1.5胰腺组织病理学评分
胰腺组织切片HE染色后，采用盲法由专科医师在光镜下阅片，每张切片随机选择10个高倍视野(×200)，观察胰腺组织病理变化，参照Schmidt等[[20]Schmidt J,RattnerDW,Lewandrowski K,et al.A better model of acute pancreatitis for evaluatingtherapy[J].Ann Surg,1992:215(1):44-56.]镜下病理评分法进行评分(水肿、炎症、腺细胞坏死每项0～4分，出血为0～1分，4项总分为13分，见表1)。
表1 SAP胰腺局部病变光镜下评分标准
1.6脑组织HE染色
具体方法同胰腺组织苏木素-伊红(HE)染色。
1.7透射电镜观察各组小鼠脑组织细胞超微结构
取各组小鼠脑组织，在3％的戊二醛固定2h。取出后，用磷酸缓冲液清洗3次，每次5min。将样本放入2％的锇酸中固定2h，然后用磷酸缓冲液清洗3次，每次5min。之后将样本依次浸入50％、70％、80％、90％的梯度乙醇中脱水，在浓度乙醇中浸泡15min，最后在100％乙醇中脱水30min。然后将样本浸入环氧丙烷中置换3次，每次30min。将样本依次浸入丙酮和包埋剂(环氧树脂)的混合物中，每次浸渍10h。将样本置于包埋剂中进行包埋。将样本切成50nm厚的薄片并进行铀染色，清洗后，在电镜下观察并拍照。
1.8脑组织病理学评分
采用盲法行光镜及透射电镜观察，对神经元、胶质细胞、髓鞘和血管分别作组织学评分[[21]孔雷,韩天权,于颖彦,等.胰酶、细胞因子、高渗液和感染对大鼠脑损伤的形态学研究[J].胰腺病学,2004,4(2):98-101.](见表2)。总分12分。
表2脑组织损伤评分标准
1.9脑组织含水量测定
将脑组织从液氮中取出后置于秤量杯中用电子天平秤出脑湿重，然后置于真空恒温干燥箱，100℃烘烤24h称干重，并计算脑组织含水量，脑组织含水量＝(湿重-干重)÷湿重×100％。
1.10血清磷脂酶A2(PLA2)、TNF-α、IL-6及IL-0含量测定
采用陈氏法[[22]陈思锋,吴中立.体液和组织磷脂酶A2简便快速测定法[J].第二军医大学学报,1989,10(3):254-256.]测定血清PLA2含量：采用盐酸滴定法测定，规定在37℃，每分钟每毫升样本反应消耗1nmol/L盐酸为1个PLA2活性单位(U)；采用ELISA法检测血清TNF-α、IL-6及IL-10含量，严格按试剂盒说明进行操作，试剂盒购自南京建成生物工程研究所。
1.11各组小鼠神经功能评分
采用改良神经功能缺损评分(mNSS)对各组存活小鼠进行神经功能评价，评分项目由运动功能、平衡功能、感觉功能、反射功能及异常体征(癫痫、肌痉挛、肌张力障碍)组成评分系统[[23]Gold EM,Su D,López-Velázquez L,Haus DL,Perez H,Lacuesta GA,Anderson AJ,Cummings BJ.Functional assessment of long-term deficits in rodentmodels of traumatic brain injury[J].Regen Med.2013；8(4):483-516.doi:10.2217/rme.13.41.]，见表3。得分越高则表示神经功能缺损情况越严重，总得分最低为0分，提示小鼠完全正常，没有神经功能缺陷，最高为18分，提示小鼠意识丧失或死亡。不能执行任务或反射缺乏加1分，13-18分为重度损伤，7-12分为中度损伤，1-6分为轻度损伤。
表3改良神经功能缺损评分表(mNSS)
1.12统计学方法
使用SAS 8.1统计软件。计量资料数据以表示，采用单因素方差分析对各组均数差异进行检验，组间多重比较采用最小显著差异(Least significant difference,LSD)法，P<0.05为差异有统计学意义。
2.结果
2.1小鼠24h存活率：SO组小鼠全部存活，存活率100％；SAP-IBI组小鼠存活5只，存活率50％；FA L+SI组小鼠存活6只，存活率60％；FAM+SI组小鼠存活7只，存活率70％；FAH+SI组存活8只，存活率80％。
