【作者】 李海芳；

【导师】 王志斌；

【作者基本信息】 北京中医药大学 ， 中药学， 2008， 硕士

【摘要】 抑郁症(depression)属于情感性障碍(affective disorder)。主要临床表现为心境抑郁,丧失兴趣,不能体验生活中的乐趣,精力不足,主观能动性降低或丧失,自我评价较低,精神运动迟缓,甚至产生自杀观念或行为,常伴有某些躯体或生物学症状。抑郁症由于其高发而且难以根治,传统的针对单一环节、单一靶点的抗抑郁药物毒副作用比较大,费用比较高、易反复等特点,所以研究开发新的、安全有效的抗抑郁药物有很重要的社会及经济效益。甘麦大枣汤是传统的有较好疗效的抗抑郁复方,经过拆方对比试验,以及单味药试验,表明甘草醇提取物有效。有效部位的分离及大孔吸附树脂分离,结合动物实验检测,发现50%乙醇洗脱物具有良好的抗抑郁活性。成分分析表明以甘草苷为主要成分。在前期的一系列预实验基础上,我们欲对甘草苷的药效学及机制进行探讨。一甘草苷抗抑郁作用的药效学研究1甘草苷对急性应激所致动物绝望行为的影响采用小鼠悬尾和小鼠强迫游泳致小鼠行为绝望实验,观察甘草苷对小鼠悬尾不动时间和小鼠游泳不动时间的影响。结果显示甘草苷的40mg/kg、20mg/kg、10mg/kg单次给药能显著缩短小鼠的悬尾不动时间以及小鼠游泳不动时间(p<0.05)。2甘草苷对药物诱发的抑郁动物模型的影响2.1甘草苷对利血平化小鼠行为变化的影响利血平通过耗竭脑内单胺类递质诱发动物的综合症状主要包括:体温下降、眼睑下垂和活动抑制。这些症状的发生与利血平降低脑内单胺类递质,尤其是5-HT。给予甘草苷溶液1h后,再给予利血平,观察各组小鼠体温下降的情况(t检验),以及各组运动不能和睁眼不能的动物只数(X2检验)。结果表明,甘草苷各剂量组可显著对抗小鼠利血平腹腔注射所引起的体温下降、显著对抗腹腔注射利血平所引起的运动不能及眼睑下垂,说明该药具有明显的对抗利血平作用。3甘草苷对慢性应激抑郁模型大鼠的行为的影响本研究运用慢性不可预知的应激模型(chronic unpredictable stress,CMS)和孤养两种经典方法,利用长期不可预见性的中等强度应激,造成孤养动物抑郁状态。造模期间连续灌胃给药,观察造模后药物对模型大鼠体重、蔗糖偏嗜度及行为学的影响。实验结果显示,模型组大鼠的水平穿越格数、站立次数均减少,中央格停留时间显著延长(P<0.01, P<0.05);大鼠体重增长值明显减少(P<0.01)蔗糖溶液消耗量明显减少(P<0.01);水迷宫实验结果显示CUMS大鼠出现学习记忆障碍。这些表现说明动物表现出抑郁状态、兴趣丧失和快感缺乏,与抑郁症临床诊断中的精神运动改变、兴趣或快感的丧失有一定程度的相似性,提示大鼠抑郁模型的复制是成功的。经过三周连续给药后,与模型组相比,甘草苷的各剂量组能显著增加大鼠体重(P<0.01);蔗糖消耗量显著增多(P<0.05);open-field实验中大鼠的水平穿越格数、站立次数显著增多(P<0.05),中央格停留时间显著缩短(P<0.05);水迷宫实验中学习记忆能力得到显著改善(P<0.05)。二甘草苷对抑郁症模型大鼠治疗作用的机理研究1甘草苷对CUMS大鼠脑内单胺类神经递质的影响造CUMS模型,采用高效液相色谱-电化学检测器(HPLC-ECD)对大鼠脑内海马部位的单胺类神经递质及其代谢产物进行检测。结果显示模型组大鼠海马内5-HT、NE含量显著降低,甘草苷中剂量组(20mg/kg)能显著提高5-HT、NE水平(P<0.05)。而对DA、DOPAC含量影响不明显。2甘草苷对CUMS大鼠血清中CRO、IL-1β、IL-2、IL-6含量的影响造CUMS模型,采用放免法对各组大鼠血清中皮质醇(CRO)、IL-1β、IL-2、IL-6含量进行检测。结果显示,模型组大鼠血清中皮质醇、IL-1β含量明显高于空白对照组。治疗后阳性给药组及甘草苷中剂量组能显著降低IL-1β、皮质醇水平(*P<0.05),且阳性给药组能升高IL-2、IL-6水平(*P<0.05),而甘草苷大剂量、小剂量与模型组比较差异不显著。更多还原

