CN114848639B - 玫瑰啶碱a在制备预防脑缺血药物或保健品中的应用 - Google Patents
玫瑰啶碱a在制备预防脑缺血药物或保健品中的应用 Download PDFInfo
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Abstract
本发明公开了玫瑰啶碱A在预防脑缺血药物或保健品制备中的应用。本发明发现，玫瑰啶碱A能显著改善脑缺血再灌注大鼠的神经行为学缺损症状，显著降低脑缺血再灌注大鼠的脑梗死体积。玫瑰啶碱A可用于制备预防缺血性脑卒中的药物或保健品，降低脑组织损伤程度，为疾病的预防提供一种有效的解决办法。
Description
技术领域
本发明涉及玫瑰啶碱A在制备药物或保健品中的新应用，主要涉及玫瑰啶碱A在制备预防脑缺血药物或保健品中的应用，属于医药技术领域。
背景技术
脑卒中是临床上较为常见的脑血管疾病之一，具有高发病率、高致残率、高致死率的特点，是一种严重威胁人类健康的全球性疾病。脑卒中的类型主要分为缺血性脑卒中、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或动脉硬化而使脑组织血液供应不足，造成脑组织损伤。而出血性脑卒中主要是由于脑部血管破裂，血液渗入大脑，导致正常脑组织血流中断，从而造成脑组织损伤。缺血性脑卒中占所有脑卒中类型的70～80％。脑卒中的发病机制和病理生理过程复杂，至今尚未彻底阐明，目前认为可能与脑组织能量代谢障碍、自由基损伤、钙超载、兴奋性氨基酸(EEA)的过度释放、脑细胞凋亡、炎症反应等有关。
目前,临床上缺乏明确疗效的抗脑卒中治疗药物,迄今为止，组织纤溶酶原激活物(Tissue plasminogen activator，tPA)是美国食品和药物管理局批准用于治疗局灶性脑缺血的唯一药物，但是，tPA的溶栓治疗时间窗窄、出血风险大、再灌注损伤严重，因而其仅能使小部分临床病人因溶栓治疗而受益。常规的药物如他汀类药物、抗血小板聚集药物以及血管扩张剂等虽能够起到一定的治疗效果,但其不良反应对患者的危害不容小觑。从总体上看，脑卒中的相关治疗药物和治疗方法依旧处于十分缺乏的状态。因此，脑卒中治疗药物的开发显得尤为重要和迫切。
玫瑰啶碱A为哌啶类物质，本发明人于2016年首次从玫瑰石斛 (Dendrobiumcrepidatum Lindl.ex Paxt.)中获得。目前，未见任何关于此类物质治疗脑卒中疾病的研究报道，及在制备脑卒中治疗药物中的应用。有关玫瑰啶碱A的活性主要涉及炎症。其化学结构如下：
发明目的
本发明解决的技术问题在于提供玫瑰啶碱A在制备预防脑缺血药物或保健品中的应用，从而为脑缺血的治疗提供一种有效的解决办法。
技术方案
发明提供了玫瑰啶碱A在制备预防脑缺血药物或保健品中的应用，本发明是关于玫瑰啶碱A用于预防脑缺血药物或保健品新医药用途。所述的玫瑰啶碱A结构式为：
进一步，所述脑缺血的预防为各种因素引起的急性缺血性脑卒中、短暂性脑缺血发作以及慢性脑供血不足的预防；
进一步，玫瑰啶碱A对脑缺血的预防作用的特征是针对没有急性症状的高危人群，以及已经发生脑缺血获得治疗后的病人，其目的在于避免再次发作；
进一步，所述玫瑰啶碱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抗脑卒中药物。
进一步，所述玫瑰啶碱A可与保健品包括保健食品和功能食品可接受的辅料按常规制剂方法制成各种抗脑卒中的保健品。
有益效果
本发明采用脑缺血再灌注大鼠模型，对玫瑰啶碱A抗脑缺血作用进行了考察，结果显示，通过口服玫瑰啶碱A可显著改善脑缺血大鼠的神经行为学缺损症状，降低脑缺血大鼠脑梗死体积，为脑卒中的预防提供了一种有效的解决办法。
附图说明
图1玫瑰啶碱A对脑缺血再灌注大鼠神经行为学缺损症状的影响(