胰腺组织苏木素-伊红(HE)染色的结果如图1～图5所示，图1是3.5％牛磺胆酸钠造模给药后24h胰腺组织HE(HE×200)假手术组(SO组)的染色图。图2是3.5％牛磺胆酸钠造模给药后24h胰腺组织HE(HE×200)重症急性胰腺炎并发脑损伤(胰性脑病)模型组(SAP-IBI组)的染色图。图3是3.5％牛磺胆酸钠造模给药后24h胰腺组织HE(HE×200)小剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAL+SI组)的染色图。图4是3.5％牛磺胆酸钠造模给药后24h胰腺组织HE(HE×200)中剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAM+SI组)的染色图。图5是3.5％牛磺胆酸钠造模给药后24h胰腺组织HE(HE×200)大剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAH+SI组)的染色图。图1中SO组胰腺组织未见明显病理改变，图2中SAP-IBI组、图3中FA L+SI组可见胰腺腺泡水肿、脂肪液化、间质增宽、小叶间隙增大、中性粒细胞浸润，胰腺局灶或片状出血坏死、细胞溶解、出血、坏死和小叶轮廓损伤等程度不等的病理学改变，图4中FAM+SI组、图5中FAH+SI组病理损伤程度较图2SAP-IBI组减轻。
脑组织HE染色的结果如图6～图10所示，图6是3.5％牛磺胆酸钠造模给药后24h脑组织HE(HE×200)假手术组(SO组)染色图。图7是3.5％牛磺胆酸钠造模给药后24h脑组织HE(HE×200)重症急性胰腺炎并发脑损伤(胰性脑病)模型组(SAP-IBI组)染色图。图8是3.5％牛磺胆酸钠造模给药后24h脑组织HE(HE×200)小剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAL+SI组)染色图。图9是3.5％牛磺胆酸钠造模给药后24h脑组织HE(HE×200)中剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAM+SI组)染色图。图10是3.5％牛磺胆酸钠造模给药后24h脑组织HE(HE×200)大剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAH+SI组)染色图。图6中SO组脑组织未见明显病理改变，图7中SAP-IBI组、图8中FA L+SI组、图9中FAM+SI组脑组织可见多发性神经细胞增大伴气球样变、小血管和毛细血管充血、多灶性毛细血管扩张和出血、血管周围水肿、间质炎症细胞浸润和微血管白细胞附壁等程度不等的病理学改变，图10中FAH+SI组病理损伤程度较图7中SAP-IBI组减轻。
透射电镜观察各组小鼠脑组织细胞超微结构的结果如图11～图15所示，图11是3.5％牛磺胆酸钠造模给药后24h脑组织假手术组(SO组)透射电镜图。图12是3.5％牛磺胆酸钠造模给药后24h脑组织重症急性胰腺炎并发脑损伤(胰性脑病)模型组(SAP-IBI组)透射电镜图。图13是3.5％牛磺胆酸钠造模给药后24h脑组织小剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAL+SI组)透射电镜图。图14是3.5％牛磺胆酸钠造模给药后24h脑组织中剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAM+SI组)透射电镜图。图15是3.5％牛磺胆酸钠造模给药后24h脑组织大剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(FAH+SI组)透射电镜图。图11中SO组脑组织透射电镜下未见明显病理改变，图12中SAP-IBI组、图13中FA L+SI组、图14中FAM+SI组脑组织透射电镜下可见染色质边集、核仁缺失、细胞质水肿、细胞内容物含量减少、细胞核固缩、线粒体肿胀、空泡变性、核膜破裂、间质水肿和脱髓鞘等程度不等的病理学改变，图15中FAH+SI组病理损伤程度较图12中SAP-IBI组减轻。
2.2各组胰腺组织、脑组织病理学评分及脑组织含水量比较
(1)胰腺组织病理学评分结果见图16所示，图16是胰腺组织病理学评分结果的柱状图。从图中可以看出，SAP-IBI组胰腺组织病理学评分明显高于SO组(P<0.01)，FAM+SI组、FAH+SI组胰腺组织病理学评分均显著低于SAP-IBI组(P<0.05)，见表4。
