CN116473955A - 衣康酸二甲酯在治疗心肌梗死中的应用 - Google Patents
衣康酸二甲酯在治疗心肌梗死中的应用 Download PDFInfo
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Abstract
本发明涉及生物医药领域,具体涉及衣康酸二甲酯在治疗心肌梗死中的作用。本发明首次发现衣康酸二甲酯具有改善小鼠心脏心肌梗死症状的作用,其作用通过缓解小鼠在冠状动脉左前降支缩窄后心脏发生的炎症、心肌纤维化、心肌细胞死亡等症状,进而发挥治疗小鼠心肌梗死的作用。且其改善心肌梗死效果更优于衣康酸,增加了该化合物在临床的新用途,为心肌梗死药物的研究与开发提供新思路。
Description
技术领域
本发明涉及生物医药领域,具体涉及衣康酸二甲酯在治疗心肌梗死中的应用。
背景技术
心肌梗死(myocardial infarction,MI)是由冠状动脉急性闭塞,使相应心肌持久地、严重地急性缺血所致,常伴随组织坏死和炎性细胞浸润,是一种临床常见的心脏疾病。研究证明,多种炎性介质参与心肌梗死的过程,其中包括补体激活、白细胞介素释放、中性粒细胞聚集/浸润等。
衣康酸二甲酯,如式(Ⅰ)所示。
衣康酸二甲酯的英文名为Dimethyl Itaconate,别名为亚甲基丁二酸二甲酯,在本专利中简称DMI。式(Ⅰ)中的结构式为DMI,它的分子式为C7H10O4,分子量为158.15,CAS号为617-52-7。研究证明,内源性抗炎代谢物衣康酸是巨噬细胞功能的调节因子,具有抗炎作用。DMI作为衣康酸衍生物,其结构中共轭酯基上负电荷的缺失增加了其对迈克尔加成反应的活性,具有较衣康酸更强的抗炎作用。而大量文献报道,心肌梗死的发生发展与心脏梗死部位发生的炎症反应有一定关联,因此DMI可因其抗炎活性而对改善心肌梗死发挥有益作用。但目前并没有关于DMI在治疗心肌梗死方面研究的记载与报道,本发明可为后续临床上开发新型治疗心肌梗死的药物提供一种新思路。
发明内容
为了克服现有技术的不足,本发明的目的旨在提供DMI在治疗心肌梗死(MI)中的应用。
本发明通过结扎小鼠心脏冠状动脉左前降支(LAD)建立MI动物模型,观察DMI对心肌梗死是否具有治疗效果。研究结果表明,DMI对小鼠心脏心肌梗死具有有益作用。
本发明以ICR雄性小鼠为动物模型,研究DMI对由MI引起的心肌纤维化、心肌细胞死亡等症状是否具有缓解作用。MI+DMI组小鼠从术后第二天开始以100mg/kg·BW的剂量连续6天腹腔注射DMI,给药周期结束后处死小鼠并进行实验分析。实验结果分析表明,MI+DMI组小鼠由心肌梗死造成的死亡得到缓解,且有效改善了心肌纤维化、心肌细胞死亡的现象和心肌炎症症状,减弱了由MI所造成的心肌损伤,显示出DMI在治疗心肌梗死方面具有一定的有益作用。这些实验结果表明DMI能有效改善小鼠由心肌梗死所诱发的系列症状。
术语
MI:心肌梗死
DMI:衣康酸二甲酯
LAD::冠状动脉左前降支
LVMass:左心室质量
LVID:左心室内径
cTnI:超敏肌钙蛋白
NRCMs:乳大鼠原代心肌细胞
MTT:噻唑蓝
DMSO:二甲基亚砜
附图说明
图1是实施例2处理后小鼠生存曲线图;
图2是实施例3处理后小鼠心脏切片Masson染色图和心肌纤维化面积定量图;
图3是实施例4处理后小鼠心脏超声图;
图4是实施例4处理后小鼠左心室质量(LVMass)和左心室内径(LVID)图;
图5是实施例5处理后小鼠血清cTnI含量图;
图6是实施例6处理后NRCMs细胞结晶紫染色图;
