贯归定志方抗焦虑作用药效学研究及机制探讨
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摘要
近年来,随着社会经济的快速发展,社会工作、人际关系、经济压力等诸多因素作用的影响,人们普遍感到沉重的精神压力。进入21世纪,人们对精神健康的关注已从传统的重型精神障碍如精神分裂症,逐渐向轻型精神障碍如神经症转变。焦虑症作为神经症的一个亚型,其发病率在我国呈逐年上升趋势,日益成为现代生活中对人们健康危害严重的精神疾病。
本课题通过查阅大量的相关文献以及古今中医名家的用药经验,参考现代药理学的科研成果,并结合临床与市场的需求,以疏肝降火,交通心肾,镇惊安神为组方原则,拟定出治疗焦虑症的中药复方——贯归定志方。我们采用国际通用的焦虑症动物模型进行行为学实验,考察贯归定志方抗焦虑作用。运用饮水冲突模型实验进行贯归定志方发挥抗焦虑作用的γ-氨基丁酸能神经通路调节机制的探讨。并且,针对目前缺少公认的焦虑症的中医学病证结合模型的情况,本课题通过查阅文献及结合实验摸索,初步探索建立了焦虑症的病证结合的动物模型。
1.药效学实验
1.1贯归定志方对小鼠高架十字迷宫模型的影响
目的:采用小鼠高架十字迷宫实验模型,观察贯归定志方的抗焦虑作用。
方法:采用小鼠高架十字迷宫,设立空白对照组、DZP、贯归定志方Ⅰ(GGDZⅠ)、贯归定志方Ⅱ(GGDZⅡ)、贯归定志方Ⅲ(GGDZⅢ)共5组,其中中药GGDZⅠ、Ⅱ、Ⅲ组分别按生药量2.5g/kg/d、5g/kg/d、10.0g/kg/d给予灌胃,DZP组给予2.0 mg/kg/d灌胃,空白对照组灌服等容积的生理盐水。连续给药10天,第10天进行行为学测试。
结果:与空白对照组比较,地西泮可显著增加EPM大鼠的OT%和OE%(P<0.05或P<0.01),同时贯归定志方5.0 g/kg/d亦能显著增加EPM大鼠的OT%和OE%(P<0.05),而不增加其TE。而2.5 g/kg/d、10.0g/kg/d组与空白组比较,大鼠的OT%、OE%也表现出增加的趋势,但未见统计学意义。
结论:表明贯归定志方剂量在5.0 g/kg/d时有明显的抗焦虑作用,但抗焦虑作用未随着剂量的增加或减少而增强。初步显示了贯归定志方对小鼠焦虑行为有肯定的干预作用。
1.2贯归定志方对小鼠明暗箱模型的影响
目的:采用小鼠明暗箱实验模型,观察贯归定志方的抗焦虑作用。
方法:采用小鼠明暗箱模型,分组和给药同上。连续给药10天,第10天进行行为学测试。
结果:地西泮、贯归定志方5.0 g/kg可显著增加小鼠的穿梭次数和明箱时间(P<0.05),10.0 g/kg/d也能显著增加小鼠的明箱时间(P<0.05)。
结论:贯归定志方在5.0～10.0 g/kg/d剂量范围内,具有一定的抗焦虑效应,与DZP的作用方向一致,从对明暗箱小鼠各项指标来看,以5.0 g/kg/d剂量效果最佳,与EPM的实验结果基本一致。
1.3贯归定志方对大鼠高架十字迷宫模型的影响
目的:采用大鼠高架十字迷宫实验模型,利用不同的动物实验,重复验证贯归定志方的抗焦虑作用。
方法:采用大鼠高架十字迷宫实验模型,分组同前,其中中药GGDZⅠ、Ⅱ、Ⅲ组分别按生药量2.0 g/kg/d、4.0 g/kg/d、8.0 g/kg/d给予灌胃,DZP组给予1.0 mg/kg/d灌胃,空白对照组灌服等容积的生理盐水。连续给药10天,第10天进行行为学测试。
结果:DZP组、达尔康4.0 g/kg/d能显著提高大鼠开臂时间百分比(OT%)(P<0.05),且可非常显著增加大鼠开臂次数百分比(OE%)(P<0.01),不增加进入两臂的总次数(TE)。
结论:此与小鼠行为学实验结果基本一致,提示贯归定志方在不增加动物活动性的前提下,有确切稳定的抗焦虑作用。
1.4贯归定志方对大鼠饮水电击冲突实验的影响
目的:vogel饮水电击冲突实验属条件反射模型,高架十字迷宫实验属非条件反射型模型,本实验采用不同的模型,验证贯归定志方抗焦虑药效的稳定性和可靠性。
方法:采用大鼠vogel饮水冲突实验模型,分组同前,给药同大鼠EMP实验。各组连续给药10d,末次给药前48h禁水。第9d进行非惩罚饮水训练,第10d,中药组、空白对照组末次给药1h后,DZP组灌胃1.0mg/kg 0.5h后,进行惩罚实验测试。
结果:与空白对照组比较,DZP组、贯归定志方4.0 g/kg组、8.0 g/kg组均能增加大鼠接受电击的次数和在电击情况下的舔水次数,有极显著的统计意义(P<0.01);同时,贯归定志方2.0 g/kg组也显示出显著的统计意义(P<0.05)。
结论:贯归定志方各剂量组均能增加大鼠的电击和舔水次数,有较好的抗焦虑作用,说明贯归定志方对饮水冲突实验模型比较敏感,故下述机制探讨实验均采用饮水冲突模型。
1.5贯归定志方对病证结合动物模型的影响
目的:采用大鼠急性应激+高架十字迷宫复制焦虑症的病证结合模型,从行为学考察模型复制的成功与否,以及贯归定志方的对此模型的疗效。
方法:将动物分为模型组Ⅰ(ModelⅠ,空白对照)、模型组Ⅱ(ModelⅡ,病证结合动物模型)、DZP组、GGDZⅠ(4倍量组)、GGDZⅡ(8倍量组)、GGDZⅢ(16倍量组)共6组。其中GGDZⅠ、GGDZⅡ、GGDZⅢ组分别按生药量2.0 g/kg/d、4.0 g/kg/d、8.0 g/kg/d给予灌胃,DZP组按每日1.0mg/kg给以DZP混悬液灌胃,ModelⅠ、ModelⅡ灌服等容积的生理盐水。连续灌胃10d,第8d开始造模,具体过程为:除空白对照组外的其余各组的动物,用海绵钳(以海绵和胶布包裹的止血钳)夹住大鼠的尾巴尖部,激怒大鼠,使之与其他大鼠保持相斗状态(注意使大鼠保持相互争斗状态后即可松开海绵钳,防止长时间钳夹损伤尾巴,并且海绵钳夹尾巴产生的压强以夹住尾巴不脱落为宜),每次刺激30min,每隔4h一次,每日3次,夜间单笼饲养,连续2日。第10日给药后进行十字迷宫测试。
结果:本实验的病证结合的动物模型经过2天的刺激后,大鼠表现为频繁在笼中走动、稍有响动呈现惊吓状、尖叫、毛须竖立、易激惹,刺激解除后相互之间仍时有撕咬、打斗,排便次数增加,饮食、饮水减少等;通过高架十字迷宫模型观察到,病证结合模型的大鼠在迷宫中排尿、排便次数增多,经药物干预后整体来看,地西泮组和贯归定志方4.0 g/kg/d组的症状较其他组轻,可见到动物的躁动行为减轻,且高架十字迷宫实验中排便、排尿减少。就两个模型组比较而言,在高架十字迷宫实验中,急性应激模型组二便增多的症状较空白对照组表现明显。从高架十字迷宫数据统计结果可以看出,与模型组Ⅰ相比,模型组Ⅱ大鼠进入开臂时间的百分数(OT%)和进入开臂次数的百分数(OE%)显著减少(P<0.05),DZP组、贯归定志方Ⅱ(GGDZⅡ)可以明显增加大鼠进入开臂时间的百分数(OT%)和进入开臂次数的百分数(OE%)(P<0.05或P<0.01)。与模型组Ⅱ相比,模型组Ⅰ大鼠进入开臂时间的百分数(OT%)和进入开臂次数的百分数(OE%)显著增多(P<0.05),DZP组、贯归定志方各剂量组均可明显增加大鼠进入开臂时间的百分数(OT%)和进入开臂次数的百分数(OE%)(P<0.01)。而总入臂次数(TE)则无明显变化,表明各组并未增加大鼠的运动性。其他各组间无显著差异。
结论:就十字迷宫数据来看,本病证结合模型的各项指标均较单纯的高架十字迷宫实验有所降低,表明通过前期的急性应激作用,进一步激发了动物的焦虑反应,而且反之也通过高架十字迷宫实验对前期造模的效果进行了验证。从动物症状来看,单纯的高架十字迷宫模型动物表现为短暂的焦虑状态,而持续的急性应激刺激后,动物的各种表现与临床焦虑症属肝郁证的症状较为相似,并且通过高架十字迷宫的再次造模,增加了焦虑症状的持续性,使模型复制的稳定性和成功率增高。
