摘要
目的:本文主要对LST的抗血管性痴呆作用进行了药效学研究,并初步探讨了其作用机制。方法:采用行为药理学实验方法——跳台法、避暗法、Y迷宫法和水迷宫法等考察LST对小鼠缺血-再灌注致痴呆模型、对大鼠大脑中动脉电凝致痴呆模型以及大鼠多发梗塞型痴呆模型的改善作用;采用大鼠颈动-静脉旁路血栓形成实验、小鼠体内血栓形成实验来考察LST对血栓形成的影响。结果:实验结果表明,在缺血-再灌注致小鼠痴呆实验中,LST显著减少避暗实验和跳台实验中小鼠的错误次数、总电击时间,并显著延长潜伏期,显著缩短水迷宫实验中找到安全台的时间,增加正确反应次数;在大脑中动脉电凝和多发梗塞致大鼠痴呆实验中,LST能显著提高大鼠Y迷宫实验中自发交替反应的正确反应率,显著缩短Morris水迷宫实验的定向游泳实验中大鼠找到安全台的潜伏期,增加probe test中在原安全台所在象限的停留时间,显著延长避暗实验中大鼠进入暗室的潜伏期,提示LST可显著改善血管性痴呆模型动物学习记忆功能。在大鼠大脑中动脉电凝致痴呆实验中,模型组大鼠大脑皮质及海马CA1区神经元稀疏,水肿,轴突消失,尼氏小体不明显,而LST能显著改善上述病理改变,提示LST能保护大脑皮质及海马神经细胞免受缺血缺氧的损害。LST能够显著降低缺血-再灌注小鼠脑组织中MDA含量,增加SOD活性。此外,LST还具有一定的抗血栓作用。结论:LST具有抗血管性痴呆作用,其机制可能与缓解脑缺血、缺氧状态,减少活性氧的生成,提高脑组织抗氧化酶活力,抑制脂质过氧化反应相关。
Objective: The purpose of this paper was to study the anti-vascular dementia effects of LST and its mechanism. Methods: Using the methods of behavioral pharmacology including the one-trial step-down and the step-through passive advoidance test, Y-maze test and the water maze test to investigate the effects of LST against the vascular dementia induced by cerebral ischemia reperfusion in mice, middle cerebral artery occlusion(MCAO) model in rats and multi-infarct dementia (MID) model in rats. Furthermore, the antithrombtic effect of LST was also detected. Results: It reduced numbers of errors in step-down test, prolonged the latency of entry into dark room in step-through test, decreased the time of swimming from the original area to the goal area and increased the numbers of right reflects in water maze task in mice performed cerebral ischemia-reperfusion. In Morris water maze task LST shortened the latency of searching the hidden platform in directional swimming test and increased the time spent swimming in the target quadrant during 90s in probe test in rats performed MCAO and MID. Moreover, LST prolonged the latency of entry into dark room in step-through test and increased the percent alternation in Y maze task in these rats. Furthermore, a correlation between histological injury and behavioral deficits was shown pathologically. The increase of contents of malonic aldehyde (MDA) and the inhibition of superoxide dismutase (SOD)'s activity in the cerebrum in mice performed cerebral ischemia-reperfusion were significantly prevented by the administration of LST .Conclusion: Summarizing all the experimental results, LST showed the anti-vascular dementia effects. The mechanism maybe involve relieving the condition of cerebral ischemia, inhibiting the oxygen free radical reaction,elevating the activity of antioxidase in brain.
引文
[1] 刘石梅,苏南湘,何明大.血管性痴呆动物模型[J].中医药学报,2005,11(9):77~81.
[2] 田金洲,王永炎,Judy HGW.血管性痴呆研究述评[J].北京中医药大学学报,1997,20(4):2~7.
[3] Tatemichi TK, Desmond DW, Mayeux R, et al. Dementia after stroke: baseline frequency, risks, and clinical features in a hospitalized cohort[J]. Neurology, 1992, 42(3): 1185~1193.
[4] 高素荣.痴呆的诊断与鉴别诊断[J].脑与神经病杂志,1998,6(2):65.
[5] 丁素菊.血管性痴呆.中国老年学杂志[J].2003,4(23):200~202.
[6] 周国庆,金水清,孙中玉.血管性痴呆与偶然发现的白质损害[J].临床神经病学杂志,1994,7(2):104.
[7] Desmond DW, Moroney JT, Pal RMC et al. Frequency and clinical determinants of dementia after isehemic stroke[J]. Neurology, 2000, 54: 1124~1131.
[8] 冯德光,黄纪昌,刘泽.颈动脉粥样硬化程度与老年血管性痴呆程度的相关性分析[J].实用医学杂志,2002,18(9):949~950.
[9] 单培彦,王淑贞,焉传祝,等.血管性痴呆相关因素的分析[J].中风与神经疾病杂志,1999,16(6):567~56.
[10] 林琅.血管性痴呆的病因研究[J].国外医学老年医学分册,2001,22(2):78~80.
