CN106727497A - Application of the rotenone in acute and chronic injury of blood vessel disease medicament is prepared - Google Patents
Application of the rotenone in acute and chronic injury of blood vessel disease medicament is prepared Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
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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。
The invention relates to the application of rotenone in the preparation of medicines, in particular to a new application of rotenone in the preparation of medicines for acute and chronic vascular injury diseases. In the present invention, after applying small dose (250ppm) rotenone to the mouse model of arterial injury caused by the metal guide wire, it is found that the vessel wall remodeling, lumen stenosis, thrombosis, etc. are all significantly improved, showing that rotenone is a therapeutic agent for acute An effective means for chronic vascular injury, thus providing the possibility for the later research and development of drugs related to acute and chronic vascular injury.
Description
技术领域technical field
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。The invention relates to the application of rotenone in the preparation of medicines, in particular to a new application of rotenone in the preparation of medicines for acute and chronic vascular injury diseases, and belongs to the technical field of biomedicine.
背景技术Background technique
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。With the rapid development of the economy, the living standards of Chinese people have been greatly improved, and correspondingly, the incidence and mortality of cardiovascular diseases have increased greatly. a huge economic burden. Effective prevention and treatment of cardiovascular disease has become particularly important. Vascular injury is the main pathological cause of cardiovascular disease, and vascular injury is very common in clinical practice. Iatrogenic vascular intubation, angiography examination and interventional treatment of vascular stenosis may cause vascular injury, and vascular injury is mainly arterial injury. After that, the body will start the repair of blood vessels. However, in the process of repairing vascular injury, vascular smooth muscle cells will proliferate and migrate, resulting in thickening of neovascular intima, causing vascular stenosis and even occlusion. Vascular stenosis after iatrogenic vascular injury is a clinical problem that bothers doctors and patients. Therefore, it is very important and urgent to seek an effective method for treating stenosis after vascular injury.
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。Rotenone, present in the seeds, stems and roots of leguminous plants of the genus Rotenone, is insoluble in water and soluble in organic reagents. It is mainly used as an agricultural insecticide, and it can also be used to control human and animal ectoparasites and biochemical research. The control objects are: aphids, planthoppers, flea beetle, thrips, yellow shougua, ape leafworm, cabbage caterpillar, spodoptera litura, beet armyworm, diamondback moth, etc. It is a highly specific substance in toxicology, and has strong contact and stomach poisoning effects on insects, especially cabbage butterfly larvae, diamondback moths and aphids. Early studies have shown that rotenone mainly interacts with a certain component between NADH dehydrogenase and coenzyme Q, which inhibits the electron transfer chain of pest cells, thereby reducing the ATP level in the organism and finally making the pests unable to obtain energy supply. Then the action is sluggish, paralyzed and dies slowly.
目前，尚无关于鱼藤酮用于治疗血管损伤修复的任何报道。Currently, there is no report on the use of rotenone in the treatment of vascular injury repair.
发明内容Contents of the invention
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。The purpose of the present invention is to provide the application of rotenone in the preparation of drugs for acute and chronic vascular injury diseases, so as to provide a new drug for patients with the disease, which is a new method that can effectively treat excessive repair of vascular injuries.
实现上述目的的技术解决方案是：The technical solution to achieve the above purpose is:
鱼藤酮在制备急慢性血管损伤疾病药物中的应用。Application of rotenone in the preparation of drugs for acute and chronic vascular injury diseases.
进一步地，所述鱼藤酮的剂量是低剂量。Further, the dose of the rotenone is a low dose.
更进一步地，所述鱼藤酮的剂量250ppm。Furthermore, the dose of rotenone is 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。In the process of damage to cells and tissues and organs, mitochondrial function and structure will be damaged. Damaged mitochondria will produce excessive oxygen free radicals, which will lead to oxidative damage, and even secondary activation of inflammation and apoptosis. Therefore, moderate inhibition of mitochondrial function, on the one hand, can reduce energy supply and reduce excessive proliferative repair at vascular injury sites, and at the same time reduce the generation of damaging products such as superoxide anion, thereby reducing the formation and progression of vascular injury.
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。In the C57BL/6 mouse femoral artery guidewire injury mouse model, after the application of small dose (250ppm) rotenone treatment, it was found that the repair of mouse femoral artery intima injury was significantly improved; in vitro experiments, rotenone effectively reduced the level of smooth muscle cells Migration, showing that moderately restricting mitochondrial activity with a small dose of rotenone can reduce the release of mitochondria-derived cytotoxic substances, thereby reducing the damage of cells and tissues and organs.