因以上高架十字迷宫、明暗箱、Vogel饮水冲突实验三个模型对苯二氮卓类抗焦虑剂尤为敏感,地西泮所属的苯二氮卓类抗焦虑剂主要是通过γ-氨基丁酸能神经通路发挥抗焦虑作用,而本实验中贯归定志方与苯二氮卓类地西泮的抗焦虑作用趋势一致,故实验结果提示贯归定志方发挥抗焦虑作用机制可能与γ-氨基丁酸能神经通路有关。
2.机制研究——贯归定志方对γ-氨基丁酸能神经通路的影响
2.1贯归定志方对饮水电击冲突实验大鼠脑组织氨基酸类神经递质含量的影响
目的:采用大鼠vogel饮水冲突实验,观察大鼠海马中氨基酸类神经递质的含量变化,来评价贯归定志方对神经元兴奋性的影响。
方法:给药分组同前,大鼠饮水电击冲突实验结束后,立即断头处死,迅速取出大脑于冰盘上快速分离出海马,用氨基酸自动分析仪检测大鼠脑组织海马中的氨基酸含量。
结果:Vogel饮水冲突模型组大鼠脑组织海马中的GABA、Gly的含量降低,Glu/GABA比值升高,Glu含量显示出升高趋势。而与模型组相比,DZP组、贯归定志方4.0g/kg/d能显著增加Vogel饮水冲突大鼠海马中的GABA、Gly的含量(P<0.05或P<0.01),降低Glu/GABA比值(P<0.01),Glu的含量虽未有统计学意义,却显示下降的趋势。而贯归定志方2.0 g/kg/d与8.0g/kg/d也可显著降低Glu/GABA比值(P<0.01)。
结论:焦虑模型组动物脑组织中GABA、Gly含量降低,使神经元的兴奋得不到正常控制,导致焦虑的发生。而贯归定志方通过增加GABA、Gly的含量,并降低Glu/GABA比值来发挥抗焦虑作用。
2.2贯归定志方对饮水电击冲突实验大鼠脑组织谷氨酸脱羧酶表达的影响
目的:采用大鼠vogel饮水冲突实验,观察大鼠海马中谷氨酸脱羧酶的表达变化,来评价贯归定志方对GABA合成的影响。
方法:给药分组同前,大鼠饮水电击冲突实验结束后,立即断头处死,迅速取出大脑于冰盘上快速分离出海马,用中性福尔马林固定,采用免疫组织化学法检测大鼠脑组织海马中的谷氨酸脱羧酶(GAD)表达。
结果:空白对照组GAD_(65)蛋白表达细胞质着色浅,而且着色细胞数少;DZP组GAD_(65)表达强,细胞胞浆内呈黄褐色,而且着色细胞数多;贯归定志方Ⅱ(GGDZⅡ)及贯归定志方Ⅲ(GGDZⅢ)组GAD_(65)蛋白表达较强,可见细胞胞浆内呈黄褐色,着色深,着色细胞多;贯归定志方Ⅰ(GGDZⅠ)组GAD_(65)蛋白表达较弱,细胞质淡染,着色较浅。各组神经节细胞GAD_(65)蛋白表达积分光密度值统计结果为:与空白对照组比较,DZP组、GGDZⅡ组GAD_(65)蛋白表达积分光密度值显著增高(P<0.05),而GGDZⅠ和GGDZⅢ组虽未见统计学意义,但显示出升高的趋势。
结论:焦虑症模型动物大鼠海马中GAD表达下降。而贯归定志方能使GAD蛋白表达增多,因GAD是GABA合成酶和限速酶,故可增加脑内抑制性神经递质GABA浓度。结合上述氨基酸检测结果可以看出,GABA改变与GAD表达变化一致,说明大鼠海马脑组织GABA浓度升高可能是由GAD活性增强所致。
2.3贯归定志方对饮水电击冲突实验大鼠脑组织γ-氨基丁酸转氨酶活性的影响
目的:采用大鼠vogel饮水冲突实验,观察大鼠海马中γ-氨基丁酸转氨酶的活性变化,来评价贯归定志方对GABA代谢的影响。
方法:给药分组同前,大鼠饮水电击冲突实验结束后,立即断头处死,迅速取出大脑于冰盘上快速分离出海马,用ELISA法检测大鼠脑组织海马中的γ-氨基丁酸转氨酶(GABA-T)活性。
结果:与对照组相比,DZP组、贯归定志方Ⅱ(GGDZⅡ)、贯归定志方Ⅲ(GGDZⅢ)可以明显降低大鼠海马内GABA-T的活性(P<0.05),而贯归定志方Ⅰ(GGDZⅠ)组虽未有统计学意义,但也显示了同样的趋势。
结论:贯归定志方降低海马内GABA-T活性,可抑制GABA-T对GABA的降解作用,从而使得GABA增多,抑制中枢神经系统的兴奋性而起到抗焦虑作用。
2.4贯归定志方对饮水电击冲突实验大鼠脑组织GABA与GABA_A受体结合活性和结合数量的影响
目的:采用大鼠vogel饮水冲突实验,观察大鼠海马中GABA与GABA_A受体结合活性和结合数量的变化,来评价贯归定志方对GABA与GABA_A受体结合的影响。
方法:给药分组同前,大鼠饮水电击冲突实验结束后,立即断头处死,迅速取出大脑于冰盘上快速分离出海马,用ELISA法检测大鼠脑组织海马中的GABA与GABA_A受体的结合活性和结合数量。
结果:从结果可以看出,与对照组相比,DZP组、贯归定志方Ⅱ(66DZⅡ)可极显著增强大鼠海马内GABA与GABA_A受体的结合活性,升高与GABA_A受体的结合数量(P<0.01),贯归定志方Ⅲ(GGDZⅢ)也可显著增加大鼠海马内GABA_A受体的含量(P<0.05),而贯归定志方Ⅰ(GGDZⅠ)组虽未有统计学意义,但也显示了同样的趋势。
结论:从检测结果可以看出,对照模型组大鼠海马脑组织中的GABA与受体的结合活性下降、受体的结合数量减少,即GABA_A受体功能下调。而地西泮和贯归定志方可以上调GABA与受体的结合数量,并且增强了其结合活性,提示贯归定志方可能通过增加GABA与受体的结合数量及上调与GABA受体的结合活性,发挥抗焦虑作用。
2.5贯归定志方对小鼠自主活性的影响
目的:采用小鼠自主活动模型,观察贯归定志方是否具有镇静的副作用。
方法:给药分组同前小鼠EPM实验,连续给药10d,第10d进行行为学测试。
结果:与空白对照组比较,地西泮未减少小鼠自主活动次数,贯归定志方各剂量组也未减少小鼠的自主活动次数,未见统计学意义。
结论:贯归定志方在抗焦虑作用的剂量下无镇静的副作用。
结论
本课题通过小鼠的高架十字迷宫(EPM)、明暗箱实验初步得出了贯归定志方抗焦虑的作用,又进一步采用大鼠高架十字迷宫、vogel饮水冲突实验重复验证了贯归定志方的疗效,得出了一致的确切可靠的结果。整个实验采用EPM、明暗箱、饮水冲突实验三个模型互参,从非条件反应模型和条件反应型惩罚性模型等不同角度观察贯归定志方对动物的抗焦虑作用,大大增加了药效学评价的可靠性。通过机制实验研究,发现贯归定志方发挥抗焦虑作用主要通过降低脑组织中Glu的含量、增高GABA、Gly的含量,降低Glu/GABA比值来调整中枢神经系统的兴奋状态;增强GABA合成酶的表达、抑制GABA代谢酶的活性,进一步使GABA含量增多,控制神经元的兴奋性;增强GABA与GABA_A受体的结合活性、增加其结合数量,使GABA与GABA_A受体更好的结合来发挥抗焦虑作用。通过本实验的研究,为中药复方发挥作用的确切靶点的机制探讨提供系统的完整思路。
本实验初步探索建立了焦虑症的病证结合动物模型,在中医证候理论指导下研究药物作用进行了初步的探索,本研究有利于进一步揭示证候的本质,为研究中医病证结合模型进行了有益的尝试。
Recently,people feel heavy stress generally because of the influence of social work, interpersonal relationship and economic pressure,along with the rapid development of the society and the economy.People pay attention to mitis mental disease such as neurosis from serious mental disease as if schizophrenic in 21 century.The occurrence of anxiety as a subtype of neurosis is increasing year by year.Anxiety which harms people'health becomes increasingly a severe mental disease.
