CN110638823A - 淫羊藿苷在制备治疗血管性痴呆疾病的药物中的应用 - Google Patents
淫羊藿苷在制备治疗血管性痴呆疾病的药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种淫羊藿苷在制备治疗血管性痴呆疾病的药物中的应用。本发明通过永久性结扎双侧颈总动脉建立大鼠VD模型,观察淫羊藿苷对VD大鼠神经功能及海马组织BDNF表达的影响,研究淫羊藿苷在治疗VD的相关作用机理,证明了淫羊藿苷在治疗血管性痴呆(VD)方面具有明确疗效,以其制备相应药物,具有良好的临床应用前景。
Description
技术领域
本发明涉及一种药物的应用,尤其涉及淫羊藿苷在制备治疗血管性痴呆疾病药物中的应用,属于医药的技术领域。
背景技术
血管性痴呆(vascular dementia,VD)是指因长期慢性脑缺血或者多次脑卒中等脑血管发生异常造成的神经退行性疾病,是各种脑血管病(缺血性、出血性以及脑缺血缺氧性损害)引起的痴呆总称,主要表现为记忆、认知功能减退、情绪改变与行为障碍等方面,是引起老年期痴呆的第二病因,在痴呆中占10%~50%。其机制与内皮功能异常以及脑血管损伤等有关,尤其是与脑皮层、丘脑及海马等部位的缺血性病变关系密切相联。脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)是中枢神经***中分布最广泛的神经营养因子,其在神经元的生长、分化以及存亡过程中起着至关重要作用。目前国内外市场上用于治疗血管性痴呆疾病的药物主要是胆碱能药物,常见的主要是胆碱酯酶抑制剂,但其疗效并不理想,迄今还没有理想的治疗血管性痴呆疾病的“特效药”。
淫羊藿,(学名:Epimedium brevicornu Maxim.)多年生草本植物,植株高20-60厘米,根状茎粗短,暗棕褐色,二回三出复叶基生和茎生,具长柄,小叶纸质或厚纸质,叶缘具刺齿,花白色或淡黄色,花期5-6月,果期6-8月,味辛甘性温,走肝肾二经,又称仙灵脾,具有补肾壮阳、祛风湿的作用,临床常用于男子阳痿不举、滑精早泄、小便不禁以及女子***等症,目前未见用于治疗血管性痴呆的报道。
发明内容
本发明所要解决的技术问题在于探索淫羊藿苷在治疗血管性痴呆疾病中的用途,为研发治疗血管性痴呆疾病的新药提供基础。
为了解决上述技术问题,本发明提供一种淫羊藿苷在制备治疗血管性痴呆疾病的药物中的应用。
更具体的说,本发明是提供一种淫羊藿苷在制备治疗缺血性痴呆疾病的药物中的应用。
本发明还提供一种淫羊藿苷在制备治疗阿尔茨海默病的药物中的应用。
本发明的淫羊藿苷是通过促进BDNF mRNA及其蛋白表达来改善与保护神经元损伤,在缺血性脑损伤、抗衰老方面发挥治疗作用。
本发明的淫羊藿苷还可以通过上调大脑海马组织中SOD、GSH-PX活性,下调NOS活性,增加海马内AchE、ChAT蛋白表达,提高大脑学习记忆能力。
本发明的淫羊藿苷还可以淫羊藿苷通过维生素D轴调节小胶质细胞(MG),参与控制炎症因子的释放,促进内源性神经营养因子的释放,发挥对阿尔茨海默病的干预作用。
上述本发明淫羊藿苷在制备治疗血管性痴呆疾病的药物中的应用,是将淫羊藿苷作为唯一活性成分,加上药学上常用的辅料或辅助性成分制备成治疗血管性痴呆疾病的药物制剂。
上述淫羊藿苷在制备治疗血管性痴呆疾病的药物中的应用中,所述的治疗血管性痴呆疾病的药物制剂优选为口服制剂。
