香豆素对淋巴滞留性脑水肿治疗作用的实验研究
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摘要
目的
脑淋巴引流对维持正常脑功能有重要意义。各种原因阻断颈部淋巴回流,都会使脑内淋巴液发生滞留,产生严重的淋巴性脑水肿,进而影响脑的形态结构和功能。目前,临床上治疗该病的方法有限。因此,根据发病机制寻找有效治疗药物成为该领域研究的热点问题。
香豆素是一种天然植物提取物,在治疗高蛋白性淋巴水肿性疾病如丝虫病等方面具有良好的疗效。该物质是否能够有效缓解淋巴滞留性脑水肿,为临床所用,目前国内尚未见相关报道。为此,本实验进行了相关研究,以期为临床治疗淋巴滞留性脑水肿提供理论依据。
材料与方法
将大鼠随机分为正常组(n=8)、模型组(n=24)、模型用药组(n=24),并进行Morris水迷宫测试筛选。模型组和模型用药组行颈淋巴引流阻断术,制作淋巴滞留性脑水肿动物模型,模型用药组于术后当天开始用香豆素腹腔注射,然后于术后7天、14天、21天分别对模型组和模型用药组进行水迷宫(空间探索试验)行为学测试、脑电图和血压记录、海马的透射电镜观察、突触素免疫组织化学染色,于术后21天进行正常组的上述各项检测,并进行统计学分析。
结果
1.行为学测试:
模型用药组术后7天平均逃避潜伏期与模型组相比,无显著性差异(P>0.05),与正常组相比明显延长(P<0.05);模型用药组术后14天、21天平均逃避潜伏期
ObjectiveThe lymph flows in the brain, which is very important for the normal role of brain. All causes that can occlude lymphatic drainage of the brain in rats will lead to the animals suffering from lymphostatic cerebroedema and the normal function of its brain is disturbed. The research results from the animals' experiment found that it was obviously altered in the configuration and function of the brain and the stress of the cerebrospinal fluid. But the treatment of this disease is not reported in home.So finding out a kind of medicine to cure this disease has been brought into focus.Coumarin is a kind of medicine which is effective to the lymphedema. So we use Coumarin to treat Lymphostatic cerebroedema.And we hope to provide some information for the clinical treatment of LC from our experiment.Materials and methodsThe rats were divided into normal rats and model rats and the Coumarin group. Ligate all the lymphatic vessel in the neck and make the model of Lymphostatic cerebroedema.To the Coumarin group rats Coumarin were continuously injected intraperitoneally from the first day of operation to 21d after operation. Then the Morris water maze task was performed among all groups in 7d , 14d , 21d after the operation. The EEG and Blood pressure was recorded in model group rats and the medicine group rats in the same time. The hippocampus tissues of their brains were studied in transmission electron microscopic level. And the synaptophysin
immuno label ing density was estimated in freezed hippocampus of rats.In 21d after the operation all items were measured in control group rats.Finally make analyzed of all data.Results1. Morris water maze ethologicai test:In the 7d after the operation the medicine group had no significant difference in the escape latency with the model group,while had longer escape latency than the control group and had significant difference with them;In the I4d and 21d after the operation the medicine group had significantly shorter escape latency than the model group and had significant difference compared with them(P <0.05); In the 14d after the operation the medicine group had significantly longer escape latency than the control group and the medicine group and had significant difference compared with them(P <0.05). In the 2Id after the operation the medicine group had no significant difference compared with the control group(P >0.05).In the Id. I4d> 21 d after the operation the model group had significantly longer escape latency than the control group and had significant difference compared with them(P<0.05).2. Blood pressure(BP)The model group had higher blood pressure than the control group in 7d after the operation,but had no significant difference compared with the control group(P>0.05). The model group had significantly higher blood pressure than the control group in 14d and 21d after the operation and had significant difference compared with the control group (P<0.05).The medcine group had higher blood pressure than the control group in 7d and 2Id after the operation and the medicine group and had no significant difference
compared with the control group(P>0.05). The medcine group had significantly higher blood pressure than the control group in 14d after the operation and the medicine group and had significant difference compared with the control group(P <0.05). The medcine group had significant difference in 14d and 2Id after the operation compared with the model group.3. EEGThe control rats have the medium wave amplitude of EEG. The model group had no significantly altered in wave amplitude of EEG in 7d after the operation. The model rats had significantly lowered in wave amplitude of EEG in 14d and 2Id after the operation. The medcine group had significantly higher wave amplitude of EEG than the model