本发明的技术效果：Technical effect of the present invention:
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。1. The present invention finds that vessel wall remodeling, luminal stenosis, thrombosis, etc. have been significantly improved after the application of small doses of rotenone to the mouse model of arterial injury caused by a metal guide wire, showing that rotenone is a therapeutic agent for acute and chronic diseases. An effective means of vascular injury, thus providing the possibility for the later research and development of drugs for acute and chronic vascular injury diseases.
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。2. Through the intervention of low-dose rotenone (in general studies, the dose of rotenone is 500-600ppm, the dose used in this study is 250ppm), the thickening of angiogenesis neointimal was improved by more than 80%.
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。3. Rotenone is an inhibitor of mitochondrial activity. The results of this study suggest that proper inhibition of mitochondrial activity can effectively improve neointimal thickening caused by excessive repair of vascular injury, and has a certain clinical application prospect.
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)。4. Rotenone, currently mainly used as an agricultural insecticide, has a strong poisonous effect on insects. High doses of rotenone have toxic and side effects on cells and living individuals, so we choose a relatively safe low dose (250ppm).
附图说明Description of drawings
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)；Fig. 1 is the intima area (under the microscope) after femoral artery injury repair of control group (a)/rotenone treatment group (b) mice under HE staining;
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)；Figure 2: Statistical diagram (bar graph) of intima area after femoral artery injury repair in mice of control group/rotenone treatment group;
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)Figure 3: Figure 3a is the number of mouse smooth muscle cells without any treatment, Figure 3b is the number of mouse smooth muscle cells that were treated with angiotensin II (AngII), and Figure 3c is the mouse smooth muscle cells given rotenone ( 0.2μM) was treated for 2 hours, and then angiotensin II (AngII) was added, and the number of mouse smooth muscle cell migration was reduced (under the microscope)
图4：图3的结果进行染色细胞统计计数分析(柱状图)。Figure 4: The results of Figure 3 were analyzed by statistical counting of stained cells (histogram).
具体实施方式detailed description
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。The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments and accompanying drawings.
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。Rotenone used in the following examples of the present invention was purchased from Sigma; C57BL/6 mice were purchased from Model Animal Center of Nanjing University; mouse smooth muscle cells were purchased from Guangzhou Geneo Biotechnology Co., Ltd.
实施例1Example 1
鱼藤酮可以降低小鼠股动脉损伤修复后内膜面积Rotenone can reduce the intima area after femoral artery injury repair in mice
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。Select C57BL/6 mice aged 10-12 weeks, anesthetize with chloral hydrate before operation, expose the right lower limb; select a spiral guide wire with a diameter of 0.45 mm, and insert the guide wire from the deep femoral artery branch of the femoral artery to the femoral artery 1-1.5cm, after 1 minute, take out the guide wire and ligate the deep femoral artery; After the operation, the mice were randomly divided into two groups: the control group and the rotenone treatment group, 6 in each group, and the mice in the rotenone treatment group were given rotenone in food (250ppm); 4 weeks after the operation, femoral artery blood vessels were taken, embedded in paraffin, sectioned, and HE staining was photographed to analyze the degree of neointimal thickening after vascular injury; The area of intimal thickening was smaller than that of the control group. The area of neointima thickening in 6 mice was counted, and the graphpad software was used to make a statistical graph, as shown in Figure 2, with statistical differences. The results in Fig. 2 show that the thickening of neovascularized intimal in mice treated with rotenone was improved by more than 80%.
实施例2鱼藤酮可以降低平滑肌细胞的迁移Example 2 Rotenone can reduce the migration of smooth muscle cells
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。Smooth muscle proliferation and migration play a very important role in the repair process of mouse intimal injury, so we tested whether rotenone affects the migration of mouse smooth muscle cells. The specific implementation is as follows: mouse smooth muscle cells are inoculated into a 12-well plate, after adhering to the wall overnight, rotenone (0.2 μM) is given for 2 hours, and then 0.1 μM angiotensin II (AngII) is added, and after 24 hours, the cells are treated Digest and resuspend, count the cells, adjust the cell concentration to 15000 cells/200 μl, take 200 μl of cell suspension and add it to the migration chamber, add 600 μl complete medium to the culture well below the chamber, and stain with crystal violet stain after 24 hours, As shown in Figure 3, rotenone can reduce the migration of smooth muscle cells; Figure 3a is the migration number of mouse smooth muscle cells without any treatment, and Figure 3b is the migration number of mouse smooth muscle cells treated with angiotensin II (AngII) , the number of mouse smooth muscle cell migration increased after AngII treatment, and Figure 3c shows that mouse smooth muscle cells were treated with rotenone (0.2 μM) for 2 hours, and then angiotensin II (AngII) was added, and the number of mouse smooth muscle cell migration decreased. The above results were analyzed by statistical counting of stained cells, the results are shown in Figure 4, rotenone can reduce the migration of smooth muscle cells.
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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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| 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 |
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