上述淫羊藿苷在制备治疗血管性痴呆疾病的药物中的应用中,所述的口服制剂为临床上常见的口服液、丸剂、颗粒剂、胶囊剂、片剂、滴丸或散剂;上述剂型的药物均可以按照中药制剂的常规方法制备。
本发明的有益效果:本发明通过研究表明,淫羊藿可以上调脑内单胺类递质水平,降低中枢及外周胆碱酯酶活性,有效延缓脑组织衰老。淫羊藿苷为淫羊藿的主要有效成分,可以上调老龄动物红细胞及肝组织中超氧化物歧化酶、谷胱甘肽过氧化物酶活性,降低过氧化脂质含量,清除氧自由基,进而发挥抗氧化、延缓衰老等作用。本发明的贡献在于证明了淫羊藿苷在治疗血管性痴呆(VD)方面具有明确疗效,以其制备相应药物,具有良好的临床应用前景。
附图说明
图1为VD大鼠海马组织病理HE染色结果(×200)图;
图2为VD大鼠血清BDNF水平影响直方图;
图3为VD大鼠海马神经元细胞凋亡(×400)图;
图4为VD大鼠脑组织海马神经元细胞凋亡率直方图;
图5为VD大鼠海马BDNF mRNA表达影响直方图;
图6为VD大鼠海马BDNF蛋白表达胶片图;
图7为VD大鼠海马BDNF蛋白表达胶片灰度值直方图;
图中1-假手术组,2-模型组,3-维生素D组,4-淫羊藿苷低剂量组,5-淫羊藿苷中剂量组,6-淫羊藿苷高剂量。
具体实施方式
下面通过具体实施方式对本发明做进一步详细说明。
实施例1:淫羊藿苷在治疗血管性痴呆的作用机理。通过永久性结扎双侧颈总动脉建立大鼠VD模型,观察淫羊藿苷对VD大鼠神经功能及海马组织BDNF表达的影响,研究淫羊藿苷在治疗VD的相关作用机理。
材料与仪器
1.1 实验动物 雄性SD大鼠,SPF级,80只,体重(170±20)g,购买于解放军第三军医大学实验动物中心,生产许可证号:SCXK(军)2012-0011。
药物与试剂 淫羊藿苷(陕西森弗天然制品有限公司,批号:SFY161009),苏木素(Sigma,H9627),伊红水溶液(国药集团,71014544),兔多抗BDNF(武汉三鹰生物技术有限公司25699-1-AP),HRP标记羊抗兔二抗(武汉博士德生物工程有限公司,BA1054)。
主要仪器显微镜(奥林巴斯BX53型生物显微镜),病理切片机(德国Leica RM2016轮转式切片机)。
方法
2.1 动物模型制作及分组 将80只SD大鼠随机分为假手术组(即对照组)10只、VD造模组70只。参照文献(毛西京,王敏,于挺敏,等.丁苯酞对血管性痴呆大鼠海马CA1区脑源性神经营养因子表达的影响[J].吉林大学学报(医学版),2017,43(5):857-861)方法复制VD大鼠模型,大鼠术前禁食禁水12h,腹腔注射10%水合氯醛(0.3 mL·100g-1),待全身麻醉完全,固定在鼠板上,仰卧位,分离并永久性结扎双侧颈总动脉。假手术组仅仅分离但不结扎,其余操作与VD模型组一致。由于术后感染、相互撕咬等情况死亡20只。
给药方法及取材 造模后1个月,经确认成功后开始分组,将大鼠随机分为假手术组,模型组,淫羊藿苷低、中、高剂量组和维生素D组,每组10只。假手术组和模型组大鼠给予生理盐水2.0ml/(kg·d)灌胃;淫羊藿苷低、中、高剂量组分别按200mg、400mg、800mg/(kg·d)灌胃;维生素D组按0.025ug /(kg·d)灌胃。每日1次,连续药物干预8周。无痛取血,离心取血清,-80℃保存。断头取大脑组织,将血液用冰生理盐水冲洗干净,部分置于4%多聚甲醛液中固定,部分放于-80℃冰箱保存。