图7是实施例7处理后NRCMs细胞在缺血后不同处理下的存活率图;
*,p<0.05;**,p<0.01;***,p<0.001;ns,无显著性差异。
具体实施方式
通过以下实施例进一步举例描述本发明,并不以任何方式限制本发明,在不背离本发明的技术解决方案的前提下,对本发明所作的本领域普通技术人员容易实现的任何改动或改变都将落入本发明的权利要求范围之内。
以下实施例中所用材料如下:
衣康酸二甲酯由阿拉丁(中国,上海阿拉丁生化科技股份有限公司)提供,商品货号:CAS No.617-52-7。涉及的ICR小鼠均购自南京大学动物模式研究所,年龄为6周龄,饲养于中国药科大学动物实验中心,所有动物实验均符合《实验动物护理和使用指南》并经中国药科大学实验动物伦理委员会批准进行。
实施例1:构建小鼠心肌梗死模型
对成年ICR雄性小鼠进行胸部脱毛处理,使用2%异氟烷气体吸入式麻醉小鼠,夹趾检测小鼠无反应后,打开呼吸机,设置参数(呼吸比2:1,潮气量6~8mL,频率70次/min),将气管插管沿声门插入小鼠气管,观察小鼠呼吸状况,胸廓起伏与呼吸机频率一致即为插管成功,可进行MI手术。小鼠采用右侧卧位,消毒局部皮肤,剪开肋间皮肤,钝性分离三、四肋间肌肉,打开心包膜,暴露心脏冠状动脉左前降支(LAD),使用6-0无菌丝线快速结扎LAD,形成左心室前壁心肌缺血,用荷包缝合法迅速关闭胸腔,挤压胸部防止气胸。将成年ICR雄性小鼠随机分为2组,分别为MI组(12只)和MI+DMI(10只)组。
实施例2:DMI改善由心肌梗死引起的小鼠死亡
首先通过LAD缩窄术构建小鼠心肌梗死模型,将成年ICR雄性小鼠随机分为2组,分别为MI组(12只)和MI+DMI(10只)组,在术后连续6天对MI+DMI组小鼠腹腔注射DMI。MI造模期间持续记录小鼠的存活情况,MI造模结束后作生存曲线图并进行分析。
如图1所示,MI+DMI组小鼠的死亡率明显低于MI组小鼠。以上实验结果提示,DMI能显著改善由心肌梗死造成的小鼠死亡,提高小鼠的生存率。
实施例3:DMI改善小鼠由心肌梗死引起的心肌纤维化
MI造模结束后在异氟烷麻醉条件下对小鼠采取颈椎脱臼处死,摘取心脏并保证左右心室完整,挤压除去残留血液,并在无菌生理盐水中漂洗干净。沿心脏长轴切取各组小鼠同一部位心脏组织,以10%的中性福尔马林液固定24小时,用Masson染色进行病理组织胶原结构的观察。
如图2所示,LAD缩窄术后诱发了小鼠心脏心肌纤维化面积的明显增加,而DMI则缓解了由MI引起的心肌纤维化现象。以上实验结果提示,DMI能显著改善小鼠由心肌梗死造成的心肌纤维化。
实施例4:DMI改善小鼠由心肌梗死引起的心脏功能损伤
MI造模第七天对小鼠进行心脏超声检测并分析。超声心动图由南京医科大学的动物核心设施进行,使用Vevo 2100超声系统(Visual Sonics,加拿大多伦多),换能器为30MHz,心室尺寸等数据以M型方式记录。
如图3和图4所示,与MI组小鼠相比,MI+DMI组小鼠表现出心脏功能受损的减轻,且LVMass和LVID显著增加。以上实验结果提示,DMI可缓解MI导致的小鼠心脏功能障碍,但可能发生了心肌肥厚现象。
实施例5:DMI改善小鼠由心肌梗死引起的心脏损伤
血清cTnI是临床上心脏损伤的一个关键指标,是心肌损伤的生物标志物,通过测定小鼠血清中cTnI的含量来观测小鼠心肌梗死后心肌损伤的程度。
小鼠血清cTnI的测定:
1)标准品的加样:设置标准品孔和样品孔,标准品孔各加不同浓度的标准品50μL。
2)加样:分别设空白孔(空白对照孔不加样品及酶标试剂,其余步骤均相同)、待测样品孔。在酶标包被板上待测样品孔中先加样品稀释液40μL,然后再加待测样品10μL(样品最终稀释度为5倍)。