group in 14d and 2Id after the operation, and in 2Id after the operation had as high wave amplitude as the control rats.4.Ultrastructural alteration of hippocampus in the model group and the medicine groupThe brain tissue was obviously loose and the perivasular spaces around the capillaries were full of tissue fluid and found the edematous fluid in the brain tissue of model rats in 14d and 2 Id after the operation. The mitochondrin were swelling and mitochondrial cristae were fragmented or disappeared,some mitochondrina showed vacuolar degeneration.In 14d after the operation the hippocampus tissue of medicine group fluid was still exist in perivasular spaces around the capillaries,but reduced a lot. In 2Id after the operation the brain tissue of medicine group perivasular spaces around the capillaries was minished and was close to normal.5. the synaptophysin immunolabeling density in freezed hippocampus of rats
The synaptophysin immunolabeling density in freezed hippocampus of model rats in I4d after the operation had significant difference compared with the controlled group and the medicine group(P<0.05) .In 14d after the operation the synaptophysin immunolabeling density in freezed hippocampus of medicine group had significant difference compared with the controlled group; In 2Id after the operation the synaptophysin immunolabeling density in freezed hippocampus of medicine group had no significant difference compared with the controlled group.ConclusionThe model of Lymphostatic cerebroedema which was produced by ligating all the lymphatic vessels in the neck is credible model for studying related experiment. Lymphostatic cerebroedema has obviously influence in the function of brain,which can exert an influence on the configuration of the model rats' brain and the spatial reference memory and on the EEG and blood pressure of the model animals.Coumarin can reduce the Lymphostatic cerebroedema.
脑淋巴引流对维持正常脑功能有重要意义。各种原因阻断颈部淋巴回流,都会使脑内淋巴液发生滞留,产生严重的淋巴性脑水肿,进而影响脑的形态结构和功能。目前,临床上治疗该病的方法有限。因此,根据发病机制寻找有效治疗药物成为该领域研究的热点问题。
香豆素是一种天然植物提取物,在治疗高蛋白性淋巴水肿性疾病如丝虫病等方面具有良好的疗效。该物质是否能够有效缓解淋巴滞留性脑水肿,为临床所用,目前国内尚未见相关报道。为此,本实验进行了相关研究,以期为临床治疗淋巴滞留性脑水肿提供理论依据。
材料与方法
将大鼠随机分为正常组(n=8)、模型组(n=24)、模型用药组(n=24),并进行Morris水迷宫测试筛选。模型组和模型用药组行颈淋巴引流阻断术,制作淋巴滞留性脑水肿动物模型,模型用药组于术后当天开始用香豆素腹腔注射,然后于术后7天、14天、21天分别对模型组和模型用药组进行水迷宫(空间探索试验)行为学测试、脑电图和血压记录、海马的透射电镜观察、突触素免疫组织化学染色,于术后21天进行正常组的上述各项检测,并进行统计学分析。
结果
1.行为学测试:
模型用药组术后7天平均逃避潜伏期与模型组相比,无显著性差异(P>0.05),与正常组相比明显延长(P<0.05);模型用药组术后14天、21天平均逃避潜伏期
ObjectiveThe lymph flows in the brain, which is very important for the normal role of brain. All causes that can occlude lymphatic drainage of the brain in rats will lead to the animals suffering from lymphostatic cerebroedema and the normal function of its brain is disturbed. The research results from the animals' experiment found that it was obviously altered in the configuration and function of the brain and the stress of the cerebrospinal fluid. But the treatment of this disease is not reported in home.So finding out a kind of medicine to cure this disease has been brought into focus.Coumarin is a kind of medicine which is effective to the lymphedema. So we use Coumarin to treat Lymphostatic cerebroedema.And we hope to provide some information for the clinical treatment of LC from our experiment.Materials and methodsThe rats were divided into normal rats and model rats and the Coumarin group. Ligate all the lymphatic vessel in the neck and make the model of Lymphostatic cerebroedema.To the Coumarin group rats Coumarin were continuously injected intraperitoneally from the first day of operation to 21d after operation. Then the Morris water maze task was performed among all groups in 7d , 14d , 21d after the operation. The EEG and Blood pressure was recorded in model group rats and the medicine group rats in the same time. The hippocampus tissues of their brains were studied in transmission electron microscopic level. And the synaptophysin