染色检测 采用4%多聚甲醛固定后,经石蜡切片(厚度 5μm)包埋,苏木精-伊红染色,封片后于光镜下观察。
检测大鼠血清BDNF水平 按照ELISA试剂盒提供的实验步骤进行操作、检测。
法观察大鼠海马区神经元细胞凋亡 将海马组织脱水、透明、浸蜡、包埋、切片和烤片、切片脱蜡;滴加蛋白酶K工作液(20μg/ml)用PBS洗涤2次,每次5min;再将切片浸入4%的多聚甲醛(pH7.4)溶液中室温固定5min;处理好的组织切片,用吸水纸小心吸去载玻片上的多余液体,滴加100μL的滴加100μL的Equilibration Buffer(平衡缓冲液)于样本区域上,室温平衡5~10min;载玻片平衡时,将生物素化的核苷混合物置冰上解冻,同时配制足够的TdT酶反应液(98µl Equilibratin Buffer + 1µl Biotinylated Nucleotide + 1µl TdTEnzyme),于冰上保存待用,每个切片100ul反应液足以覆盖样本区域;用去离子水1:10稀释20X SSC;在0.3%的过氧化氢中浸洗3-5min,抑制内源性过氧化氢酶,PBS洗3次,每次5min;在样本上加100µl的Streptavidin HRP(链霉亲和素辣根过氧化酶)溶液,溶液按1:500 PBS稀释,室温孵育30min,PBS洗涤3次,每次5min;在样本上加100µlDAB显色液,室温显色30s-5min或者根据显色情况延长显色时间,最后用蒸馏水冲洗终止显色;最后复染、脱水透明、晾干的切片可以在显微镜下观察采集图像。
检测BDNF的表达 Trizol法提取总RNA,用紫外分光光度计测定OD260、OD280以及OD260/OD280值,计算RNA的纯度和浓度。根据OD260/OD280比值,估测RNA质量,比值在1.8-2.0之间满足实验要求。将总RNA逆转录为cDNA,并置于-20℃保存。以逆转录产物cDNA作为模版,加入目的基因引物及内参引物进行扩增。根据扩增曲线数据,最终数据以2-△△Ct进行分析。扩增条件:预变性:95℃,10min;变性:95℃,15s;退火温度:60℃,15s;延伸:72℃,35s;循环35次。BDNF mRNA上游引物序列:5’-ATCCGAGAGCTTTGTGTGGA-3’;下游引物序列:5’-GTGCTCAAAAGTGTCAGCCA-3’;内参引物β-actin,上游序列: 5’-CACGATGGAGGGGCCGGACTCATC-3’;下游序列:5’- TAAAGACCTCTATGCCAACACAGT -3’。
检测BDNF蛋白表达 提取组织总蛋白,离心机离心后取上清液并置于-20℃保存。根据蛋白样品OD值,利用回归方程计算出蛋白浓度。电泳跑胶后转膜,用5%脱脂奶粉的TBST封闭2h,加相应的一抗,4℃孵育过夜,TBST充分洗涤5-6次,用封闭液稀释相应的HRP标记二抗,摇床孵育2h,洗去多余二抗,X光胶片压片后依次放入显影液显影、定影液定影,冲洗胶片,采用BandScan分析胶片灰度值。
统计学方法分析
采用SPSS17.0进行单因素方差检验,P <0.05表示统计结果有意义。
结果
3.1 对VD大鼠海马组织病理形态学的影响 HE染色结果表明,假手术组大鼠海马组织细胞结构正常,排列整齐,形态完整;模型组大鼠海马呈现弥散性损伤,海马组织细胞数目较少,结构不完整,形态不整齐,细胞核固缩,排列无规律、较紊乱;与模型组相比,淫羊藿苷低、中、高各组以及维生素D组海马组织损伤有不同程度的改善,神经元较模型组损伤减轻,神经细胞变性、坏死减轻,排列较整齐。见图1。