(2)脑组织病理学评分见图17所示，图17是脑组织病理学评分结果的柱状图。从图中可以看出，SAP-IBI组脑组织病理学评分明显高于SO组(P<0.01)，FAH+SI组脑组织病理学评分显著低于SAP-IBI组(P<0.01)，见表4。
(3)脑组织含水量见图18所示，图18是脑组织含水量结果的柱状图。从图中可以看出，SAP-IBI组脑组织含水量明显高于SO组(P<0.01)，FAH+SI组脑组织含水量显著低于SAP-IBI组(P<0.01)，见表4。
表4各组胰腺组织、脑组织病理学评分及脑组织含水量比较
| 分组 | 只数 | 胰腺组织病理学评分(分) | 脑组织病理学评分(分) | 脑组织含水量(％) |
| SO组 | 10 | 1.000±0.667B | 1.100±0.738B | 75.50±0.845B |
| SAP-IBI组 | 5 | 11.40±0.548A | 10.20±0.837A | 80.30±0.570A |
| FAL+SI组 | 6 | 11.00±0.632A | 10.00±0.894A | 79.93±0.579A |
| FAM+SI组 | 7 | 10.57±0.535A,B1 | 9.714±0.951A | 79.69±0.687A |
| FAH+SI组 | 8 | 7.375±0.744A,B | 5.625±0.916A,B | 78.34±0.835A,B |
注：与SO组比较，AP<0.01；与SAP-IBI组比较，B1P<0.05，BP<0.01.SO组：假手术组；SAP-IBI组：重症急性胰腺炎并发脑损伤(胰性脑病)模型组；FAL+SI组：小剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(给予连翘酯苷A20 mg/kg)；FA M+SI组：中剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(给予连翘酯苷A 40mg/kg)；FAH+SI组：大剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(给予连翘酯苷A 80mg/kg)。
由表4可见，模型组中的胰腺组织病理学评分、脑组织病理学评分及脑组织含水量都显著高于假手术组，证明建模成功，随着连翘酯苷A给药剂量的增大，高剂量连翘酯苷A(80mg/kg)处理重症急性胰腺炎并发脑损伤(胰性脑病)组的胰腺组织病理学评分、脑组织病理学评分及脑组织含水量均较模型组显著降低，并结合图1～15，说明连翘酯苷A对重症急性胰腺炎并发脑损伤(胰性脑病)具有保护和治疗作用，可以作为保护和治疗重症急性胰腺炎并发脑损伤(胰性脑病)的药物使用。
2.3各组血清TNF-α、IL-6及IL-10含量比较
结果如图19～21所示，图19是各组血清TNF-α含量结果的柱状图。图20是各组血清IL-6含量结果的柱状图。图21是各组血清IL-10含量结果的柱状图。从图中可以看出，SAP-IBI组血清TNF-α、IL-6、IL-10含量明显高于SO组(P<0.01)，FAH+SI组血清TNF-α、IL-6水平显著低于SAP-IBI组(P<0.01)，而IL-10含量则显著高于SAP-IBI组(P<0.01)，见表5。
表5各组血清TNF-α、IL-6及IL-10含量比较/>
| 分组 | 只数 | 血清TNF-α(pg/mL) | 血清IL-6(pg/mL) | 血清IL-10(pg/mL) |
| SO组 | 10 | 114.5±14.15B | 104.8±11.43B | 32.46±5.190B |
| SAP-IBI组 | 5 | 346.0±44.71A | 548.4±45.24A | 100.6±9.610A |
| FAL+SI组 | 6 | 337.7±49.25A | 534.7±37.60A | 104.8±11.27A |
| FAM+SI组 | 7 | 329.9±52.91A | 528.5±39.81A | 108.8±7.900A |
| FAH+SI组 | 8 | 231.4±28.84A,B | 348.0±47.52A,B | 150.1±14.50A,B |