【Abstract】 Depression is an affective disorder disease with higher outbreak rate . Tthe symptom is diverse, such as the motion low fall, appetite and sleep obstacle, cynical and suicide obsession, and so on. At present ,the synthetic chemical medicines were mainly taken as treatment to depression have been proofed that have the defects and side effects and expensive .Medicinal plants from natural resources,especially the traditional Chinese medicine have a long time experience in cure depression.Among many traditional Chinese medicine recipes ,the classic recipe“Ganmai Dazao Decotion”showed significant antidepressant effect.And the effect element is Liquiritin.We want to make use of the modern pharmacology to learn method evaluate Liquiritin the treatment suppresses the efficacy of medicine and possible mechanis ms of depression.Study of Liquiritin to treat depression on pharmacodynamics1 Effects of Liquiritin on Behavior despair of animal1.1 Forced swimming test(FST)The test was performed essentially as described by Porsolt et al. (1977). Mice were individually placed in a vertical glass container (20 cm high, 10 cm in diameter), containing 16cm of water maintained at 22°C–25°C. The total duration of immobility was recorded during the last 4 min of the 6min test period. The immobility time was recorded using the EthoVision video tracking system.1.2 Tail suspension test(TST)The grouping and drug administration matter were the same as FST .The mouse was individually suspended by its tail with a clamp (2 cm from the end )for 6min and the duration of immobility was recorded in last 5min.2 Effect of liquiritin on induced to the medicine of the depression animal modelAfter administration of liquiritin for 2 days, and then give reserpine to induce depression symptoms, observe the ptosis, akinesia and hypothermia which occurred by reserpine.3 Unpredictable Chronic stress test(CUMS )After chronic unpredictable stress which exerted on each rat excluding the control ones for 3 weeks , we found that the liquiritin can improve the symptoms which appeared in the mod- el rats. The three doses of liquiritin 40mg/kg、20mg/kg、10mg/kg) all increased the quantity of the water wi th carbohydrate which was drunk by rats. The rat weight increment. The number of crossings- and rearings in the open field test (OF) and stop over time of central space and number of excrement were increased as well. according to our findings of water maze , Shorten the Escape l atent period of the third day and the forth day obviously, and raise to cross the Platform num- ber of times.Study on mechanism of liquiritin on depression models in rats1 Effects of liquiritin on monamine transmitter of inside brain in the CUMS ratsMake use of the CUMS model.And adopt HPLC-ECD measurement brain inside transmitter and it metabolizes the outcome in the rat brain by CUMS. According to our findings,show that model group showed reduced the 5-HT、NE、DA level (**P<0.01,*P<0.05),and increased the 5-HIAA、5-HIAA/5-HT、DOPAC level . After treatment of Clomipramine and middle dose of liquiritin , the level of 5-HT、NE increased ( **P<0.01, *P<0.05 ) ,but reduced the 5-HIAA、5 - HIAA/5-HT ( **P<0.01, *P<0.05).and there have no significant changes to DA and DOPAC.2 Effects of liquiritin on COR、ACTH、IL-2、IL-6 of the bloodMake use of the CUMS model. Make use of the immunity analysis method measurement the content of the IL-2, IL-6 in plasma andACTH, COR in serums.According to our findings, Model group showed increased IL-1? and cortisol level versus normal group(P<0.05). after treatment of Clomipramine and middle dose of liquiritin ,the level of IL-1? , IL-6 and cortisol reduced to normal (P<0.05),but high and low dose have no significant changes.And in this experiment ,there has no significant change of IL-2 before and after stress .更多还原