对大鼠血清BDNF水平的影响 与假手术组相比,模型组大鼠血清BDNF水平降低(P<0.05);不同剂量淫羊藿苷组干预后,相对于模型组升高(P <0.05)。与模型组比较:#P<0.05,##P<0.01;与假手术组比较:*P<0.05。见图2。
对大鼠海马神经元细胞的影响 与假手术组相比,模型组的凋亡率升高(P <0.05);与模型组相比,淫羊藿苷干预后细胞凋亡率不同程度的降低。与模型组比较:#P<0.05,##P<0.01;与假手术组比较:**P<0.01。见图3、图4。
法检测BDNF mRNA表达与假手术组相比,模型组大鼠海马组织中BDNF mRNA 表达水平比假手术组降低,差异有统计学意义(P <0.05);淫羊藿苷干预后BDNF mRNA表达上调(P <0.05)。与模型组比较:##P<0.01;与假手术组比较:**P<0.01。见图5。
法检测BDNF蛋白表达水平与假手术组相比,模型组大鼠海马组织中BDNF蛋白表达水平比假手术组降低,差异有统计学意义(P <0.05);淫羊藿苷干预后BDNF蛋白表达上调(P<0.05)。见图6、图7。
讨论
VD是一种病机复杂、疗效不理想的临床常见老年性疾病。随着老龄化人口数目不断上升,问题不断加大,形势特别严峻。VD在老年人群中的发病率以及死亡率也在逐年上升,目前阿尔茨海默病(AD)为第一大痴呆类型,VD已成为第二大痴呆类型。研究发现VD患者认知、学***明显降低。通过不同剂量的淫羊藿苷(ICA)干预后,可以从蛋白和基因水平升高VD大鼠BDNF的表达,说明淫羊藿苷可以通过上调BDNF的表达从而起到改善神经元损伤的作用。本发明研究证明淫羊藿苷在改善缺血性脑损伤、抗衰老等方面发挥作用,也可广泛作用于中枢神经***。还发现ICA具有保护神经的作用,对脑缺血再灌注损伤具有保护作用。还能通过上调海马组织中SOD、GSH-PX活性,下调NOS活性,增加海马内AchE、ChAT蛋白表达,发挥改善淀粉样β蛋白片段25-35(Aβ25-35)所致AD模型大鼠学习记忆能力作用。
综上所述,淫羊藿苷通过促进BDNF mRNA以及蛋白表达,一定程度上发挥对神经元损伤的改善与保护作用,表明淫羊藿苷在治疗血管性痴呆(VD)方面具有明确疗效,为以后临床用药与开发应用提供新的研究方向。
实施例2:淫羊藿苷通过维生素D轴调控小胶质细胞极化功能达到干预AD作用
1.维生素D缺乏在AD患者中普遍存在,通过维生素D轴调节小胶质细胞在治疗AD中具有重要作用。
维生素D(vitamin D,Vit D)是重要的类固醇衍生物之一。维生素D轴包含维生素D受体(VDR )、维生素D及参与维生素D代谢的酶(CYP27B,CYP24A)。流行病学研究结果显示,在AD患者中,Vit D缺乏现象普遍存在,且与认知能力改变具有密切相关性,而高水平Vit D与降低某些神经***疾病风险具有相关性。
Vit D可从食物及皮肤两个合成途径获得。其前体Vit D3在肝细胞线粒体内25-羟化酶作用下形成25-(OH)D3,再经近端肾小管上皮细胞线粒体内1α-羟化酶的催化作用,进一步形成具有生物活性的1,25(OH)2D3,并主要通过与Vit D受体(vitamin D receptor,VDR)特异性结合后发挥生理作用。VDR在许多组织和细胞中均存在,如大脑的毛细血管内皮细胞、前额皮质、海马等。有实验证实,在大脑皮层中存在1α-羟化酶的表达,表明在中枢神经***中可以产生1,25(OH)2D3。