The object of this paper layings a Chinese materia medica prescription of treating anxiety----GUANGUIDINGZHIFANG(GGDZ),by consulting a lot of pertinent literature and paleo-modern TCM famous doctors' medicational experience,referring to technological research findings of modern pharmacology,combining clinical and market requirement.This prescription is on the base of composing principles of soothing liver and sending down fire, restoring normal coordination between heart and hidney,relieving convulsion and anchoring the mind.We adopt the international universal anxiety animal models to investigate antianxiety effect of GGDZ.We apply Vogel's conflict test to approach possible GABA nervous pathway of GGDZ antianxiety mechanism.To aim directly at the deficiency of received anxiety animal model of TCM disease-syndrome,this topic explores initially to build a anxiety animal model of TCM disease-syndrome by consulting literature and combining protophase experimental crocidismus.
1.Pharmacodynamics research
1.1 Effects of GGDZ on the mice EMP test
Objective:to observe the antianxiety effect of GGDZ on the mice EMP test.
Methods:to adopt the mice EMP model,mice is divided into model,DZP,GGDZⅠ, GGDZⅡ,GGDZⅢfive groups randomly.GGDZⅠ,Ⅱ,Ⅲgroups are administrated orally with 2.5g/kg/d,5.0g/kg/d,10.0g/kg/d respectively,DZP group 2.0mg/kg/d,model group equivalent saline,they are administrated 10 days continuously,the praxiological test, observation,and comparing various praxiological index on the tenth day.
Results:DZP and GGDZⅡgroups can increase the open entries percent(OE%) and open times percent(OT%) significantly,but not raise total entries(TE).
Conclusion:GGDZ in the dosage of 5.0 g/kg/d does have antianxiety effect,but its effect doesn't strengthen following the dosage augmentation or decrease.It shows initially that GGDZ has certain intervention on mice anxious behavior.
1.2 Effects of GGDZ on the mice light-dark box test
Objective:to observe the anti-anxiety effect of GGDZ on the mice light-dark box test.
Methods:to adopt the mice light-dark box model,groups and administration are the same as the above test.Mice is administrated 10 days continuously,the praxiological test is carried out on the tenth day.
Results:DZP and GGDZⅡgroups can increase the number of transitions and light times, GGDZⅢgroup can also increase light times significantly.
Conclusion:GGDZ does have antianxiety effect in the dosage of ranging from 5.0 g/kg/d to 10.0 g/kg/d,which is the same as DZP effective direction.According to various index in light-dark box test mice,the 5.0 g/kg/d dosage is the best.That is similar to the result of EPM.
1.3 Effects of GGDZ on the rat EMP test
Objective:to verificate repeatly the antianxiety effect of GGDZ on the rats EMP test by using different animal.
Methods:to adopt the rat EMP model,rats are divided into model,DZP, GGDZⅠ,GGDZⅡ,GGDZⅢfive groups randomly.GGDZⅠ,Ⅱ,Ⅲgroups are administrated orally with 2.0g/kg/d,4.0g/kg/d,8.0g/kg/d respectively,DZP group 1.0mg/kg/d, model group equivalent saline,they are administrated 10 days continuously,the praxiological test,observation,and comparing various praxiological index on the tenth day.