immuno label ing density was estimated in freezed hippocampus of rats.In 21d after the operation all items were measured in control group rats.Finally make analyzed of all data.Results1. Morris water maze ethologicai test:In the 7d after the operation the medicine group had no significant difference in the escape latency with the model group,while had longer escape latency than the control group and had significant difference with them;In the I4d and 21d after the operation the medicine group had significantly shorter escape latency than the model group and had significant difference compared with them(P <0.05); In the 14d after the operation the medicine group had significantly longer escape latency than the control group and the medicine group and had significant difference compared with them(P <0.05). In the 2Id after the operation the medicine group had no significant difference compared with the control group(P >0.05).In the Id. I4d> 21 d after the operation the model group had significantly longer escape latency than the control group and had significant difference compared with them(P<0.05).2. Blood pressure(BP)The model group had higher blood pressure than the control group in 7d after the operation,but had no significant difference compared with the control group(P>0.05). The model group had significantly higher blood pressure than the control group in 14d and 21d after the operation and had significant difference compared with the control group (P<0.05).The medcine group had higher blood pressure than the control group in 7d and 2Id after the operation and the medicine group and had no significant difference
compared with the control group(P>0.05). The medcine group had significantly higher blood pressure than the control group in 14d after the operation and the medicine group and had significant difference compared with the control group(P <0.05). The medcine group had significant difference in 14d and 2Id after the operation compared with the model group.3. EEGThe control rats have the medium wave amplitude of EEG. The model group had no significantly altered in wave amplitude of EEG in 7d after the operation. The model rats had significantly lowered in wave amplitude of EEG in 14d and 2Id after the operation. The medcine group had significantly higher wave amplitude of EEG than the model group in 14d and 2Id after the operation, and in 2Id after the operation had as high wave amplitude as the control rats.4.Ultrastructural alteration of hippocampus in the model group and the medicine groupThe brain tissue was obviously loose and the perivasular spaces around the capillaries were full of tissue fluid and found the edematous fluid in the brain tissue of model rats in 14d and 2 Id after the operation. The mitochondrin were swelling and mitochondrial cristae were fragmented or disappeared,some mitochondrina showed vacuolar degeneration.In 14d after the operation the hippocampus tissue of medicine group fluid was still exist in perivasular spaces around the capillaries,but reduced a lot. In 2Id after the operation the brain tissue of medicine group perivasular spaces around the capillaries was minished and was close to normal.5. the synaptophysin immunolabeling density in freezed hippocampus of rats
The synaptophysin immunolabeling density in freezed hippocampus of model rats in I4d after the operation had significant difference compared with the controlled group and the medicine group(P<0.05) .In 14d after the operation the synaptophysin immunolabeling density in freezed hippocampus of medicine group had significant difference compared with the controlled group; In 2Id after the operation the synaptophysin immunolabeling density in freezed hippocampus of medicine group had no significant difference compared with the controlled group.ConclusionThe model of Lymphostatic cerebroedema which was produced by ligating all the lymphatic vessels in the neck is credible model for studying related experiment. Lymphostatic cerebroedema has obviously influence in the function of brain,which can exert an influence on the configuration of the model rats' brain and the spatial reference memory and on the EEG and blood pressure of the model animals.Coumarin can reduce the Lymphostatic cerebroedema.
引文
1.王怀经,张宪涛,陈连璧等,阻断大鼠颈部淋巴引流对脑的形态,结构,脑电图及血压的影响.山东医科大学学报,1995;33:271-274
2. CSANDA E, OBALjr F. Central Nervous System and Lymphatic System. P475-505. FoldiM, Casley-Smith JR. (Eds)Lymphangiology. NewYork: Schattauer, 1983
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4. Boulton M, Young A, Hay J, etal. Drainage of CSF through lymphatic pathways and arachnoidvilli in sheep: measurement of ~(125)I albumi nclearance. Neuropathol Appl Nrurobiol, 1996, 22 (4): 325-333
5. Boulton M, Flessner M, Armstrong D, etal. Lymphatic drainage of the CNS: effects of lymphatic diversion ligation on CSF protein transport to plasma. Am J Physiol, 1997, 272 (5Pt2): R1613-1619.
