益肾调气法对脑血管病后精神症状组群神经可塑性的干预作用研究
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摘要
目的：采用动物在体实验研究的方法,以颐脑解郁方作为干预手段,从多发性脑梗塞模型大鼠行为学演变趋势、Papez回路微观结构变化及神经细胞微环境变化三个方面,并与PSD及VD大鼠模型进行比较,阐明脑血管病后行为学变化发生病理基础及生物学基础,以及颐脑解郁方治疗脑血管病后精神症状组群的效应物质基础,深化对中医“既病防变”的认识,丰富中医基础理论和中药药理的内容,并为脑血管病后精神症状组群的治疗提供研究思路。
方法：选择雄性Wistar大鼠,1周后经open-field行为评分,评分相近大鼠随机分为正常组、假手术组、MCI组、中药组、西药组、PSD组、VD组。正常组常规饲养。假手术组行假手术后予灌胃蒸馏水。MCI组、中药组、西药组采用同种系微栓子体外注入法制备MCI模型,分别给予蒸馏水、颐脑解郁方、尼莫地平。PSD组首先行同种系微栓子体外注入法制备MCI模型,后复合21天慢性应激结合孤养法制备PSD模型；VD组首先采用同种系微栓子体外注入法制备MCI模型,28天经Morrs水迷宫筛查,复合VD标准的进入实验。PSD组及VD组造模成功后4周进行行为学评定进行筛选。并分别于1、2、4周进行行为学测定,包括蔗糖水消耗量、Morris水迷宫实验。行为学测定结束后,进行指标检测,①采用电镜观察Papez回路形态结构的变化；②用免疫组织化学SABC去测定脑GAP-43、Nogo-A、NgR表达,对Papez回路相关部位进行图像分析,观察所测定指标阳性表达的细胞数。
结果：
1行为学测定
1.1蔗糖水消耗实验：模型组1、2、4周大鼠蔗糖水消耗量逐渐减少,均明显低于正常组及假手术组(p<0.01)。VD组及PSD组大鼠较MCI组大鼠蔗糖水消耗量减少,其中PSD下降尤为明显。中药组大鼠蔗糖水消耗量较模型组高,但低于正常组大鼠。
1.2 Morris水迷宫测定：第1、2、4周MCI组、中药组、西药组大鼠初始角度及穿越平台次数与正常组大鼠均有差异(p<0.01～0.05)；VD组、PSD大鼠1、2、4周初始角度增大及穿越平台次数减少程度均低于正常组(p<0.01)；VD组、PSD组1、2、4周初始角度及穿越平台次数与模型组均有差异(p<0.01)
2电镜观察：
正常组：海马、下丘脑、杏仁核区神经原细胞结构正常,可见胞核核膜完整清晰,呈双层膜结构,核孔清楚,核染色质分布均匀、细颗粒状,核仁清晰；细胞浆内糖元颗粒丰富,线粒体丰富,线粒体膜及嵴结构完整,粗面内质网膜上核蛋白小体丰富呈颗粒状；假手术组海马、下丘脑、杏仁核区神经原细胞结构正常；正常组和假手术组在海马、下丘脑、杏仁核区均可见毛细血管管腔正常,血管内皮细胞不肿胀；髓鞘纤维分布均匀、形态正常,髓鞘致密均匀呈黑色。
MCI组：海马、下丘脑、杏仁核区个别神经原细胞可见胞核核膜不清晰,核孔不清楚,核染色质着色不匀,核仁肿大；细胞浆内糖元颗粒减少,线粒体少、肿胀、呈空泡状,轴突水肿、扩大。
PSD组：海马、下丘脑、杏仁核区部分神经原细胞胞核肿胀、结构不清,核染色质均质状不呈细颗粒状；髓鞘神经纤维结构不规则,排列紊乱、成团,髓鞘分层、着色不均,毛细血管扩张。
VD组：海马、下丘脑、杏仁核区部分神经原细胞结构不清,髓鞘神经纤维结构不规则,排列紊乱、成团,髓鞘分层、着色不均,神经细胞核固缩。
MCI、PSD和VD各组超微结构病变尚未见有特殊的差别。
中药治疗组、西药治疗组：海马、下丘脑、杏仁核区神经原细胞结构基本正常,髓鞘神经纤维结构未见异常变化,接近正常组,说明起到治疗效应。
3神经营养因子及血管再生因子免疫组化测定：
3.1GAP-43测定
海马、下丘脑、杏仁核GAP-43第1、2、4周表达越来越少,且MCI组表达较PSD组及VD组较多,PSD组及VD组之间无明显差异。中药组GAP-43表达能维持在正常水平,无明显下降。3.2Nogo-A、NgR测定
MCI组、VD组及PSD组Nogo-A、NgR阳性细胞数较正常组增多；MCI组各时段表达均明显高于正常组；VD及PSD组Nogo-A、NgR表达高于MCI组。中药组、西药组Nogo-A、NgR第1、2、4周表达明显低于正常组、MCI组及PSD与VD组(p<0.01)
结论：
1通过制备MCI、PSD及VD模型,在行为学改变上观察发现,大鼠表现出兴趣和快感缺乏,活动性减少,学习和记忆能力下降等一系列精神症状组群的改变。以益肾调气为组方原则的颐脑解郁方具有可改善模型大鼠精神症状组群的作用,显示中药早期干预可阻断或延缓脑卒中后的精神症状组群的演变趋势。
2建立的模型大鼠存在Papez回路形态学改变,提示Papez回路在脑卒中病后精神症状组群演变过程中内在机制。而颐脑解郁方可减轻这种病理改变。
3建立的模型大鼠存在脑内Papez回路GAP-43、Nogo-A及NgR异常表达,而中药颐脑解郁方干预后,可调节Papez回路相关因子的表达。因此调节Papez回路相关因子的表达是对脑卒中后精神症状组群演变干预作用的环节之一。
Objective:Through observing three aspects of MCI,PSD and VD rats:the evolutionary tendency of the group spirit symptoms,microcosmic structure changes of Papez loop,nerve repair and regeneration of NTF,we try to clarify the pathological and biological bases of psychiatric symptoms after cerebrovascular diseases.Using Yinao Jieyu prescription on MCI rats to observe the material foundation and mechanism in order to enrich the basic theory of TCM and the contents of Chinese pharmacology.Through this study,we hope it can provides a new treatment for cerebrovascular disease symptoms.
