曲美他嗪对大鼠脑缺血再灌注损伤保护作用的研究
摘要
目的:通过大鼠局灶性脑缺血再灌注模型,研究曲美他嗪(TMZ)对脑缺血再灌注损伤的保护作用。
方法:参照Zea Longa线栓法并加以改进建立局灶性脑缺血再灌注模型。健康雄性SD大鼠,随机分为假手术组(sham,NS 5ml/kg)、缺血再灌注组(I/R, NS 5ml/kg)、TMZ低剂量组(5mg/kg)、TMZ高剂量组(10mg/kg)。每日上午灌胃给药1次,连续用药2周,末次给药1h后施行手术。缺血2h后将线拔出再灌注。各组动物于再灌注24h后,进行大鼠神经功能缺损评分,评分后处死,行脑病理组织学观察、脑组织含水量及脑梗死体积检测,SOD、ATP酶活性和MDA含量测定。
结果:1.大鼠缺血2h再灌注24h后,各组动物均出现神经缺损症状,缺血再灌注组尤为显著,TMZ组症状改善,大鼠神经功能损害评分降低(P<0.05);TMZ两个剂量组均使脑梗死体积缩小,脑含水量明显低于缺血再灌注组(P<0.01);病理组织学观察缺血再灌注组可见广泛的脑水肿,神经细胞固缩坏死,TMZ组病变减轻。
2.大鼠缺血2h再灌注24h后,SOD、ATP酶活性明显降低,MDA含量显著增加,TMZ组SOD、ATP酶活性亦下降,MDA含量增加,但幅度较小,与缺血再灌注组相比有显著性差异(P<0.01)。
结论:1.线栓法大鼠局灶性脑缺血再灌注损伤模型制作方法简单,病理改变与人脑缺血后的病变相似,具有较高的可靠性、重复性和实用性,是研究脑缺血再灌注损伤的较为理想的动物模型。2. TMZ能降低缺血再灌注后脑组织的MDA含量,增强SOD、ATP酶活力,可减轻脑缺血再灌注损伤,对脑细胞有明显的保护作用。
Objective: In this study, the rat model of focal cerebral ischemia reperfusion was established with the middle cerebral artery occlusion by reversible inserting a nylon thread method ,to study the anti-cerebral ischemia reperfusion injury effects of TMZ and its mechanisms.
Methods: The model of local ischemia-reperfusion in rats was established with the suture occluded method invented by Zea Longa and improved properly in our lab. Male SD rats were randomly divided into four groups: rats in group1 (sham)only received anesthesia and vessel separation; rats in group 2 received ischemia reperfusion operation and NS ig; in group 3 and 4 received ischemia-reperfusion and TMZ 5 mg/kg and 10mg/kg daily respectively. Rats in each group had been administered drugs for 2 weeks and then operation was done. Two hours later, we drew out the suture to recover perfusion. The neurological deficit score of rats in each group was evaluated after 24h ischemia-reperfusion. Then the subjects were killed .The infarct volume and water content were measured and pathological examination was performed. Influence of TMZ on activity of SOD, ATPase and the content of MDA in cerebral cortex were tested by spectrophotometry.