Results:DZP and GGDZⅡgroups can increase the open entries percent(OE%) and open times percent(OT%) significantly,but not raise total entries(TE).
Conclusion:this result is the same as the mice EMP test.GGDZ has certain stationary antianxiety effect without increasing the activity of animal.
1.4 Effects of GGDZ on the Vogel's conflict test
Objective:the Vogel's conflict belongs to a conditional reflex animal model,but EMP is a nonconditional reflex animal model.This test adopts different model to verificate the stability and the reliability of GGDZ on the anti-anxiety effect.
Methods:to adopt the Vogel's conflict model,groups and administration are the same as the above test.Rats are administrated 10 days continuously,and they are prohibitted drinking within 48 hours before the last administration,carried out to the un-punished train on the ninth day and the punished train on the tenth day.
Results:DZP and GGDZⅡ,Ⅲgroups can increase the numbers of licking and shocking very significantly,GGDZⅠcan increase above two indexs significantly.
Conclusion:GGDZ has better anti-anxiety effect,because All GGDZ groups can increase the numbers of licking and shocking.It proves that GGDZ is very sensitive to the Vogel's conflict model,so we adopt this model to approach effective mechanism of GGDZ.
1.5 Effects of GGDZ on the animal model of TCM disease-syndrome test
Objective:to adopt acute stress plus EPM to build the animal model of TCM disease-syndrome test.We investigate replicative success of animal model on the aspect of praxiology and GGDZ's effect on this model.
Methods:to adopt the mice EMP model,rats are divided into modelⅠ,modelⅡ,DZP, GGDZⅠ,GGDZⅡ,GGDZⅢsix groups randomly.GGDZⅠ,Ⅱ,Ⅲgroups are administrated orally with 2.0g/kg/d,4.0g/kg/d,8.0g/kg/d respectively,DZP group 2.0mg/kg/d, modelⅠ,modelⅡgroups equivalent saline.The process of building the model is:beside modelⅠ,other groups rats are clamped the point of tails with sponge holding forceps,so that rats are infuriated to fight each other.They are stimulated about 30 minutes every time,one time every 4 hour,three times every day,and social-isolated in night.They are built model for 2 days continuously,carried out to EPM test on the tenth day.
Results:symptoms after 2 days acute stress:walking frequently in the cage,frighten appearance,screaming,palpi pilosi erection when hearing sound slightly,irritability,tearing and biting each other after removed stimulation,increasing the numbers of defecation, decreasing the quantity of meat and drink;symptoms on EMP test:increasing the numbers of defecation and emiction about the animals of TCM disease-syndrome model.But on the whole, symptoms of DZP,GGDZⅡ,groups are lighter than other groups.DZP and GGDZⅡgroups can increase the open entries percent(OE%) and open times percent(OT%) significantly,but not raise total entries.Furthermore,OE%and OT%of modelⅡgroup are lower than that of modelⅠgroup significantly.
Conclusion:symptoms of TCM disease-syndrome model is similar to clinical appearance of depressed syndrome.GGDZ has effect on this model.
2.Mechanism study----effects of GGDZ on the GABA pathway
2.1 Effects of GGDZ on the amino acid contents in rat brain tissue
Objective:to observe the amino acid contents change in rat hippocampus of GGDZ on the Vogel's conflict test,which can appraise the GGDZ's effect on controlling the neuronal excitability.
Methods:to adopt the Vogel's conflict model,groups and administration are the same as the above Vogel's conflict test.After finished the test,we put rats to death by decapitation, take out of hippocampus immediately in the ice plate,then detect the amino acid contents with automatic amino acid analyzer.
Results:model group shows degression of GABA,Gly contents and augmentation of Glu/GABA ratio.DZP and GGDZⅡgroups can increase GABA,Gly contents and decrease Glu/GABA ratio significantly.
Conclusion:GGDZ can control the neuronal excitability by increasing GABA,Gly contents and decreasing Glu/GABA ratio.
2.2 Effects of GGDZ on GAD expression in rat brain tissue
Objective:to observe GAD expression in rat hippocampus of GGDZ on the Vogel's conflict test,which can appraise the GGDZ's effect on GABA synthesize.
Methods:to adopt the Vogel's conflict model,groups and administration are the same as the above Vogel's conflict test.After finished the test,we put rats to death by decapitation, take out of hippocampus immediately in the ice plate,fix hippocampus with 10% formalin,then detect GAD expression with immunohistochemical method.
Results:model group shows degression of GAD expression level.GAD expression level can be increased by DZP and GGDZ.
Conclusion:GGDZ can increase GABA contents by upregulating GAD(GABA synthetase)expression.
2.3 Effects of GGDZ on GABA-T activity in rat brain tissue
Objective:to observe GABA-T activity in rat hippocampus of GGDZ on the Vogel's conflict test,which can appraise the GGDZ's effect on GABA metabolism.
Methods:to adopt the Vogel's conflict model,groups and administration are the same as the above Vogel's conflict test.After finished the test,we put rats to death by decapitation, take out of hippocampus immediately in the ice plate,then detect GABA-T activity with ELISA method.
Results:model group shows augmentation of GABA-T activity.GABA-T activity can be degraded by DZP and GGDZ.
Conclusion:GGDZ can increase GABA contents by inhibiting GABA-T(GABA metabolic enzyme) activity.
2.4 Effects of GGDZ on combining activity and combining numbers of GABA with GABAa receptor in rat brain tissue
Objective:to observe combining activity and combining numbers of GABA with GABA_a receptor in rat hippocampus of GGDZ on the Vogel's conflict test,which can appraise the GGDZ's effect on the condition of GABA with GABA_a receptor.
Methods:to adopt the Vogel's conflict model,groups and administration are the same as the above Vogel's conflict test.After finished the test,we put rats to death by decapitation, take out of hippocampus immediately in the ice plate,then detect combining activity and combining numbers of GABA with GABA_a receptor by ELISA method.
Results:model group shows degression of combining activity and combining numbers of GABA with GABA_A receptor.Which can be increased by DZP and GGDZ.
Conclusion:GGDZ has antianxiety effect by augmentation of combining activity and combining numbers of GABA with GABA_A receptor.
2.5 Effects of GGDZ on the mice spontaneous locomotor activity test
Objective:to observe that if GGDZ has sedative side effect by the mice spontaneous locomotor activity test.
Methods:to adopt the mice spontaneous locomotor activity model,groups and administration are the same as the above mice test.Mice is administrated 10 days continuously, the praxiological test is carried out on the tenth day.
Results:comparing with control group,GGDZ groups don't increase the numbers of spontaneous locomotor activity.There was nosignificant difference about spontaneous locomotor activity between groups.
Conclusion:GGDZ does not have sedative side effect in the antianxiety dosage.