Methods:Male wistar rats were randomly divided into normal group,sham-operation group,MCI group,VD group,PSD group,TCM(troditional chinese medicine) group and western medicine group according to the scores of open-field test.The normal group received no intervention.The sham-operation group received sham operation,and intragastric administration of distilled water.Those rats in other groups were duplicated MCI model first.The treatment group and control group received intragastric administration of Yinao Jieyu prescription and Nimodipineand respectively.All of rats in 1,2,4 weeks were observed characterizations including weight,food intake,sucrose water consumption,open-field test,jumping stair and shuttle box experiment.Then we observed ultrastructural changes of Papez loop through light and electron microscope.we also observed the BDNF,VEGF,bFGF expression changes through SABC immunohistochemistry test of brain.
Results:
1 The group spirit symptoms observation
1.1 Behavioral evaluation
1.1.1 Sucrose water consumption:The sucrose water consumption of model rats declined on 1.2.2 weeks,and significantly lower than the normal,sham-operation rats(p<0.01).The sucrose water consumption of VD and PSD rats were more lower than MCI rats,and PSD rats dropped apparently.TCM rats'sucrose water consumption were higher than model groups,but lower than the normal.
2 dyeing observation:MCI rats could be observed ischemic changes,necrotic areas,cell lossed seriously,cytopathy,vascular dilatation and congestion of MCI rats in the left brain could be observed.And by observing three positions in the same mouse,we found that the hippocampus structure were destroyed obviously than hypothalamus and amygdala.
3 NTF and vascular regeneration factor determination
3.1 GAP-43 determination:The expression of BDNF in the hippocampus, hypotha-lamus and hippocampus,hypothalamus and amygdala decreased in 1,2,4 weeks;MCI rats had higher expression than PSD and VD rats,but PSD and VD rats had no obvious difference between them.TCM rats'BDNF expression could maintain at the normal level.
3.2Nogo-A and NgR determination:MCI,VD and PSD rats had a lower Nogo-A, NgR expression than normal rats.MCI rats in 1 week had a higher expression than the other two time position,and had no obvious difference with norml rats in 4 week.VD and PSD group of Nogo-A, NgR expression were compared to MCI group.TCM rats had a significantly higher expression of Nogo-A and NgR in 1,2,4 weeks than normal and MCI rats(p<0.01).
Conclusions:
1 MCI,PSD and VD,the three kinds of model rats had a series mental symptoms group changes:interest and pleasure lacking,active movement reducing,learning and memory ability droping and so on.