[11] 张雪朝,孙国杰.血管性痴呆相关基因研究进展[J].湖北中医学院学报,2002,4(2)::51~52.
[12] 杨惠玲主编.高级生理病理学[M].北京科学出版社,1998:4~38.
[13] 刘国卿.神经元保护剂的研究进展[J].药学学报,2002,37(8):657~662.
[14] 王德生,张守信.老年性痴呆[M].人民卫生出版社,2001,10:235.
[15] Tohgi H.Abe T, Kinrura M, et al. Cerebrospinal fluid acetyleholine and choline in vascular dementia of Binswanger and multiple small infarct types as compared with Alzheimer-type dementia[J]. Journal of Neural Transmission 1996; 103:1211~1220
[16] 王柠,吴志英.一氧化氮合酶与脑缺血亚急性期神经损伤的关[J].福建医科大学学报,2003,37(1):23~25.
[17] 阎超华,冯亦璞,张均田.NO,脑循环与缺血缺氧性脑损伤[J].中国药理学通报,1996,12(5):397~401.
[18] 邵福元,黄流清,薛红,等.血管性痴呆研究[J].中国临床神经科学,2001,9(1):92~95.
[19] 何建成,张晓峰.兴奋性氨基酸与缺血型脑损伤[J].2001,18(4):334~336.
[20] 刘萍.钙离子与脑缺血关系的研究进展[J].医学文选,2001,20(5):709~711.
[21] Blausten MP. Cellular Calcium: Nervous System. In: Nordin BEC, ed. Calcium in human biology. London: Springer-Vedag, 1988:357~358
[22] Chu GX, Chen X. Protective effect of ginsenosides on acute cerebral ischemia/reperfusion injury of rats[J]. Chin J Pharmacol Toxicol. 1989, 3(1): 18~23.
[23] 王敬卿,徐伟.血管性痴呆的脑血流及代谢研究进展[J].内蒙古医学杂志,2000,32(4):299~302.
[24] 周武,于步润.脑梗塞患者血浆内皮素与降钙素基因相关肽动态观察[J].中风与神经疾病杂志,1996,13(3):145~147.
[25] 王玉梅,袁彬,马铭心,等.血管性痴呆患者血浆内皮素和超氧化物岐化酶的定量分析[J].中国航天医药杂志,2002,4(2):41~42.
[26] 高唱,王景周,王琳,等.血管性痴呆患者血小板活化机制的研究[J].解放军医学杂志,2002,27(9):800~801.
[27] Ziv H, Fleminger G, Djaldetil R, et al. Increased plasma endothelin-Ⅱ in acute ischemic[J]. stroke, 1992, 23: 1014~1016.
[28] 谭兰,苏净,刘震.抗磷脂抗体与血管性痴呆的相关性研究[J].山东医药,2001,41(19):3~5.
[29] 赵青菊,谭兰,刁振明.抗心磷脂抗体与血管性痴呆的关系[J].山东医药,2003,43(7):44~45.
[30] 陈攸,梅又雪.血管性痴呆患者脑脊液微量元素的变化[J].临床神经病学杂志,1999,12(1):34~36
[31] 张雪玲,丁新生,程虹,等.血管性痴呆脑脊液中Tau蛋白及Aβ检测[J].江苏医药杂志,2003,29(5):362~363.
[32] 陈振虎,江刚辉,赖新生.电针治疗血管性痴呆临床疗效观察[J].针灸临床杂志,2000,16(12):18.
[33] 周渲芸.血管性痴呆的针灸治疗概况[J].针灸临床杂志,2000,16(11):53.
[34] 高汉义,闫乐法,刘百波,等.针灸治疗老年血管性痴呆的临床研究[J].中医杂志,1999,40(8):471.
[35] 陈奇主编.中药药理研究方法学(第一版)[M].人民卫生出版社,1993,9:669~670.
[36] 张均田,斋藤洋.十二种化学药品破坏小鼠被动回避性行为—跳台试验和避暗试验的作用的比较观察[J].药学学报,1986,21(1):12~19.
[37] 于庆海,吴春福,庄丽萍,等.归脾汤对小鼠记忆行为和胆碱酯酶活性的影响[J].中药药理与临床,1990,6(5):2~3.
[38] Kiyofumi Yamada, Tomoko Tanaka, Zou L B, et al. Long-term deprivation of oesrtrogens by ovariectomy potentiates β-amyloid-induced working memory deficits in rats[J]. British Journal of Pharmacology, 1999, 128: 419~427.
[39] Thomas X. Gionet, Jennifer D. Thomas, David S. Warner, et al. Forebrain Ischemia Induces Selective Behavioral Impairments Associated With Hippocampal Injury in Rats [J]. Stroke, 1991, 22(8): 1040~1047.
[40] 么冬爱,刘汉兴,张晓琴,等.雌激素鱼脑缺血[J].国外医学脑血管疾病分册,2000,8(1):6~8.
[41] 徐叔云,卞如濂,陈修.药理实验方法学第三版[M].1998,1065~1066.