Conclusion
The praxiology tests verify that GGDZ has stable antianxiety effect.The mechanism research tests prove that GGDZ has antianxiety effect by increasing the contents of GABA and Gly,decreasing Glu/GABA ratio,upregulaing GAD expression,downregulating GABA-T activity,enhancing the combining activity and combining numbers of GABA with GABAa receptor.GGDZ influences the GABA pathway to play a role in anti-anxiey.
本课题通过查阅大量的相关文献以及古今中医名家的用药经验,参考现代药理学的科研成果,并结合临床与市场的需求,以疏肝降火,交通心肾,镇惊安神为组方原则,拟定出治疗焦虑症的中药复方——贯归定志方。我们采用国际通用的焦虑症动物模型进行行为学实验,考察贯归定志方抗焦虑作用。运用饮水冲突模型实验进行贯归定志方发挥抗焦虑作用的γ-氨基丁酸能神经通路调节机制的探讨。并且,针对目前缺少公认的焦虑症的中医学病证结合模型的情况,本课题通过查阅文献及结合实验摸索,初步探索建立了焦虑症的病证结合的动物模型。
1.药效学实验
1.1贯归定志方对小鼠高架十字迷宫模型的影响
目的:采用小鼠高架十字迷宫实验模型,观察贯归定志方的抗焦虑作用。
方法:采用小鼠高架十字迷宫,设立空白对照组、DZP、贯归定志方Ⅰ(GGDZⅠ)、贯归定志方Ⅱ(GGDZⅡ)、贯归定志方Ⅲ(GGDZⅢ)共5组,其中中药GGDZⅠ、Ⅱ、Ⅲ组分别按生药量2.5g/kg/d、5g/kg/d、10.0g/kg/d给予灌胃,DZP组给予2.0 mg/kg/d灌胃,空白对照组灌服等容积的生理盐水。连续给药10天,第10天进行行为学测试。
结果:与空白对照组比较,地西泮可显著增加EPM大鼠的OT%和OE%(P<0.05或P<0.01),同时贯归定志方5.0 g/kg/d亦能显著增加EPM大鼠的OT%和OE%(P<0.05),而不增加其TE。而2.5 g/kg/d、10.0g/kg/d组与空白组比较,大鼠的OT%、OE%也表现出增加的趋势,但未见统计学意义。
结论:表明贯归定志方剂量在5.0 g/kg/d时有明显的抗焦虑作用,但抗焦虑作用未随着剂量的增加或减少而增强。初步显示了贯归定志方对小鼠焦虑行为有肯定的干预作用。
1.2贯归定志方对小鼠明暗箱模型的影响
目的:采用小鼠明暗箱实验模型,观察贯归定志方的抗焦虑作用。
方法:采用小鼠明暗箱模型,分组和给药同上。连续给药10天,第10天进行行为学测试。
结果:地西泮、贯归定志方5.0 g/kg可显著增加小鼠的穿梭次数和明箱时间(P<0.05),10.0 g/kg/d也能显著增加小鼠的明箱时间(P<0.05)。
结论:贯归定志方在5.0～10.0 g/kg/d剂量范围内,具有一定的抗焦虑效应,与DZP的作用方向一致,从对明暗箱小鼠各项指标来看,以5.0 g/kg/d剂量效果最佳,与EPM的实验结果基本一致。
1.3贯归定志方对大鼠高架十字迷宫模型的影响
目的:采用大鼠高架十字迷宫实验模型,利用不同的动物实验,重复验证贯归定志方的抗焦虑作用。
方法:采用大鼠高架十字迷宫实验模型,分组同前,其中中药GGDZⅠ、Ⅱ、Ⅲ组分别按生药量2.0 g/kg/d、4.0 g/kg/d、8.0 g/kg/d给予灌胃,DZP组给予1.0 mg/kg/d灌胃,空白对照组灌服等容积的生理盐水。连续给药10天,第10天进行行为学测试。
结果:DZP组、达尔康4.0 g/kg/d能显著提高大鼠开臂时间百分比(OT%)(P<0.05),且可非常显著增加大鼠开臂次数百分比(OE%)(P<0.01),不增加进入两臂的总次数(TE)。
结论:此与小鼠行为学实验结果基本一致,提示贯归定志方在不增加动物活动性的前提下,有确切稳定的抗焦虑作用。
1.4贯归定志方对大鼠饮水电击冲突实验的影响
目的:vogel饮水电击冲突实验属条件反射模型,高架十字迷宫实验属非条件反射型模型,本实验采用不同的模型,验证贯归定志方抗焦虑药效的稳定性和可靠性。
方法:采用大鼠vogel饮水冲突实验模型,分组同前,给药同大鼠EMP实验。各组连续给药10d,末次给药前48h禁水。第9d进行非惩罚饮水训练,第10d,中药组、空白对照组末次给药1h后,DZP组灌胃1.0mg/kg 0.5h后,进行惩罚实验测试。
结果:与空白对照组比较,DZP组、贯归定志方4.0 g/kg组、8.0 g/kg组均能增加大鼠接受电击的次数和在电击情况下的舔水次数,有极显著的统计意义(P<0.01);同时,贯归定志方2.0 g/kg组也显示出显著的统计意义(P<0.05)。
结论:贯归定志方各剂量组均能增加大鼠的电击和舔水次数,有较好的抗焦虑作用,说明贯归定志方对饮水冲突实验模型比较敏感,故下述机制探讨实验均采用饮水冲突模型。
1.5贯归定志方对病证结合动物模型的影响
目的:采用大鼠急性应激+高架十字迷宫复制焦虑症的病证结合模型,从行为学考察模型复制的成功与否,以及贯归定志方的对此模型的疗效。
方法:将动物分为模型组Ⅰ(ModelⅠ,空白对照)、模型组Ⅱ(ModelⅡ,病证结合动物模型)、DZP组、GGDZⅠ(4倍量组)、GGDZⅡ(8倍量组)、GGDZⅢ(16倍量组)共6组。其中GGDZⅠ、GGDZⅡ、GGDZⅢ组分别按生药量2.0 g/kg/d、4.0 g/kg/d、8.0 g/kg/d给予灌胃,DZP组按每日1.0mg/kg给以DZP混悬液灌胃,ModelⅠ、ModelⅡ灌服等容积的生理盐水。连续灌胃10d,第8d开始造模,具体过程为:除空白对照组外的其余各组的动物,用海绵钳(以海绵和胶布包裹的止血钳)夹住大鼠的尾巴尖部,激怒大鼠,使之与其他大鼠保持相斗状态(注意使大鼠保持相互争斗状态后即可松开海绵钳,防止长时间钳夹损伤尾巴,并且海绵钳夹尾巴产生的压强以夹住尾巴不脱落为宜),每次刺激30min,每隔4h一次,每日3次,夜间单笼饲养,连续2日。第10日给药后进行十字迷宫测试。
结果:本实验的病证结合的动物模型经过2天的刺激后,大鼠表现为频繁在笼中走动、稍有响动呈现惊吓状、尖叫、毛须竖立、易激惹,刺激解除后相互之间仍时有撕咬、打斗,排便次数增加,饮食、饮水减少等;通过高架十字迷宫模型观察到,病证结合模型的大鼠在迷宫中排尿、排便次数增多,经药物干预后整体来看,地西泮组和贯归定志方4.0 g/kg/d组的症状较其他组轻,可见到动物的躁动行为减轻,且高架十字迷宫实验中排便、排尿减少。就两个模型组比较而言,在高架十字迷宫实验中,急性应激模型组二便增多的症状较空白对照组表现明显。从高架十字迷宫数据统计结果可以看出,与模型组Ⅰ相比,模型组Ⅱ大鼠进入开臂时间的百分数(OT%)和进入开臂次数的百分数(OE%)显著减少(P<0.05),DZP组、贯归定志方Ⅱ(GGDZⅡ)可以明显增加大鼠进入开臂时间的百分数(OT%)和进入开臂次数的百分数(OE%)(P<0.05或P<0.01)。与模型组Ⅱ相比,模型组Ⅰ大鼠进入开臂时间的百分数(OT%)和进入开臂次数的百分数(OE%)显著增多(P<0.05),DZP组、贯归定志方各剂量组均可明显增加大鼠进入开臂时间的百分数(OT%)和进入开臂次数的百分数(OE%)(P<0.01)。而总入臂次数(TE)则无明显变化,表明各组并未增加大鼠的运动性。其他各组间无显著差异。
结论:就十字迷宫数据来看,本病证结合模型的各项指标均较单纯的高架十字迷宫实验有所降低,表明通过前期的急性应激作用,进一步激发了动物的焦虑反应,而且反之也通过高架十字迷宫实验对前期造模的效果进行了验证。从动物症状来看,单纯的高架十字迷宫模型动物表现为短暂的焦虑状态,而持续的急性应激刺激后,动物的各种表现与临床焦虑症属肝郁证的症状较为相似,并且通过高架十字迷宫的再次造模,增加了焦虑症状的持续性,使模型复制的稳定性和成功率增高。