注：与SO组比较，AP<0.01；与SAP-IBI组比较，BP<0.01。注：与SO组比较，AP<0.01；与SAP-IBI组比较，B1P<0.05，BP<0.01。SO组：假手术组；SAP-IBI组：重症急性胰腺炎并发脑损伤(胰性脑病)模型组；FAL+SI组：小剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(给予连翘酯苷A 20mg/kg)；FAM+SI组：中剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(给予连翘酯苷A 40mg/kg)；FA H+SI组：大剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(给予连翘酯苷A 80mg/kg)。
由表5可见，连翘酯苷A可显著降低重症急性胰腺炎并发脑损伤(胰性脑病)小鼠血清中TNF-α、IL-6的含量，但能显著升高重症急性胰腺炎并发脑损伤(胰性脑病)小鼠血清IL-10的含量，说明连翘酯苷A能调节重症急性胰腺炎并发脑损伤(胰性脑病)血清炎症因子释放，说明连翘酯苷A具有抑制重症急性胰腺炎并发脑损伤(胰性脑病)小鼠炎症反应的作用。
2.4各组血清磷脂酶A2(PLA2)含量及神经功能评分
结果如图22和23所示，图22是各组血清磷脂酶A2(PLA2)结果的柱状图。图23是各组神经功能评分结果的柱状图。从图中可以看出，SAP-IBI组血清PLA2含量、神经功能评分明显高于SO组(P<0.01)，而FA H+SI组血清PLA2含量及神经功能评分则显著低于SAP-IBI组(P<0.01)，见表6。
表6各组血清PLA2含量及神经功能评分比较
| 分组 | 只数 | 血清PLA2(U) | 神经功能评分(分) |
| SO组 | 10 | 87.20±8.496B | 0.500±0.527B |
| SAP-IBI组 | 5 | 335.2±38.56A | 13.80±0.837A |
| FAL+SI组 | 6 | 314.8±27.59A | 13.50±1.049A |
| FAM+SI组 | 7 | 310.9±19.06A | 13.29±0.951A |
| FAH+SI组 | 8 | 183.8±20.49A,B | 8.625±1.061A,B |
注：与SO组比较，AP<0.01；与SAP-IBI组比较，BP<0.01.注：与SO组比较，AP<0.01；与SAP-IBI组比较，B1P<0.05，BP<0.01。SO组：假手术组；SAP-IBI组：重症急性胰腺炎并发脑损伤(胰性脑病)模型组；FAL+SI组：小剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(给予连翘酯苷A 20mg/kg)；FAM+SI组：中剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(给予连翘酯苷A 40mg/kg)；FAH+SI组：大剂量连翘酯苷A处理重症急性胰腺炎并发脑损伤(胰性脑病)组(给予连翘酯苷A 80mg/kg)。
由表6可见，连翘酯苷A可显著降低重症急性胰腺炎并发脑损伤(胰性脑病)小鼠磷脂酶A2(PLA2)含量及神经功能评分的作用，其中PLA2是参与重症急性胰腺炎并发脑损伤(胰性脑病)发生发展重要的胰酶。说明连翘酯苷A能有效保护和治疗重症急性胰腺炎并发脑损伤(胰性脑病)，可以作为保护和治疗重症急性胰腺炎并发脑损伤(胰性脑病)的药物使用。
以上实验结果表明，连翘酯苷A具有保护和治疗重症急性胰腺炎并发脑损伤(胰性脑病)的作用，可以作为保护和治疗重症急性胰腺炎并发脑损伤(胰性脑病)的药物使用。
以上所述仅是本发明的较佳实施例而已，并非对本发明作任何形式上的限制，虽然本发明已以较佳实施例揭露如上，然而并非用以限定本发明，任何熟悉本专利的技术人员在不脱离本发明技术方案范围内，当可利用上述提示的技术内容作出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明方案的范围内。
Claims (4)
1.一种连翘酯苷A作为单一活性成分在制备预防或治疗重症急性胰腺炎并发脑损伤的药物中的应用，所述连翘酯苷A的结构如下所示：
2.根据权利要求1所述的应用，其特征在于，所述连翘酯苷A作为单一活性成分的重量含量为0.1％～99.9％。
3.根据权利要求1所述的应用，其特征在于，所述药物的剂型为注射剂、胶囊剂、片剂、颗粒剂、丸剂。
4.根据权利要求1所述的应用，其特征在于，所述药物的剂型为微囊微球制剂。
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