将样品加于孔底部,尽量不触及孔壁,轻轻晃匀。
3)加酶:除空白孔外,每孔加入酶标试剂100μL。
4)温育:用封板膜封板后置于37℃恒温培养箱中温育60min。
5)配液:将20倍浓缩洗涤液用ddH2O稀释后备用。
6)洗涤:小心揭掉封板膜,弃去液体,甩干,每孔加满洗涤液,静置30s后弃去,重复以上操作5次,拍干。
7)显色:每孔先加入显色剂A50μL,再加入显色剂B 50μL,轻轻晃匀,37℃避光显色15min。
8)终止:每孔加入终止液50μL,终止反应。
9)测定:以空白孔调零,在450nm波长处测定各孔吸光度。测定应在加终止液后15min内进行。
如图5所示,与接受假手术的小鼠相比,LAD缩窄术诱发了小鼠血清cTnI含量的明显升高,而MI+DMI组小鼠血清cTnI含量比MI组小鼠低25%。以上实验结果提示,DMI可减弱小鼠由心肌梗死所致的心脏损伤。
实施例6:DMI改善由缺血引起的NRCMs细胞死亡
为了在体外证实图5结果,用结晶紫染色观察NRCMs细胞的细胞形态。
NRCMs细胞的培养与处理:NRCMs细胞用24孔板培养,在缺血或缺血+10μM DMI处理后,用4%多聚甲醛固定细胞15分钟,用ddH2O冲洗细胞两次。然后每孔加500μL结晶紫染色液(Beyotime,中国上海,C0121),将孔板置于37℃恒温培养箱中避光染色15分钟,再用ddH2O冲洗细胞两次,然后将孔板置于倒置荧光显微镜(Carl ZEISS,Axio Vert.A1,Dublin,CA,U.S.A.)下观察并拍照。
如图6所示,缺血可明显引起NRCMs细胞死亡,主要表现为由细胞碎片组成的着色团块增多,而缺血+DMI组NRCMs细胞相较于缺血组NRCMs细胞,其细胞死亡率明显降低。以上实验结果提示,DMI可改善NRCMs细胞由缺血所致的细胞死亡,在体外实验中亦证实了DMI可减弱由心肌梗死所致的心脏损伤。
实施例7:DMI发挥改善由缺血所致NRCMs细胞死亡的作用更优于衣康酸
为了验证DMI是否具有较衣康酸更强的抗心肌梗死能力,用MTT实验测定NRCMs细胞在缺血后不同处理下的存活率。
NRCMs细胞的培养与处理:NRCMs细胞用96孔板培养,在缺血+10μM DMI或缺血+10μM衣康酸处理24小时后,用正常血清培养基按所需体积将MTT染料稀释10倍,每孔加200μL,放回培养箱中孵育4小时。之后每孔加200μL DMSO,将平板置于摇床上振荡10分钟,然后用酶标仪测量各孔在490nm下的吸光度值。
从图6实验结果已知NRCMs细胞在缺血后会出现明显的死亡现象,再结合图7实验结果所示,NRCMs细胞在缺血条件下分别给相同浓度的衣康酸或DMI,发现给DMI组的NRCMs细胞在缺血后的存活率与给衣康酸组的NRCMs细胞存活率相比显著增加。以上实验结果提示,DMI相较于衣康酸可更显著地改善由缺血所致NRCMs细胞死亡。
Claims (4)
1.衣康酸二甲酯在治疗心肌梗死中的应用,其中所述的衣康酸二甲酯的结构式为式(I)所示。
2.根据权利要求1所述的应用,其特征在于:所述衣康酸二甲酯具有改善心肌梗死症状的作用。
3.根据权利要求1所述的应用,其特征在于:所述的衣康酸二甲酯可改善小鼠由心肌梗死引发的心脏炎症、心肌纤维化、心肌损伤和心肌细胞死亡等症状。
4.根据权利要求1所述的应用,其特征在于:所述的衣康酸二甲酯相较于衣康酸可更显著地提高NRCMs细胞缺血后的存活率。
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