[42] 姚炜,库宝善,张疆寅,等.姚海燕 L-盐酸赖氨酸对局部脑缺血大鼠地治疗作用[J].药学学报,1999,34:401~404.
[43] 刘存志,于建春,王彤,等.大鼠多发梗塞性痴呆模型的建立及针刺的干预作用[J].中国中医药信息杂志,2005,9:31~33.
[44] 李红,王秀华,崔佳乐,等.注射用蒺藜皂苷的抗血栓形成作用[J].吉林大学学报(医学版),2005,31(1):14~16.
[45] 朱虹,吴强,徐明,等.黄芪总提物体内外抗血栓作用的实验研究[J].中国临床药理学与治疗学,2005,10(8):917~920.
[46] 徐秋萍,李云谷,蒋爱华,等.脑缺血再灌致学习记忆损伤小鼠模型的建立及益脑冲剂的保护作用[J].北京中医药大学学报,1996,19(6):62~64.
[47] Deven BD, Goad EH, Petri HL. Dissociation of hippocampal and striatal contributions to spatial navigation in the water maze[J]. Neurobiol Learn Mere, 1996; 66(3): 305~323
[48] Myron D,Ginsberg MD,Raul Busto BS.Rodent models of cerebral ischemia[J].Stroke, 1989,20:1628.
[49] Tamura A,Graham DI,McCulloch J,et al.Focal cerebral ischemia in the rat:1.Description of technique and early neuropathological consequences following middle cerebral artery occlusion[J].J Cerb Blood Flow Metab,1981,1:15.
[50] Bederson JB,Pitts LH,Tsuji M,et al.Rat middle cerebral artery occlusion:Evaluation of the model and development of a neurologic examination[J].Stroke, 1986,17:472.
[51] 王军.大鼠脑缺血模型研究进展[J].中医研究,2002,15(5):60~61.
[52] Wishart TB, Ijaz S, Shuaib A. Differential effects of amphetamine and haloperidol on recovery after global forebrain ischemia[J]. Pharmacol Biochem Behav, 1994, 47: 963~968.
[53] 陈俊旭,田时雨,于薇薇,等.多发性脑梗塞痴呆动物模型的研究[J].中华神经科杂志.1994,27(5):311~312.
[54] Kancko D, Nakamura N, Ogawa T. Cerebral infarction in rats using homologous blood emboli: Development of a new experimental modal[J]. Stroke, 1985. 16: 76~84.
[55] Morii K. Pathological and pathophysiological studies on central nervous system in experimental cerebral isehemia of the rot[J]. Hokkaido Igaku Zasshi 1992. (1): 109~129.
[56] Smith CD. Thonlas GS. Kryscio RJ.et al.31P spectroscopy in experimental embolic stroke: correlation with infarct size[J]. NMR Biomed. 1990. 3(6): 251~264.
[57] 彭康,郑文权,臧坤堂,等.乌龙丹对多发性脑梗塞痴呆大鼠学习记忆功能的影响及其机理[J].中医杂志,1999,40(12):746~748.
[58] 张崇泉,孙兆泉,张炜宁,等.健脑通络胶囊对血管性痴呆大鼠大脑神经递质的影响[J].中国医药学报,2000,15(1):33~35.
[59] 胡国华,杜志军,吴杰,等.多发性脑梗塞痴呆大鼠脑区内生长抑素含量的变化[J].中风与神经疾病杂志,1998,15(4):211~212.
[60] 孙兆泉,张崇泉,首第武,等.健脑通络方对脑梗塞大鼠脑内氧自由基代谢的影响[J].中医药研究,1999,15(3):35~37.
[61] 刘晓湘,李东培,方秀斌,等.NGF和Svme-3对多发性脑梗塞大鼠纹旁区神经元作用的实验研究[J].中国医科大学学报,2000,29(3):175~176.179.
[62] 梅建勋,张云岭,张伯礼.健脑益智冲剂对多发梗塞性痴呆大鼠模型血液流变学的影响[J].天津中医,1998,15(6):269~271.
[63] 张崇泉,孙兆泉,张炜宁,等.健脑通络益智方对血管性痴呆大鼠脑DNA合成影响的实验研究[J].湖南中医药导报,2001,7(1):8~10.
[64] Kaneko D, Nakamura N, Ogawa T.Cerebral infarction in rats using homologous blood emboli:Development of a new experimental model [J].Stroke, 1985, 16(1): 76~84.
[65] 张爱林,徐秋萍,孙建宁.多发性脑梗塞痴呆动物模型评价[J].上海实验动物科学,2003,23(3):186~188.
[66] Seif EL, Nasr M, Fattah AA. Lipid peroxide, phospholipids, glutachione levels and superoxide dismutase zctivity in rat brain after ischaemia: effect of gingo biloba extract [J]. Pharmacol Res, 1995,32(5): 273.
[67] Schmidley JW.. Free radicals in central nervous system ischemia[J]. Stroke, 1990, 21: 1086.