研究发现,Vit D对中枢神经***的保护作用主要是通过调节神经营养因子实现的。AD患者基底核处神经生长因子(Nerve Growth Factor,NGF)、海马和顶叶皮层内脑源神经营养因子(brain derived neurotrophic factor,BDNF)的含量均显著降低,维生素D缺乏增加AD发病概率,1,25(OH)2D3能够通过调节NGF、BDNF、神经营养因子3(neurotrophins-3,NT-3)、神经营养因子4(neurotrophins-4,NT-4)以及胶质细胞源性神经营养因子(glialcellline derived neurotrophic factor,GDNF)等,发挥对中枢神经***的保护作用和维持神经传递和突触的可塑性,AD患者前脑成熟NGF水平明显下降,而在植入转基因表达人NGF的自体成纤维细胞后,患者认知评价等级可以在一定程度上得到改善。在1α-羟化酶敲除小鼠中,1,25(OH)2D3缺乏会导致NGF mRNA含量降低,补充1,25(OH)2D3可以增加APP转基因小鼠脑内NGF的表达。本专利发明人在研究中也发现在淫羊藿苷对血管性痴呆大鼠模型的实验中,模型组大鼠BDNF mRNA水平以及维生素D代谢相关酶(CYP27B1、CYP24A1)、维生素D亦会相应降低,而在采用维生素D以及淫羊藿苷干预后BDNF mRNA以及维生素D代谢相关酶(CYP27B1、 CYP24A1)、维生素D表达上调。
最近研究表明,在IFN-γ、LPS或病毒感染激活MG模型中,前炎细胞因子、趋化因子、效应分子出现高表达的同时,VDR和CYP27B1的表达上调,CYP27B1正是编码1α-羟化酶并催化维生素D转为活性的关键基因。巨噬细胞是体内表达VDR的众多细胞之一,1,25(OH)2D3在早期可以促进炎症反应的Ml型巨噬细胞活化,减少巨噬细胞浸润;在晚期则可以诱导巨噬细胞向M2型分化。
综上所述,控制炎症因子释放,除了直接通过抑制MG的过度激活实现以外,还可以通过上调VDR受体表达,加强MG自身对维生素D的应答,抑制M1型过度激活,调控M2型极化。因此,维生素D轴对AD的调节机制除了促进内源性神经营养因子释放外,还可能通过调节MG实现。
2.中医对AD的认识及淫羊藿苷对AD大鼠模型的治疗作用。
中医对AD早有认识,据其主要临床表现,应属于“呆病”范畴。其病位在脑,涉及心、脾、肝、肾,基本病机是肾精亏虚,脑髓失养,神机失用。即病位在脑,肾虚为本,邪实为标。诚如王清任《医林改错·脑髓说》:“所以小儿无记性者,脑髓未满;高年无记性者,脑髓渐空”所言,先天愚型和高年痴呆均因脑髓未满或渐空,清灵之腑失于濡养。同时,中医学还认为“肾主藏精,精主生髓,髓聚于脑”。脑为髓海,由肾中精气所化生。肾精充盛则髓海得养;肾精亏虚,则不能上充于脑,脑髓空虚而致神机失用发为呆病。“肾”与“脑”功能上存在密切的联系,肾精亏虚是导致“髓海不足”的重要原因,因此通过“补肾填精,益髓充脑”可以防治衰老引起的记忆力下降,起到“益脑髓”作用。