n＝12)。Sham：假手术对照组；MCAO/R：模型组；MCAO/R+10mg/kg MED：玫瑰啶碱A低剂量组 (10mg/kg)；MCAO/R+20mg/kg MED：玫瑰啶碱A高剂量组(20mg/kg)； MCAO/R+NBP：丁苯酞阳性药组；##与假手术对照组相比，##P<0.01； **与模型组相比，**P<0.01，*P<0.05。
图2玫瑰啶碱A对脑缺血再灌注大鼠脑梗死体积的影响A：TTC 染色脑片图；B：脑梗死体积百分比；Sham：假手术对照组；MCAO/R：模型组；MCAO/R+10mg/kg MED：玫瑰啶碱A低剂量组(10mg/kg)； MCAO/R+20mg/kg MED：玫瑰啶碱A高剂量组(20mg/kg)； MCAO/R+NBP：丁苯酞阳性药组；##与假手术对照组相比，##P<0.01； **与模型组相比，**P<0.01，*P<0.05。
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。
实施例1：玫瑰啶碱A的制备和结构确认
玫瑰石斛为兰科石斛属植物玫瑰石斛(Dendrobium crepidatum Lindl.exPaxt.)的新鲜或干燥茎，购于安徽亳州。乙醇、石油醚等试剂均为分析纯。
玫瑰石斛干燥茎，以15倍于生药量的80％乙醇回流提取3 次，每次2.5h，过滤，合并提取液，减压去除乙醇，得总浸膏；将总浸膏溶于5倍于生药量的水中，依次以石油醚(60-90℃)、乙酸乙酯和正丁醇进行萃取，乙酸乙酯提取物经硅胶柱层析(石油醚/乙酸乙酯，98：2→1：1)分离，然后继续用硅胶柱层析(CHCl3/→5:1)进一步分离，最后在RP-18硅胶柱上纯化得到化合物玫瑰啶碱A。
波谱数据及其结构如下：无色晶体(CHCl3/MeOH,10:1)；
mp164-165℃；[α]25 D-2.8(c 0.2,MeOH)；UV(MeOH)λmax (logε)203nm；IR(KBr)Vmax 3421,1720,1639,1447cm-1；1H and 13CNMR见下表；positive HRESIMS m/z 517.3436[M+H]+(Calcd for C33 H45N2 O3,517.3425)。
表1玫瑰啶碱A的核磁共振波谱数据(500MHZ，CDCl3,δppm)
实施例2：玫瑰啶碱A对脑缺血再灌注大鼠神经行为学缺损症状的影响
实验材料：健康雄性SD大鼠(体重280-300g)。由南京市青龙山动物繁殖场提供，饲养于SPF级动物实验中心实验室(温度：22℃±1℃，湿度：60％±5％)，以标准饲料喂养并饮用纯净水。实验方案依据中国实验动物应用指南设计并获得动物伦理委员会批准。在试验过程中尽可能地减少动物的使用数量和对动物的伤害。玫瑰啶碱A委托成都普瑞法科技开发有限公司制备。丁苯酞 (Butylphthalide)购自石药集团恩必普药业有限公司。
实验分组：SD大鼠随机分为假手术对照组、模型组、玫瑰啶碱 A低剂量组(10mg/kg)、高剂量组(20mg/kg)、丁苯酞组(20mg/kg，阳性对照)，每组10只。
脑缺血再灌注动物模型建立：采用线栓法制备大脑中动脉闭塞/ 再灌注(MCAO/R)模型。采用氯胺酮(80mg/kg)和甲苯噻嗪 (10mg/kg)腹腔注射麻醉大鼠，分离出颈总动脉(CCA)、颈外动脉 (ECA)和颈内动脉(ICA)，用微动脉夹夹闭颈总动脉,游离颈外动脉主干，在距颈总动脉分叉3～4mm处结扎。微动脉夹暂时夹闭颈内动脉，眼科剪将颈外动脉剪一小口，插入甲聚硅氧烷涂布的4-0单丝尼龙线，在颈外动脉剪口处打一松节以阻断颈内动脉的血液返流，去除颈内动脉的微动脉夹，轻推尼龙线进入颈内动脉，到达颅内的大脑前动脉，阻断大脑中动脉(MCA)的开口，插入深度约18-22 mm。去除颈总动脉的微动脉夹，消毒后逐层缝合皮下组织和皮肤，于术后2h缓慢抽出尼龙线进行再灌注。假手术组除了不插入尼龙线外,其它一切操作相同。所有大鼠在整个实验过程中的直肠温度维持在37℃。