因以上高架十字迷宫、明暗箱、Vogel饮水冲突实验三个模型对苯二氮卓类抗焦虑剂尤为敏感,地西泮所属的苯二氮卓类抗焦虑剂主要是通过γ-氨基丁酸能神经通路发挥抗焦虑作用,而本实验中贯归定志方与苯二氮卓类地西泮的抗焦虑作用趋势一致,故实验结果提示贯归定志方发挥抗焦虑作用机制可能与γ-氨基丁酸能神经通路有关。
2.机制研究——贯归定志方对γ-氨基丁酸能神经通路的影响
2.1贯归定志方对饮水电击冲突实验大鼠脑组织氨基酸类神经递质含量的影响
目的:采用大鼠vogel饮水冲突实验,观察大鼠海马中氨基酸类神经递质的含量变化,来评价贯归定志方对神经元兴奋性的影响。
方法:给药分组同前,大鼠饮水电击冲突实验结束后,立即断头处死,迅速取出大脑于冰盘上快速分离出海马,用氨基酸自动分析仪检测大鼠脑组织海马中的氨基酸含量。
结果:Vogel饮水冲突模型组大鼠脑组织海马中的GABA、Gly的含量降低,Glu/GABA比值升高,Glu含量显示出升高趋势。而与模型组相比,DZP组、贯归定志方4.0g/kg/d能显著增加Vogel饮水冲突大鼠海马中的GABA、Gly的含量(P<0.05或P<0.01),降低Glu/GABA比值(P<0.01),Glu的含量虽未有统计学意义,却显示下降的趋势。而贯归定志方2.0 g/kg/d与8.0g/kg/d也可显著降低Glu/GABA比值(P<0.01)。
结论:焦虑模型组动物脑组织中GABA、Gly含量降低,使神经元的兴奋得不到正常控制,导致焦虑的发生。而贯归定志方通过增加GABA、Gly的含量,并降低Glu/GABA比值来发挥抗焦虑作用。
2.2贯归定志方对饮水电击冲突实验大鼠脑组织谷氨酸脱羧酶表达的影响
目的:采用大鼠vogel饮水冲突实验,观察大鼠海马中谷氨酸脱羧酶的表达变化,来评价贯归定志方对GABA合成的影响。
方法:给药分组同前,大鼠饮水电击冲突实验结束后,立即断头处死,迅速取出大脑于冰盘上快速分离出海马,用中性福尔马林固定,采用免疫组织化学法检测大鼠脑组织海马中的谷氨酸脱羧酶(GAD)表达。
结果:空白对照组GAD_(65)蛋白表达细胞质着色浅,而且着色细胞数少;DZP组GAD_(65)表达强,细胞胞浆内呈黄褐色,而且着色细胞数多;贯归定志方Ⅱ(GGDZⅡ)及贯归定志方Ⅲ(GGDZⅢ)组GAD_(65)蛋白表达较强,可见细胞胞浆内呈黄褐色,着色深,着色细胞多;贯归定志方Ⅰ(GGDZⅠ)组GAD_(65)蛋白表达较弱,细胞质淡染,着色较浅。各组神经节细胞GAD_(65)蛋白表达积分光密度值统计结果为:与空白对照组比较,DZP组、GGDZⅡ组GAD_(65)蛋白表达积分光密度值显著增高(P<0.05),而GGDZⅠ和GGDZⅢ组虽未见统计学意义,但显示出升高的趋势。
结论:焦虑症模型动物大鼠海马中GAD表达下降。而贯归定志方能使GAD蛋白表达增多,因GAD是GABA合成酶和限速酶,故可增加脑内抑制性神经递质GABA浓度。结合上述氨基酸检测结果可以看出,GABA改变与GAD表达变化一致,说明大鼠海马脑组织GABA浓度升高可能是由GAD活性增强所致。
2.3贯归定志方对饮水电击冲突实验大鼠脑组织γ-氨基丁酸转氨酶活性的影响
目的:采用大鼠vogel饮水冲突实验,观察大鼠海马中γ-氨基丁酸转氨酶的活性变化,来评价贯归定志方对GABA代谢的影响。
方法:给药分组同前,大鼠饮水电击冲突实验结束后,立即断头处死,迅速取出大脑于冰盘上快速分离出海马,用ELISA法检测大鼠脑组织海马中的γ-氨基丁酸转氨酶(GABA-T)活性。
结果:与对照组相比,DZP组、贯归定志方Ⅱ(GGDZⅡ)、贯归定志方Ⅲ(GGDZⅢ)可以明显降低大鼠海马内GABA-T的活性(P<0.05),而贯归定志方Ⅰ(GGDZⅠ)组虽未有统计学意义,但也显示了同样的趋势。
结论:贯归定志方降低海马内GABA-T活性,可抑制GABA-T对GABA的降解作用,从而使得GABA增多,抑制中枢神经系统的兴奋性而起到抗焦虑作用。
2.4贯归定志方对饮水电击冲突实验大鼠脑组织GABA与GABA_A受体结合活性和结合数量的影响
目的:采用大鼠vogel饮水冲突实验,观察大鼠海马中GABA与GABA_A受体结合活性和结合数量的变化,来评价贯归定志方对GABA与GABA_A受体结合的影响。
方法:给药分组同前,大鼠饮水电击冲突实验结束后,立即断头处死,迅速取出大脑于冰盘上快速分离出海马,用ELISA法检测大鼠脑组织海马中的GABA与GABA_A受体的结合活性和结合数量。
结果:从结果可以看出,与对照组相比,DZP组、贯归定志方Ⅱ(66DZⅡ)可极显著增强大鼠海马内GABA与GABA_A受体的结合活性,升高与GABA_A受体的结合数量(P<0.01),贯归定志方Ⅲ(GGDZⅢ)也可显著增加大鼠海马内GABA_A受体的含量(P<0.05),而贯归定志方Ⅰ(GGDZⅠ)组虽未有统计学意义,但也显示了同样的趋势。
结论:从检测结果可以看出,对照模型组大鼠海马脑组织中的GABA与受体的结合活性下降、受体的结合数量减少,即GABA_A受体功能下调。而地西泮和贯归定志方可以上调GABA与受体的结合数量,并且增强了其结合活性,提示贯归定志方可能通过增加GABA与受体的结合数量及上调与GABA受体的结合活性,发挥抗焦虑作用。
2.5贯归定志方对小鼠自主活性的影响
目的:采用小鼠自主活动模型,观察贯归定志方是否具有镇静的副作用。
方法:给药分组同前小鼠EPM实验,连续给药10d,第10d进行行为学测试。
结果:与空白对照组比较,地西泮未减少小鼠自主活动次数,贯归定志方各剂量组也未减少小鼠的自主活动次数,未见统计学意义。
结论:贯归定志方在抗焦虑作用的剂量下无镇静的副作用。
结论
本课题通过小鼠的高架十字迷宫(EPM)、明暗箱实验初步得出了贯归定志方抗焦虑的作用,又进一步采用大鼠高架十字迷宫、vogel饮水冲突实验重复验证了贯归定志方的疗效,得出了一致的确切可靠的结果。整个实验采用EPM、明暗箱、饮水冲突实验三个模型互参,从非条件反应模型和条件反应型惩罚性模型等不同角度观察贯归定志方对动物的抗焦虑作用,大大增加了药效学评价的可靠性。通过机制实验研究,发现贯归定志方发挥抗焦虑作用主要通过降低脑组织中Glu的含量、增高GABA、Gly的含量,降低Glu/GABA比值来调整中枢神经系统的兴奋状态;增强GABA合成酶的表达、抑制GABA代谢酶的活性,进一步使GABA含量增多,控制神经元的兴奋性;增强GABA与GABA_A受体的结合活性、增加其结合数量,使GABA与GABA_A受体更好的结合来发挥抗焦虑作用。通过本实验的研究,为中药复方发挥作用的确切靶点的机制探讨提供系统的完整思路。
本实验初步探索建立了焦虑症的病证结合动物模型,在中医证候理论指导下研究药物作用进行了初步的探索,本研究有利于进一步揭示证候的本质,为研究中医病证结合模型进行了有益的尝试。
Recently,people feel heavy stress generally because of the influence of social work, interpersonal relationship and economic pressure,along with the rapid development of the society and the economy.People pay attention to mitis mental disease such as neurosis from serious mental disease as if schizophrenic in 21 century.The occurrence of anxiety as a subtype of neurosis is increasing year by year.Anxiety which harms people'health becomes increasingly a severe mental disease.
