CN107648213B - 恩利卡生在制备治疗缺血/再灌注损伤药物中的应用 - Google Patents
恩利卡生在制备治疗缺血/再灌注损伤药物中的应用 Download PDFInfo
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Abstract
本发明公开了恩利卡生在制备治疗缺血/再灌注损伤药物中的应用。将恩利卡生用于治疗缺血/再灌注损伤，尤其是治疗脑组织神经病，更尤其是对脑缺血/再灌注的保护作用(缺血性脑卒中)，能显著减轻脑缺血/再灌注损伤。
Description
技术领域
本发明属于生物医药领域。本发明提供了恩利卡生(Emricasan)的新用途和给药方式，包括对脑缺血/再灌注的保护作用(缺血性脑卒中)，减轻缺血/再灌注损伤，扩大了恩利卡生适应症范围。
背景技术
缺血性脑卒中是严重危害人类健康的常见和多发病，在全球已成为第一致残和第三致死的原因，缺血性脑卒中的发病率约占脑血管病的70-80％。
缺血性脑卒中涉及钙超载、兴奋性氨基酸毒性、氧化应激等多种机制，这些机制相互交集最终引起神经细胞死亡。其中凋亡是缺血性脑卒中神经细胞死亡的主要方式之一。细胞凋亡主要包括内源性细胞凋亡通路(线粒体介导的凋亡通路)和外源性细胞凋亡通路(死亡受体介导的凋亡通路)。
Caspase家族是一大类凋亡的调控因子，是细胞凋亡的启动者和最后的执行者。凋亡启动因子由caspase-2、caspase-8、caspase-9和caspase-10组成，凋亡执行因子由caspase-3、caspase-6和caspase-7组成。研究表明，在caspase家族中，caspase-3是caspase级联“瀑布”下游最关键的凋亡执行蛋白酶，它在正常细胞中是以酶原形式存在，受凋亡刺激因素(缺血、细胞内钙超载等)作用后激活，活化的caspase-3可以激活核因子、细胞骨架蛋白及DNA裂解酶等，引起细胞形态的变化如出现细胞皱缩、DNA裂解、染色质浓缩和凋亡小体的形成等，最终导致细胞凋亡，caspase-3在各种因素启动的凋亡程序中起最后的枢纽作用。脑缺血时，死亡受体介导的凋亡通路激活的caspase-8，进一步激活其下游效应蛋白酶caspase-3及活线粒体凋亡通路导致细胞凋亡。研究表明，抑制caspase酶活性，够阻止神经凋亡的发展，可减轻脑缺血损伤的程度，缩小梗死范围。
半胱天冬酶抑制剂恩利卡生能特异性抑制caspase-3/7，但未见恩利卡生治疗缺血性脑卒中的报道，尤其是用于减轻缺血/再灌注损伤。
发明内容
本发明所述恩利卡生的结构式如式Ⅰ所示：
化学名为：(S)-3-((s)-2-(2-(2-叔丁基苯基氨基)-2-氧代乙酰氨基)丙酰胺)-4-氧代-5-(2，3，5，6-四氟苯氧基)戊酸；分子式为：C26H27F4N3O7；分子量为：569.5。
本发明通过实验表明，恩利卡生通过抑制半胱天冬酶(caspases)8，3，减少神经细胞凋亡，显著降低脑缺血梗死体积，减轻脑缺血/再灌注损伤的作用优于目前常用的脑血管药物。恩利卡生可以降低脑组织的caspase-3的活性。因此，恩利卡生可应用于制备治疗缺血和/或再灌注损伤药物(本文中，以下“/”均表示“和/或”)。优选地，所述缺血/再灌注损伤包括脑缺血/再灌注损伤、心肌缺血/再灌注损伤、肝缺血/再灌注损伤和肾缺血/再灌注损伤。更优选地，所述脑缺血/再灌注损伤包括缺血性脑卒中。给药方式为皮下注射、静脉注射、肌肉注射或口服给药，优选为口服给药。
本发明扩大了恩利卡生的适应症，可适用于脑缺血/再灌注损伤；与注射给药方式相比，本发明采用口服给药，操作简单，刺激性小，增强病人的依从性。
本发明证实恩利卡生能特异性抑制caspase-8，降低缺血性脑卒中大鼠神经细胞的凋亡率，缩小脑梗死体积，改善神经学功能，说明恩利卡生有可能用于治疗缺血性脑卒中，扩大其适应症范围。
总之，恩利卡生是一种半胱天冬酶抑制剂，通过抑制半胱天冬酶活性减少肝疾病中细胞凋亡。本发明将恩利卡生用于治疗缺血/再灌注损伤，尤其是脑组织神经病，更尤其是治疗缺血性脑卒中，能显著减轻脑缺血/再灌注损伤。
附图说明
图1：手术前15分钟给药，A-大鼠脑组织TTC染色及梗死体积测定，B-大鼠神经学功能评分；