2 Yinao Jieyu prescription can improve the changes.And it shows that early intervention with Chinese medicine can prevent the evolution of post stroke.
3 The model of rats'Papez loop morphologic changed,which hinted at the internal mechanism at the evolution course of groups of mental symptoms after stroke disease for Papez loop.And Yinao Jieyu prescription may mitigate such already cerebral pathologic changes.
4 The model rats exists abnormal expression of GAP-43, Nogo-A and NgR in Papez loop.So raising such factors'expression maybe one of the link in the role of evolution intervention.
方法：选择雄性Wistar大鼠,1周后经open-field行为评分,评分相近大鼠随机分为正常组、假手术组、MCI组、中药组、西药组、PSD组、VD组。正常组常规饲养。假手术组行假手术后予灌胃蒸馏水。MCI组、中药组、西药组采用同种系微栓子体外注入法制备MCI模型,分别给予蒸馏水、颐脑解郁方、尼莫地平。PSD组首先行同种系微栓子体外注入法制备MCI模型,后复合21天慢性应激结合孤养法制备PSD模型；VD组首先采用同种系微栓子体外注入法制备MCI模型,28天经Morrs水迷宫筛查,复合VD标准的进入实验。PSD组及VD组造模成功后4周进行行为学评定进行筛选。并分别于1、2、4周进行行为学测定,包括蔗糖水消耗量、Morris水迷宫实验。行为学测定结束后,进行指标检测,①采用电镜观察Papez回路形态结构的变化；②用免疫组织化学SABC去测定脑GAP-43、Nogo-A、NgR表达,对Papez回路相关部位进行图像分析,观察所测定指标阳性表达的细胞数。
结果：
1行为学测定
1.1蔗糖水消耗实验：模型组1、2、4周大鼠蔗糖水消耗量逐渐减少,均明显低于正常组及假手术组(p<0.01)。VD组及PSD组大鼠较MCI组大鼠蔗糖水消耗量减少,其中PSD下降尤为明显。中药组大鼠蔗糖水消耗量较模型组高,但低于正常组大鼠。
1.2 Morris水迷宫测定：第1、2、4周MCI组、中药组、西药组大鼠初始角度及穿越平台次数与正常组大鼠均有差异(p<0.01～0.05)；VD组、PSD大鼠1、2、4周初始角度增大及穿越平台次数减少程度均低于正常组(p<0.01)；VD组、PSD组1、2、4周初始角度及穿越平台次数与模型组均有差异(p<0.01)
2电镜观察：
正常组：海马、下丘脑、杏仁核区神经原细胞结构正常,可见胞核核膜完整清晰,呈双层膜结构,核孔清楚,核染色质分布均匀、细颗粒状,核仁清晰；细胞浆内糖元颗粒丰富,线粒体丰富,线粒体膜及嵴结构完整,粗面内质网膜上核蛋白小体丰富呈颗粒状；假手术组海马、下丘脑、杏仁核区神经原细胞结构正常；正常组和假手术组在海马、下丘脑、杏仁核区均可见毛细血管管腔正常,血管内皮细胞不肿胀；髓鞘纤维分布均匀、形态正常,髓鞘致密均匀呈黑色。
MCI组：海马、下丘脑、杏仁核区个别神经原细胞可见胞核核膜不清晰,核孔不清楚,核染色质着色不匀,核仁肿大；细胞浆内糖元颗粒减少,线粒体少、肿胀、呈空泡状,轴突水肿、扩大。
PSD组：海马、下丘脑、杏仁核区部分神经原细胞胞核肿胀、结构不清,核染色质均质状不呈细颗粒状；髓鞘神经纤维结构不规则,排列紊乱、成团,髓鞘分层、着色不均,毛细血管扩张。
VD组：海马、下丘脑、杏仁核区部分神经原细胞结构不清,髓鞘神经纤维结构不规则,排列紊乱、成团,髓鞘分层、着色不均,神经细胞核固缩。
MCI、PSD和VD各组超微结构病变尚未见有特殊的差别。
中药治疗组、西药治疗组：海马、下丘脑、杏仁核区神经原细胞结构基本正常,髓鞘神经纤维结构未见异常变化,接近正常组,说明起到治疗效应。
3神经营养因子及血管再生因子免疫组化测定：
3.1GAP-43测定
海马、下丘脑、杏仁核GAP-43第1、2、4周表达越来越少,且MCI组表达较PSD组及VD组较多,PSD组及VD组之间无明显差异。中药组GAP-43表达能维持在正常水平,无明显下降。3.2Nogo-A、NgR测定
MCI组、VD组及PSD组Nogo-A、NgR阳性细胞数较正常组增多；MCI组各时段表达均明显高于正常组；VD及PSD组Nogo-A、NgR表达高于MCI组。中药组、西药组Nogo-A、NgR第1、2、4周表达明显低于正常组、MCI组及PSD与VD组(p<0.01)
结论：
1通过制备MCI、PSD及VD模型,在行为学改变上观察发现,大鼠表现出兴趣和快感缺乏,活动性减少,学习和记忆能力下降等一系列精神症状组群的改变。以益肾调气为组方原则的颐脑解郁方具有可改善模型大鼠精神症状组群的作用,显示中药早期干预可阻断或延缓脑卒中后的精神症状组群的演变趋势。
2建立的模型大鼠存在Papez回路形态学改变,提示Papez回路在脑卒中病后精神症状组群演变过程中内在机制。而颐脑解郁方可减轻这种病理改变。
3建立的模型大鼠存在脑内Papez回路GAP-43、Nogo-A及NgR异常表达,而中药颐脑解郁方干预后,可调节Papez回路相关因子的表达。因此调节Papez回路相关因子的表达是对脑卒中后精神症状组群演变干预作用的环节之一。
Objective:Through observing three aspects of MCI,PSD and VD rats:the evolutionary tendency of the group spirit symptoms,microcosmic structure changes of Papez loop,nerve repair and regeneration of NTF,we try to clarify the pathological and biological bases of psychiatric symptoms after cerebrovascular diseases.Using Yinao Jieyu prescription on MCI rats to observe the material foundation and mechanism in order to enrich the basic theory of TCM and the contents of Chinese pharmacology.Through this study,we hope it can provides a new treatment for cerebrovascular disease symptoms.