The object of this paper layings a Chinese materia medica prescription of treating anxiety----GUANGUIDINGZHIFANG(GGDZ),by consulting a lot of pertinent literature and paleo-modern TCM famous doctors' medicational experience,referring to technological research findings of modern pharmacology,combining clinical and market requirement.This prescription is on the base of composing principles of soothing liver and sending down fire, restoring normal coordination between heart and hidney,relieving convulsion and anchoring the mind.We adopt the international universal anxiety animal models to investigate antianxiety effect of GGDZ.We apply Vogel's conflict test to approach possible GABA nervous pathway of GGDZ antianxiety mechanism.To aim directly at the deficiency of received anxiety animal model of TCM disease-syndrome,this topic explores initially to build a anxiety animal model of TCM disease-syndrome by consulting literature and combining protophase experimental crocidismus.
1.Pharmacodynamics research
1.1 Effects of GGDZ on the mice EMP test
Objective:to observe the antianxiety effect of GGDZ on the mice EMP test.
Methods:to adopt the mice EMP model,mice is divided into model,DZP,GGDZⅠ, GGDZⅡ,GGDZⅢfive groups randomly.GGDZⅠ,Ⅱ,Ⅲgroups are administrated orally with 2.5g/kg/d,5.0g/kg/d,10.0g/kg/d respectively,DZP group 2.0mg/kg/d,model group equivalent saline,they are administrated 10 days continuously,the praxiological test, observation,and comparing various praxiological index on the tenth day.
Results:DZP and GGDZⅡgroups can increase the open entries percent(OE%) and open times percent(OT%) significantly,but not raise total entries(TE).
Conclusion:GGDZ in the dosage of 5.0 g/kg/d does have antianxiety effect,but its effect doesn't strengthen following the dosage augmentation or decrease.It shows initially that GGDZ has certain intervention on mice anxious behavior.
1.2 Effects of GGDZ on the mice light-dark box test
Objective:to observe the anti-anxiety effect of GGDZ on the mice light-dark box test.
Methods:to adopt the mice light-dark box model,groups and administration are the same as the above test.Mice is administrated 10 days continuously,the praxiological test is carried out on the tenth day.
Results:DZP and GGDZⅡgroups can increase the number of transitions and light times, GGDZⅢgroup can also increase light times significantly.
Conclusion:GGDZ does have antianxiety effect in the dosage of ranging from 5.0 g/kg/d to 10.0 g/kg/d,which is the same as DZP effective direction.According to various index in light-dark box test mice,the 5.0 g/kg/d dosage is the best.That is similar to the result of EPM.
1.3 Effects of GGDZ on the rat EMP test
Objective:to verificate repeatly the antianxiety effect of GGDZ on the rats EMP test by using different animal.
Methods:to adopt the rat EMP model,rats are divided into model,DZP, GGDZⅠ,GGDZⅡ,GGDZⅢfive groups randomly.GGDZⅠ,Ⅱ,Ⅲgroups are administrated orally with 2.0g/kg/d,4.0g/kg/d,8.0g/kg/d respectively,DZP group 1.0mg/kg/d, model group equivalent saline,they are administrated 10 days continuously,the praxiological test,observation,and comparing various praxiological index on the tenth day.
Results:DZP and GGDZⅡgroups can increase the open entries percent(OE%) and open times percent(OT%) significantly,but not raise total entries(TE).
Conclusion:this result is the same as the mice EMP test.GGDZ has certain stationary antianxiety effect without increasing the activity of animal.