6. Cserr HF, Cooper DN, Milhorat TH. Flow of cerebral interstitial fluids as indicated by the removal of extracellular markers from rat caudate nucleus. Exp Eye Res, 1977; 25:461-473
7. Caerr HF, Cooper DN, Suri PK, etal. Efflux of radiolabeled polyethylene glycols and albumin from rat brain. Am J Physiol, 1981:240:F319-F328
8. Rosenebrg GA, Kyner WT, Estrada E. Bulk flow of brain interstitial fluid under normal and hyperosmolar conditions. AM J Physiol, 1980; 238:F42- F49
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10.夏作理,康颂建,许长庆等.实验性脑淋巴引流阻滞对微区脑血流量的影响.泰山医学院学报.1994;14(4):247-250
11.房玉珍,陈连璧等.实验性脑淋巴引流障碍对大鼠血压、心率调节功能的影响.卒中与神经疾病,2000年第7卷第4期:215-217
12.陈玉社,牛敬忠等,大鼠淋巴滞留性脑水肿的病理学研究.临床与实验病理 学杂志,2000 Dec:16(6):495-498
13.刘跃,王怀经,王怀星等.淋巴滞留性脑病模型大鼠空间记忆的改变.解剖学杂志,2002;25:151-154
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17.汤臣康等.氧化前胡素的降压作用.现代应用药学,1994,11(1):14
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2. CSANDA E, OBALjr F. Central Nervous System and Lymphatic System. P475-505. FoldiM, Casley-Smith JR. (Eds)Lymphangiology. NewYork: Schattauer, 1983
3. Brasbury MW, Cserr HF, Westrog RJ, etal. Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. Am J Physiol, 1981, 240: F329-336
4. Boulton M, Young A, Hay J, etal. Drainage of CSF through lymphatic pathways and arachnoidvilli in sheep: measurement of ~(125)I albumi nclearance. Neuropathol Appl Nrurobiol, 1996, 22 (4): 325-333
5. Boulton M, Flessner M, Armstrong D, etal. Lymphatic drainage of the CNS: effects of lymphatic diversion ligation on CSF protein transport to plasma. Am J Physiol, 1997, 272 (5Pt2): R1613-1619.
6. Cserr HF, Cooper DN, Milhorat TH. Flow of cerebral interstitial fluids as indicated by the removal of extracellular markers from rat caudate nucleus. Exp Eye Res, 1977; 25:461-473
7. Caerr HF, Cooper DN, Suri PK, etal. Efflux of radiolabeled polyethylene glycols and albumin from rat brain. Am J Physiol, 1981:240:F319-F328
8. Rosenebrg GA, Kyner WT, Estrada E. Bulk flow of brain interstitial fluid under normal and hyperosmolar conditions. AM J Physiol, 1980; 238:F42- F49
9.王怀经.脑淋巴引流.见:夏作理主编.当代脑血管病研究.北京:中国科学技术出版社,1993;33-40.
10.夏作理,康颂建,许长庆等.实验性脑淋巴引流阻滞对微区脑血流量的影响.泰山医学院学报.1994;14(4):247-250
11.房玉珍,陈连璧等.实验性脑淋巴引流障碍对大鼠血压、心率调节功能的影响.卒中与神经疾病,2000年第7卷第4期:215-217
12.陈玉社,牛敬忠等,大鼠淋巴滞留性脑水肿的病理学研究.临床与实验病理 学杂志,2000 Dec:16(6):495-498
13.刘跃,王怀经,王怀星等.淋巴滞留性脑病模型大鼠空间记忆的改变.解剖学杂志,2002;25:151-154
14.韩太真,吴馥梅.学习与记忆的神经生物学.北京:北京医科大学、中国协和医科大学联合出版社,1998.4
15. Wiedenmann B, Franke WW. Identification and localization of synaptophysin: an integral membrane glycoprotein Mr. 38000 characteristic of presynaptic vesicles. Cell[J], 1985, 41:1017-28
16.陈敏为等,有机杂环化合物.高等教育出版社,1990:91-92
17.汤臣康等.氧化前胡素的降压作用.现代应用药学,1994,11(1):14
18. Jamal S, Casley-Smith JR. The effects of 5,6 benzo-[a]-pyrone (coumarin) and DEC on filaritic lymphoedema and elephantiasis in India. Preliminary results. Ann Trod Med Parasitol. 1989 Jun; 83 (3): 287-90
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