CN106727497A - 鱼藤酮在制备急慢性血管损伤疾病药物中的应用 - Google Patents
鱼藤酮在制备急慢性血管损伤疾病药物中的应用 Download PDFInfo
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Abstract
本发明涉及鱼藤酮在制备药物中的应用，具体是鱼藤酮在制备急慢性血管损伤疾病药物中的一种新应用。本发明通过在金属导丝引起的动脉损伤小鼠模型，应用小剂量(250ppm)鱼藤酮治疗后，发现血管壁重构、管腔狭窄、血栓形成等均得到显著改善，显示鱼藤酮是一种治疗急慢性血管损伤的有效手段，从而为后期研发相关制备急慢性血管损伤疾病药物提供可能。
Description
技术领域
本发明涉及鱼藤酮在制备药物中的应用，具体是鱼藤酮在制备急慢性血管损伤疾病药物中的一种新应用，属于生物医药技术领域。
背景技术
随着经济的快速发展，国人的生活水平大幅度提高，随之相对应的是心血管疾病的发生率和死亡率大大增高，这不但严重影响了患者的寿命及生活质量，也给患者家庭带来极大的经济负担。有效防治心血管疾病已经显得尤为重要。血管损伤是心血管疾病的主要病理原因，而且血管损伤在临床上十分常见，医源性血管插管，造影检查以及血管狭窄介入治疗都可能造成血管损伤，血管损伤主要以动脉损伤为主，损伤后机体会启动血管的修复。但是在血管损伤修复的过程中，血管平滑肌细胞会增殖迁移，导致血管新生内膜增厚，造成血管狭窄，甚至闭塞。医源性的血管损伤后血管狭窄是困扰医生和病人的一个临床难题。因此，寻求有效治疗血管损伤后狭窄的方法不仅显得非常重要紧迫。
鱼藤酮，存在于豆科鱼藤属植物的种子、茎部和根部，不溶于水，溶于有机试剂。主要用作农用杀虫剂，也可防治人畜体外寄生虫和生化研究。防治对象有：蚜虫、飞虱、黄条跳甲、蓟马、黄守瓜、猿叶虫、菜青虫、斜纹夜蛾、甜菜夜蛾、小菜蛾等。在毒理学上是一种专属性很强的物质，对昆虫尤其是菜粉蝶幼虫、小菜蛾和蚜虫具有强烈的触杀和胃毒两种作用。早期的研究表明鱼藤酮主要是与NADH脱氢酶与辅酶Q之间的某一成分发生作用，使害虫细胞的电子传递链受到抑制，从而降低生物体内的ATP水平最终使害虫得不到能量供应，然后行动迟滞、麻痹而缓慢死亡。
目前，尚无关于鱼藤酮用于治疗血管损伤修复的任何报道。
发明内容
本发明的目的在于提供鱼藤酮在制备急慢性血管损伤疾病药物中的应用，从而为该病患者提供一种新的药物，是一种可以有效治疗血管损伤过度修复的新方法。
实现上述目的的技术解决方案是：
鱼藤酮在制备急慢性血管损伤疾病药物中的应用。
进一步地，所述鱼藤酮的剂量是低剂量。
更进一步地，所述鱼藤酮的剂量250ppm。
在细胞及组织器官的损伤过程中，会伴有线粒体功能和结构的损伤，受损的线粒体会产生过多的氧自由基，进而导致氧化损伤，甚至继发性激活炎症和细胞凋亡等。因此，适度的抑制线粒体功能，一方面可以减少能量的供应，减轻血管损伤部位过度的增殖性修复，同时也可以减少超氧阴离子等损伤性产物的生成，进而减轻血管损伤的形成和进展。
本发明在C57BL/6小鼠股动脉导丝损伤小鼠模型，应用小剂量(250ppm)鱼藤酮治疗后，发现小鼠股动脉内膜损伤修复得到显著改善；在体外实验，鱼藤酮有效降低了平滑肌细胞的迁移，显示通过小剂量鱼藤酮适度限制线粒体活性，可以减少线粒体源性的细胞毒性物质的释放，进而减轻细胞及组织器官的损伤。
本发明的技术效果：
1、本发明通过在金属导丝引起的动脉损伤小鼠模型，应用小剂量鱼藤酮治疗后，发现血管壁重构、管腔狭窄、血栓形成等均得到显著改善，显示鱼藤酮是一种治疗急慢性血管损伤的有效手段，从而为后期研发相关制备急慢性血管损伤疾病药物提供可能。
2、通过低剂量鱼藤酮(一般研究中，鱼藤酮的剂量为500-600ppm，本研究使用的剂量为250ppm)干预，血管新生内膜增厚被改善80％以上。
3、鱼藤酮是一种线粒体活性抑制剂，该研究结果提示，通过适当抑制线粒体活性，可以有效改善血管损伤过度修复造成的新生内膜增厚，具有一定的临床应用前景。
4、鱼藤酮,目前主要用作农用杀虫剂，对昆虫有强烈的毒杀作用，高剂量的鱼藤酮对于细胞以及生命个体具有毒副作用，因此我们选择的是一个相对安全的低剂量(250ppm)。
附图说明
图1是HE染色下对照组(a)/鱼藤酮治疗组(b)小鼠股动脉损伤修复后内膜面积(镜下图)；
图2：对照组/鱼藤酮治疗组小鼠股动脉损伤修复后内膜面积统计图(柱状图)；
图3：图3a是没有经过任何处理的小鼠平滑肌细胞迁移的数目，图3b是血管紧张素II(AngII)处理过的小鼠平滑肌细胞迁移的数目，图3c是小鼠平滑肌细胞给予鱼藤酮(0.2μM)处理2小时，后加入血管紧张素II(AngII)，小鼠平滑肌细胞迁移的数目减少(镜下图)
图4：图3的结果进行染色细胞统计计数分析(柱状图)。