1.4 Effects of GGDZ on the Vogel's conflict test
Objective:the Vogel's conflict belongs to a conditional reflex animal model,but EMP is a nonconditional reflex animal model.This test adopts different model to verificate the stability and the reliability of GGDZ on the anti-anxiety effect.
Methods:to adopt the Vogel's conflict model,groups and administration are the same as the above test.Rats are administrated 10 days continuously,and they are prohibitted drinking within 48 hours before the last administration,carried out to the un-punished train on the ninth day and the punished train on the tenth day.
Results:DZP and GGDZⅡ,Ⅲgroups can increase the numbers of licking and shocking very significantly,GGDZⅠcan increase above two indexs significantly.
Conclusion:GGDZ has better anti-anxiety effect,because All GGDZ groups can increase the numbers of licking and shocking.It proves that GGDZ is very sensitive to the Vogel's conflict model,so we adopt this model to approach effective mechanism of GGDZ.
1.5 Effects of GGDZ on the animal model of TCM disease-syndrome test
Objective:to adopt acute stress plus EPM to build the animal model of TCM disease-syndrome test.We investigate replicative success of animal model on the aspect of praxiology and GGDZ's effect on this model.
Methods:to adopt the mice EMP model,rats are divided into modelⅠ,modelⅡ,DZP, GGDZⅠ,GGDZⅡ,GGDZⅢsix groups randomly.GGDZⅠ,Ⅱ,Ⅲgroups are administrated orally with 2.0g/kg/d,4.0g/kg/d,8.0g/kg/d respectively,DZP group 2.0mg/kg/d, modelⅠ,modelⅡgroups equivalent saline.The process of building the model is:beside modelⅠ,other groups rats are clamped the point of tails with sponge holding forceps,so that rats are infuriated to fight each other.They are stimulated about 30 minutes every time,one time every 4 hour,three times every day,and social-isolated in night.They are built model for 2 days continuously,carried out to EPM test on the tenth day.
Results:symptoms after 2 days acute stress:walking frequently in the cage,frighten appearance,screaming,palpi pilosi erection when hearing sound slightly,irritability,tearing and biting each other after removed stimulation,increasing the numbers of defecation, decreasing the quantity of meat and drink;symptoms on EMP test:increasing the numbers of defecation and emiction about the animals of TCM disease-syndrome model.But on the whole, symptoms of DZP,GGDZⅡ,groups are lighter than other groups.DZP and GGDZⅡgroups can increase the open entries percent(OE%) and open times percent(OT%) significantly,but not raise total entries.Furthermore,OE%and OT%of modelⅡgroup are lower than that of modelⅠgroup significantly.
Conclusion:symptoms of TCM disease-syndrome model is similar to clinical appearance of depressed syndrome.GGDZ has effect on this model.
2.Mechanism study----effects of GGDZ on the GABA pathway
2.1 Effects of GGDZ on the amino acid contents in rat brain tissue
Objective:to observe the amino acid contents change in rat hippocampus of GGDZ on the Vogel's conflict test,which can appraise the GGDZ's effect on controlling the neuronal excitability.
Methods:to adopt the Vogel's conflict model,groups and administration are the same as the above Vogel's conflict test.After finished the test,we put rats to death by decapitation, take out of hippocampus immediately in the ice plate,then detect the amino acid contents with automatic amino acid analyzer.
Results:model group shows degression of GABA,Gly contents and augmentation of Glu/GABA ratio.DZP and GGDZⅡgroups can increase GABA,Gly contents and decrease Glu/GABA ratio significantly.
Conclusion:GGDZ can control the neuronal excitability by increasing GABA,Gly contents and decreasing Glu/GABA ratio.
2.2 Effects of GGDZ on GAD expression in rat brain tissue
Objective:to observe GAD expression in rat hippocampus of GGDZ on the Vogel's conflict test,which can appraise the GGDZ's effect on GABA synthesize.
Methods:to adopt the Vogel's conflict model,groups and administration are the same as the above Vogel's conflict test.After finished the test,we put rats to death by decapitation, take out of hippocampus immediately in the ice plate,fix hippocampus with 10% formalin,then detect GAD expression with immunohistochemical method.
Results:model group shows degression of GAD expression level.GAD expression level can be increased by DZP and GGDZ.
Conclusion:GGDZ can increase GABA contents by upregulating GAD(GABA synthetase)expression.
2.3 Effects of GGDZ on GABA-T activity in rat brain tissue
Objective:to observe GABA-T activity in rat hippocampus of GGDZ on the Vogel's conflict test,which can appraise the GGDZ's effect on GABA metabolism.
Methods:to adopt the Vogel's conflict model,groups and administration are the same as the above Vogel's conflict test.After finished the test,we put rats to death by decapitation, take out of hippocampus immediately in the ice plate,then detect GABA-T activity with ELISA method.
Results:model group shows augmentation of GABA-T activity.GABA-T activity can be degraded by DZP and GGDZ.
Conclusion:GGDZ can increase GABA contents by inhibiting GABA-T(GABA metabolic enzyme) activity.
2.4 Effects of GGDZ on combining activity and combining numbers of GABA with GABAa receptor in rat brain tissue
Objective:to observe combining activity and combining numbers of GABA with GABA_a receptor in rat hippocampus of GGDZ on the Vogel's conflict test,which can appraise the GGDZ's effect on the condition of GABA with GABA_a receptor.
Methods:to adopt the Vogel's conflict model,groups and administration are the same as the above Vogel's conflict test.After finished the test,we put rats to death by decapitation, take out of hippocampus immediately in the ice plate,then detect combining activity and combining numbers of GABA with GABA_a receptor by ELISA method.
Results:model group shows degression of combining activity and combining numbers of GABA with GABA_A receptor.Which can be increased by DZP and GGDZ.
Conclusion:GGDZ has antianxiety effect by augmentation of combining activity and combining numbers of GABA with GABA_A receptor.
2.5 Effects of GGDZ on the mice spontaneous locomotor activity test
Objective:to observe that if GGDZ has sedative side effect by the mice spontaneous locomotor activity test.
Methods:to adopt the mice spontaneous locomotor activity model,groups and administration are the same as the above mice test.Mice is administrated 10 days continuously, the praxiological test is carried out on the tenth day.
Results:comparing with control group,GGDZ groups don't increase the numbers of spontaneous locomotor activity.There was nosignificant difference about spontaneous locomotor activity between groups.
Conclusion:GGDZ does not have sedative side effect in the antianxiety dosage.
Conclusion
The praxiology tests verify that GGDZ has stable antianxiety effect.The mechanism research tests prove that GGDZ has antianxiety effect by increasing the contents of GABA and Gly,decreasing Glu/GABA ratio,upregulaing GAD expression,downregulating GABA-T activity,enhancing the combining activity and combining numbers of GABA with GABAa receptor.GGDZ influences the GABA pathway to play a role in anti-anxiey.
引文
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