神经行为学缺损评分：再灌注24h，处死动物前进行神经行为学缺损评分。Longa评分标准:0，正常，无神经功能缺损；1,左前肢伸展障碍，功能减弱；2，向左打圈，左前肢瘫痪，功能严重减弱,提起大鼠尾巴后，大鼠不停的扭向受损区；3,行走时向左侧倾倒；4,肢体瘫痪，意识昏迷；5，死亡。
结果：如图1所示，Sham组动物神经功能正常。与Sham组相比，MCAO/R模型组动物神经损伤评分显著增加；与MCAO/R模型组动物相比，MED(10、20mg/kg)呈现剂量依赖性的降低神经功能缺失评分(Longa评分)。总而言之，MED呈现出对缺血性脑损伤的改善作用。
实施例3：玫瑰啶碱A对脑缺血再灌注大鼠脑梗死体积的影响
实验材料：TTC(2，3，5-三苯基氯化四氮唑)购自西格玛奥德里奇(SigmaAldrich)。其他相关实验材料同实施例1。
实验分组：SD大鼠随机分为假手术对照组、模型组、玫瑰啶碱 A低、高剂量组、丁苯酞组(20mg/kg，阳性对照)，每组12只。其他相关实验方案同实施例1。
脑梗死体积测定：大鼠(n＝10)于再灌注24h断颈处死，迅速取出全脑，置于-20℃冰箱短暂冷冻后，置于冰盘上去掉嗅球，将前脑沿冠状面切成厚度为2mm的5片，将脑片置于1.5mL 2％TTC 溶液中避光孵育30min，再将脑片置10％多聚甲醛中固定过夜，再进行拍照分析。使用Image-Pro plus 5.1软件对脑梗塞体积进行测量计算。脑梗塞体积＝脑梗塞面积总和×脑片厚度(2mm)。因为脑水肿对脑梗塞体积有影响，故对脑梗塞死面积进行修正，脑梗塞死面积＝测量的脑梗死面积×{1-[(同侧半球面积–对侧半球面积)/对侧半球面积]}。
结果：如图所示，Sham组动物脑区未见梗死灶，MCAO/R模型组动物缺血2h再灌注24h后有梗死灶出现，缺血核心区和半暗区明显；与Sham组相比，MCAO/R模型组梗死体积显著增加；与模型组动物相比，MED低、高剂量组(10、20mg/kg)动物的脑梗死体积显著减。此外，阳性对照NBP，均能明显降低梗死体积。
讨论
本发明采用脑缺血再灌注大鼠模型对玫瑰啶碱A抗脑卒中作用进行了考察，结果显示，通过口服玫瑰啶碱A能显著改善脑卒中大鼠的神经行为学缺损症状，显著降低脑卒中大鼠的脑梗死体积。因此，玫瑰啶碱A具有抗脑卒中作用。以玫瑰啶碱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抗脑卒中药物或保健品，或与其他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，可为脑卒中的预防提供了一种有效的解决办法。
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，尽管通过参照本非发明的优选实施例已对本发明进行了描述，但本领域普通技术人员应当理解，可以在实行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说明书所限定的本发明的精神和范围。
Claims (3)
1.如式I所示玫瑰啶碱A及其药学上可接受的盐在制备预防脑缺血产品中的应用
2.根据权利要求1的应用，所述脑缺血为急性缺血性脑卒中、短暂性脑缺血发作以及慢性脑供血不足。
3.一种药物组合物在制备预防脑缺血产品中的应用，其特征在于，含有权利要求1的玫瑰啶碱A及其药学上可接受的盐、及药学上可接受的载体。
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