Results: 1.All animals in each group manifested neuronal function disorder after 24h reperfusion following 2h ischemia. The symptom of model rats were especially marked. It was found that TMZ could improve the symptom of neurological deficit after cerebral ischemia reperfusion ,and decrease significantly the infarct volume and water content of cerebrum. There were great difference comparaed with the model group(P<0.05). Pathological findings showed that there were wide-ranging cerebral edema and neuronal cells necrosis. The finding also showed that TMZ treatment groups were able to abate pathological changes. 2. The activity of SOD and ATPase was remarkably lower and the content of MDA was higher in ischemia reperfusion group
方法:参照Zea Longa线栓法并加以改进建立局灶性脑缺血再灌注模型。健康雄性SD大鼠,随机分为假手术组(sham,NS 5ml/kg)、缺血再灌注组(I/R, NS 5ml/kg)、TMZ低剂量组(5mg/kg)、TMZ高剂量组(10mg/kg)。每日上午灌胃给药1次,连续用药2周,末次给药1h后施行手术。缺血2h后将线拔出再灌注。各组动物于再灌注24h后,进行大鼠神经功能缺损评分,评分后处死,行脑病理组织学观察、脑组织含水量及脑梗死体积检测,SOD、ATP酶活性和MDA含量测定。
结果:1.大鼠缺血2h再灌注24h后,各组动物均出现神经缺损症状,缺血再灌注组尤为显著,TMZ组症状改善,大鼠神经功能损害评分降低(P<0.05);TMZ两个剂量组均使脑梗死体积缩小,脑含水量明显低于缺血再灌注组(P<0.01);病理组织学观察缺血再灌注组可见广泛的脑水肿,神经细胞固缩坏死,TMZ组病变减轻。
2.大鼠缺血2h再灌注24h后,SOD、ATP酶活性明显降低,MDA含量显著增加,TMZ组SOD、ATP酶活性亦下降,MDA含量增加,但幅度较小,与缺血再灌注组相比有显著性差异(P<0.01)。
结论:1.线栓法大鼠局灶性脑缺血再灌注损伤模型制作方法简单,病理改变与人脑缺血后的病变相似,具有较高的可靠性、重复性和实用性,是研究脑缺血再灌注损伤的较为理想的动物模型。2. TMZ能降低缺血再灌注后脑组织的MDA含量,增强SOD、ATP酶活力,可减轻脑缺血再灌注损伤,对脑细胞有明显的保护作用。
Objective: In this study, the rat model of focal cerebral ischemia reperfusion was established with the middle cerebral artery occlusion by reversible inserting a nylon thread method ,to study the anti-cerebral ischemia reperfusion injury effects of TMZ and its mechanisms.
Methods: The model of local ischemia-reperfusion in rats was established with the suture occluded method invented by Zea Longa and improved properly in our lab. Male SD rats were randomly divided into four groups: rats in group1 (sham)only received anesthesia and vessel separation; rats in group 2 received ischemia reperfusion operation and NS ig; in group 3 and 4 received ischemia-reperfusion and TMZ 5 mg/kg and 10mg/kg daily respectively. Rats in each group had been administered drugs for 2 weeks and then operation was done. Two hours later, we drew out the suture to recover perfusion. The neurological deficit score of rats in each group was evaluated after 24h ischemia-reperfusion. Then the subjects were killed .The infarct volume and water content were measured and pathological examination was performed. Influence of TMZ on activity of SOD, ATPase and the content of MDA in cerebral cortex were tested by spectrophotometry.
Results: 1.All animals in each group manifested neuronal function disorder after 24h reperfusion following 2h ischemia. The symptom of model rats were especially marked. It was found that TMZ could improve the symptom of neurological deficit after cerebral ischemia reperfusion ,and decrease significantly the infarct volume and water content of cerebrum. There were great difference comparaed with the model group(P<0.05). Pathological findings showed that there were wide-ranging cerebral edema and neuronal cells necrosis. The finding also showed that TMZ treatment groups were able to abate pathological changes. 2. The activity of SOD and ATPase was remarkably lower and the content of MDA was higher in ischemia reperfusion group
引文
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[9] 刘亢丁, 苏志强, 李毅平,等.实验性局灶性脑缺血再灌注动物模型的改进及评价[J]. 中风与神经疾病杂志,1997, 14(2):87.
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[2] 张均田.现代药理实验方法学(下册)[M].北京:北京医科大学中国协和医科大学联合出版社,1998:1241.
[3] Young W, Rappaport ZH, Chalit DJ, et al. Regional brain sodium, potassium and water changes in the rat middle cerebral artery occlusion model of ischemia [J]. Stroke,1987, 18:751.
[4] 李胜. 大鼠大脑中动脉区局灶性脑缺血模型[J].国外医学脑血管疾病分册,1998, 6(1) :3.
[5] Koizumi J , Yoshida Y, Nakazawa T. Experimental studies of ischemic brain edema: A new experimental model of cerebral embolism in rats in which recirculation can be induced in the ischemic area[J] . Stroke, 1986 , 8 : 1.