具体实施方式
以下将结合具体实施例和附图对本发明的技术方案作进一步详细说明。
本发明以下实施例中使用的鱼藤酮购置于Sigma；C57BL/6小鼠购自南京大学模式动物中心购买的；小鼠平滑肌细胞购置广州吉妮欧生物科技有限公司。
实施例1
鱼藤酮可以降低小鼠股动脉损伤修复后内膜面积
选取10-12周龄的C57BL/6小鼠,术前使用水合氯醛麻醉，暴露右下肢；选取直径为0.45mm的螺旋导丝，从股动脉分支股深动脉的部位进导丝至股动脉1-1.5cm处，放置1分钟后取出导丝并结扎股深动脉；手术后小鼠随机分两组：对照组和鱼藤酮治疗组，每组6只，鱼藤酮治疗组小鼠食物内给与鱼藤酮(250ppm)；术后4周后取股动脉血管，石蜡包埋、切片，HE染色拍照后分析血管损伤后新生内膜增厚程度；如图1所示鱼藤酮治疗组小鼠的血管损伤后新生内膜增厚面积小于对照组。统计6只小鼠新生内膜增厚面积，使用graphpad软件做出统计图，如图2所示，具有统计学差异。图2结果显示经鱼藤酮治疗后的小鼠血管新生内膜增厚被改善80％以上。
实施例2鱼藤酮可以降低平滑肌细胞的迁移
在小鼠血管内膜损伤后修复过程中，平滑肌增殖迁移起到非常重要的作用，所以我们检测鱼藤酮是否影响小鼠平滑肌细胞的迁移。具体实施为：小鼠平滑肌细胞接种到12孔板中，贴壁过夜后，给予鱼藤酮(0.2μM)处理2小时，后加入0.1μM的血管紧张素II(AngII)，24小时后，对细胞进行消化重悬，计数细胞，调整细胞浓度为15000个细胞/200μl,取200μl细胞悬液加到迁移小室中，小室下方的培养孔中加入600μl完全培养基，24小时后，结晶紫染液染色，如图3所示，鱼藤酮可以降低平滑肌细胞的迁移；图3a是没有经过任何处理的小鼠平滑肌细胞迁移的数目，图3b是血管紧张素II(AngII)处理过的小鼠平滑肌细胞迁移的数目，AngII处理后小鼠平滑肌细胞迁移数目增加，图3c是小鼠平滑肌细胞给予鱼藤酮(0.2μM)处理2小时，后加入血管紧张素II(AngII)，小鼠平滑肌细胞迁移的数目减少。并对上述结果进行染色细胞统计计数分析，结果如图4所示，鱼藤酮可以降低平滑肌细胞的迁移。
Claims (3)
1.鱼藤酮在制备急慢性血管损伤疾病药物中的应用。
2.权利要求1所述的鱼藤酮在制备治疗血管损伤修复药物中的应用，其特征在于，所述鱼藤酮的剂量是低剂量。
3.权利要求2所述的鱼藤酮在制备治疗血管损伤修复药物中的应用，其特征在于，所述鱼藤酮的剂量是250ppm。
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| US6333347B1 (en) * | 1999-01-29 | 2001-12-25 | Angiotech Pharmaceuticals & Advanced Research Tech | Intrapericardial delivery of anti-microtubule agents |
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| KR20100013017A (ko) * | 2008-07-30 | 2010-02-09 | 한국과학기술원 | 미토콘드리아 전자전달계 복합체 ⅰ 억제제를 유효성분으로함유하는 허혈/재관류 손상에 의한 뇌질환 치료 및 예방용조성물 |
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2017
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| US6333347B1 (en) * | 1999-01-29 | 2001-12-25 | Angiotech Pharmaceuticals & Advanced Research Tech | Intrapericardial delivery of anti-microtubule agents |
| WO2006024488A2 (en) * | 2004-08-30 | 2006-03-09 | Interstitial Therapeutics | Medical stent provided with inhibitors of atp synthesis |
| KR20100013017A (ko) * | 2008-07-30 | 2010-02-09 | 한국과학기술원 | 미토콘드리아 전자전달계 복합체 ⅰ 억제제를 유효성분으로함유하는 허혈/재관류 손상에 의한 뇌질환 치료 및 예방용조성물 |
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