图2：缺血2h再灌1h后给药，A-大鼠脑组织TTC染色及梗死体积测定，B-大鼠神经学功能评分。
具体实施方式
动物实验：恩利卡生对缺血性脑卒中大鼠模型的保护作用。
实施药品：羧甲基纤维素钠(CMC-Na)购于上海山浦化工有限公司。
将恩利卡生用0.5％羧甲基纤维素钠(CMC-Na)作为溶媒制成混悬液。
实验动物：体重250～300g的健康雄性SD大鼠48只。将实验动物在温度25℃、相对湿度60％、自由饮水、定时定量的环境中饲养一周，然后按实验各分组要求口服给药。
缺血脑卒中建立方法：用脑中动脉阻塞(MCAO)法法制备大鼠脑缺血/再灌注模型。步骤如下：(1)分离颈外动脉(CCA)，向上分离右颈外动脉(ECA)与颈内动脉(ICA)；(2)用眼科镊暂时夹闭ECA和ICA，并结扎CCA近心端；(3)于CCA远心端放置一打好结的备用丝线，在此线下端剪一小口，将栓线插入至颈内动脉，收紧丝线，放开ECA和ICA上的动脉夹，顺ICA将栓线送至颅内；(4)遇阻力而止，从CCA分叉处算起，插入深度约为18～20mm；(5)缺血120min后，将栓线拔出，缝好皮肤，再灌注24h后处理动物。
模型成功评判标准采用Longa“5分法”对大鼠脑缺血/再灌注损伤模型的神经功能缺损进行评分。0分：无神经缺损症状；1分：右前肢不能完全伸直；2分：向右旋转；3分：行走向右侧倾倒；4分：不能自发行走，意识丧失。1～4分为有效模型。
大鼠脑TTC染色和梗死体积测定。大鼠麻醉后，迅速将脑取出，去掉嗅球及后脑，从额极开始切取4张冠状脑片，厚约2.0mm，立刻置于1％TTC溶液中，37℃避光孵育30min。然后用10％多聚甲醛溶液浸泡固定。梗死区呈现白色，非梗死区呈现红色。将每组脑片排列整齐后进行扫描。再应用ImageJ测出各脑片的梗塞面积，根据公式：梗死体积＝[(各片正面梗死面积之和+各片反面梗死面积之和)/2]×每片厚度，同样方法计算出全脑体积。
实验分组：将实验动物随机分为6组，即：
对照组(control组)：不做任何处理。
假手术组(sham组)：将栓线插到脑中动脉分叉处即停。
脑缺血/再灌注组(I/R组)：脑缺血2h，再灌注24h。
恩利卡生(Emricasan)+脑缺血/再灌注组(Emricasan+I/R)1：1.手术前15分钟灌胃(恩利卡生用0.5％羧甲基纤维素钠做成混悬液)，恩利卡生用量：15mg/kg；
恩利卡生+脑缺血/再灌注组(Emricasan+I/R)2：缺血2h，再灌1h灌胃(恩利卡生用0.5％羧甲基纤维素钠做成混悬液)，恩利卡生用量：15mg/kg。
溶媒+脑缺血/再灌注组(vehicle+I/R)：手术前15分钟或缺血2h再灌1h后灌胃0.5％羧甲基纤维素钠(10ml/kg)。
收集脑组织并测定以下指标：大鼠神经功能评分和梗死体积测定。
实验结果：
恩利卡生对大鼠脑梗死体积及神经功能的影响
如图1中的A所示，I/R组有明显的白色梗死灶，手术前15分钟给予15mg/kg恩利卡生组大鼠脑梗死灶显著缩小，明显缓解脑缺血损伤。图B，脑缺血组(I/R)大鼠出现明显的神经运动功能障碍，恩利卡生可明显改善神经功能缺损症状(p<0.01)。
图2中的A所示，I/R组有明显的白色梗死灶，缺血2h再灌1h后给予15mg/kg恩利卡生组大鼠脑梗死灶显著缩小，明显缓解脑缺血损伤。图B，恩利卡生可明显改善神经功能缺损症状(p<0.01)。
上述实施例发现恩利卡生可减轻脑缺血/再灌注损伤，改善神经功能缺损症状，为治疗脑缺血/再灌注提供了新的药物。
但本专利不局限于脑缺血/再灌注损伤，因心、肝和肾缺血/再灌注损伤同样存在Caspase酶活性上调，故该药同样适用于治疗心、肝和肾缺血/再灌注损伤。
Claims (4)
1.恩利卡生在制备治疗缺血/再灌注损伤药物中的应用，所述缺血/再灌注损伤为脑缺血/再灌注损伤。
2.如权利要求1所述的应用，其特征在于，所述脑缺血/再灌注损伤包括缺血性脑卒中。
3.如权利要求1所述的应用，其特征在于，所述应用中的给药方式为皮下注射、静脉注射、肌肉注射或口服给药。
4.如权利要求3所述的应用，其特征在于，所述应用中的给药方式为口服给药。
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