[6] Spey BS, Taylor FL, Terruli M, et al. Temporary middle cerebral artery occlusion in the rat; consistent protocol for a model of stroke and reperfusion[J]. Neuropathol Appl Neurobiol 2000, 26(3):232-242.
[7] 关云谦, 孙明, 徐超.大鼠颈内动脉线栓法制备局灶性脑缺血模型及影响因素[J] . 国外医学脑血管疾病分册, 2001, 9 (3): 151-153.
[8] 廖维靖, 刘淑红, 范明, 等. 线栓阻断大鼠大脑中动脉制作缺血性脑损伤模型的改良[J]. 中华物理医学与康复杂志,2002, 24 (6): 345-348.
[9] 刘亢丁, 苏志强, 李毅平,等.实验性局灶性脑缺血再灌注动物模型的改进及评价[J]. 中风与神经疾病杂志,1997, 14(2):87.
[10] Schmidley J W. Free radicals in central nervous system ischemia [J ] . Stroke , 1990 ,21(7) :1086 - 1090.
[11] Haley E C, kassell N F, Alves W M ,et al . Phas trial of tirilazad in aneurismal subarachnoid hemorrhage [J] . J Neurosurg , 1995 ,82 :786-790.
[12] Hallenbeck JM, Dutka AJ. Background review and current voncepts of reperfusion injury[J]. Arch Neurol, 1990, 47:1245-1249.
[13] Suzuki J.Chemiluiuminescence in hypoxic brain[J]. Stroke, 1988,19:65-81.
[14] Mccord JM.Oxygen derived free radicals in postischemic tissue injury[J]. N Engl J Med,1985,312:159-164.
[15] Chu G X, Chen X. Protective effect of ginsenosides on acute cerebral ischemia/ reperfusion injury of rats [J] . Chinese J Pharmacol and Toxical , 1989 ,3(1) :18-22.
[16] Niki E, Yamato Y, komouro E ,et al . Membrane damage due to lipid oxidation [J]. Am J Clin Nutr, 1991, 53(suppl) :201-205.
[17] 海春旭. 自由基生物学于抗氧化剂研究进展[M].西安:陕西旅游出版社,1999: 82-84。
[18] 李宏. ATPase的研究进展[J].生物学杂志,1996,1:9-12.
[19] Stojanoric T, Mrsulja BB. Alteration in synaptosmal membrane Na~+-K~+- ATPase of the gerbil cortex and hippocampus following reversible brain ischemia[J]. Metab Brain Dis, 1988, 13(4): 256.
[20] Wheeler KP, Walker JA, Barker DM.Lipid requirement of the membrane sodium-plus-potassium ion-dependent adenosine triphosphatase system[J]. Biochem J, 1975, 146:713-722.
[21] 成同怡. Na~+-K~+-ATPase酶的结构和功能[J].国外医学分子生物学分册,1990,12(5):236-238.
[22] Yung GY, Chen SF , Kinouchi H ,et al. Edema cation content and ATPase activity after middle cerebral artery occlusion in rats[J ].Stroke ,1992 ,23(9):1331-1336.
[23] Scherar M, Buch E, Stuurt J. Oxidative stress impairs the function of sarcoplasmic reticulum by oxidation of sulfhydey groups in the Ca~(2+) - ATPase [J]. Arch Bichem Biophys, 1986, 246(4):589-601.
[24] Veitch K, Maisin L, Hue L.Trimetazidine effects on the damage to mitochondrial functions caused by ischemia and reperfusion[J].Am J Cardial,1995,76(6): 25-30.
[25] Elimadi A, Morin D, Sapena R, et al. Comparison of the effects of cyclosporine A and trimetazidine on Ca~(2+)-dependent mitochondrial swelling[J]. Fundam Clin Pharmacol,1997,11(5):440-447.
[26] Guarnieri C , Muscari C.Effect of trimetazidine on mitochondrial function and oxidative damage during reperfusion of ischemiahypertrophied rat myocardium[J]. Pharmacology,1993,46(6):324-331.
[27] Williams FM,TandaK,Kus M,et al.Trimetazidine inhibits neutrophil accumulation after myocardial ischemia and reperfusion in rabbits[J].J Cardiovasc Pharmacol,1993,22(6):828-833.
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