本专利发明人前期研究发现:维生素D与中医“肾”的功能概念密切相关,并明确指出维生素D可能是“肾藏精”的重要物质基础。维生素D内分泌***在体内作用与中医肾藏象非常接近,维生素D缺乏表现出的相关疾病与中医“肾精亏虚”证型存在诸多交叉点。例如:肾藏精,主生长发育。新生儿维生素D水平普遍较低,影响到胚胎发育,导致先天不足;肾藏精,主生殖。SD大鼠在怀孕和哺乳中维生素D缺乏对后代的生理和行为均会产生影响,导致其与鼠伴嗅探、身体接触等交流活动频率和时间降低,并产生焦虑反应。通过控制日照和饮食模拟维生素D缺乏可造成大鼠肾精不足模型,该模型证实维生素D缺乏可以导致动物性激素分泌紊乱,表现出类似肾精亏虚证的异常症状;肾藏精,主水液代谢。在慢性肾脏疾病早期,随着蛋白尿增多,维生素D参与了1,25(OH)2D3-FGF23-Klotho蛋白***,通过调节该***异常可以改善蛋白尿的发生和发展。基于此,本专利发明人认为维生素D缺乏与中医“肾藏精”之间存在密切联系。
淫羊藿,又称仙灵脾,为小檗科植物淫羊藿的全草。《神农本草经》中记载其具有“益气力,强志”之效。研究表明淫羊藿苷(ICA)作为淫羊藿的主要活性成份,可以改善淀粉样β蛋白片段25-35(Aβ25-35)所致AD模型大鼠学***,上调肾上腺皮质VDR、CYP27B1,下调CYP24A1的作用。
运用 Arrowsmith 工具发现ICA与维生素D轴存在着相关性,发现具有抗炎、免疫等作用,发现ICA通过维生素D轴调节MG,参与控制炎症因子的释放,促进内源性神经营养因子的释放,发挥对AD的干预作用。
3.淫羊藿苷通过维生素D轴调控小胶质细胞极化功能达到干预AD的作用。
本专利发明人通过前期实验以及文献调研发现,AD大鼠具有Vit D缺乏,阿尔兹海默病与血清维生素D呈负相关性。调节MG或ICA干预均可改变模型1,25(OH)2D3含量及VDR表达,减轻模型大鼠AD病理表现,控制炎症因子释放,减轻AD模型炎症反应,通过直接抑制MG的过度激活实现。同时,维生素D轴还能够促进内源性神经营养因子释放,发挥神经保护作用,提高大鼠认知和记忆能力。基于以上认识,本专利认为:淫羊藿苷可以通过维生素D轴调控小胶质细胞极化功能达到干预AD的作用。
本发明的实施方式不限于上述实施例,在不脱离本发明宗旨的前提下做出的各种变化均属于本发明的保护范围之内。
Claims (9)
1.淫羊藿苷在制备治疗血管性痴呆疾病的药物中的应用。
2.淫羊藿苷在制备治疗缺血性痴呆疾病的药物中的应用。
3.淫羊藿苷在制备治疗阿尔茨海默病的药物中的应用。
4.淫羊藿苷通过促进BDNF mRNA及其蛋白表达来改善与保护神经元损伤,在缺血性脑损伤、抗衰老方面发挥治疗作用。
5.淫羊藿苷通过上调大脑海马组织中SOD、GSH-PX活性,下调NOS活性,增加海马内AchE、ChAT蛋白表达,提高大脑学习记忆能力。
6.淫羊藿苷通过维生素D轴调节小胶质细胞,参与控制炎症因子的释放,促进内源性神经营养因子的释放,发挥对阿尔茨海默病的干预作用。
7.根据权利要求1-6任意一项所述的淫羊藿苷在制备治疗血管性痴呆疾病的药物中的应用,其特征在于:将淫羊藿苷作为唯一活性成分,加上药学上常用的辅料或辅助性成分制备成治疗血管性痴呆疾病的药物制剂。
8.根据权利要求7所述的淫羊藿苷在制备治疗血管性痴呆疾病的药物中的应用,其特征在于:所述的药物制剂为口服制剂。
9.根据权利要求8所述的淫羊藿苷在制备治疗血管性痴呆疾病的药物中的应用,其特征在于:所述的口服制剂为临床上常见的口服液、丸剂、颗粒剂、胶囊剂、片剂、滴丸或散剂。
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