Methods:Male wistar rats were randomly divided into normal group,sham-operation group,MCI group,VD group,PSD group,TCM(troditional chinese medicine) group and western medicine group according to the scores of open-field test.The normal group received no intervention.The sham-operation group received sham operation,and intragastric administration of distilled water.Those rats in other groups were duplicated MCI model first.The treatment group and control group received intragastric administration of Yinao Jieyu prescription and Nimodipineand respectively.All of rats in 1,2,4 weeks were observed characterizations including weight,food intake,sucrose water consumption,open-field test,jumping stair and shuttle box experiment.Then we observed ultrastructural changes of Papez loop through light and electron microscope.we also observed the BDNF,VEGF,bFGF expression changes through SABC immunohistochemistry test of brain.
Results:
1 The group spirit symptoms observation
1.1 Behavioral evaluation
1.1.1 Sucrose water consumption:The sucrose water consumption of model rats declined on 1.2.2 weeks,and significantly lower than the normal,sham-operation rats(p<0.01).The sucrose water consumption of VD and PSD rats were more lower than MCI rats,and PSD rats dropped apparently.TCM rats'sucrose water consumption were higher than model groups,but lower than the normal.
2 dyeing observation:MCI rats could be observed ischemic changes,necrotic areas,cell lossed seriously,cytopathy,vascular dilatation and congestion of MCI rats in the left brain could be observed.And by observing three positions in the same mouse,we found that the hippocampus structure were destroyed obviously than hypothalamus and amygdala.
3 NTF and vascular regeneration factor determination
3.1 GAP-43 determination:The expression of BDNF in the hippocampus, hypotha-lamus and hippocampus,hypothalamus and amygdala decreased in 1,2,4 weeks;MCI rats had higher expression than PSD and VD rats,but PSD and VD rats had no obvious difference between them.TCM rats'BDNF expression could maintain at the normal level.
3.2Nogo-A and NgR determination:MCI,VD and PSD rats had a lower Nogo-A, NgR expression than normal rats.MCI rats in 1 week had a higher expression than the other two time position,and had no obvious difference with norml rats in 4 week.VD and PSD group of Nogo-A, NgR expression were compared to MCI group.TCM rats had a significantly higher expression of Nogo-A and NgR in 1,2,4 weeks than normal and MCI rats(p<0.01).
Conclusions:
1 MCI,PSD and VD,the three kinds of model rats had a series mental symptoms group changes:interest and pleasure lacking,active movement reducing,learning and memory ability droping and so on.
2 Yinao Jieyu prescription can improve the changes.And it shows that early intervention with Chinese medicine can prevent the evolution of post stroke.
3 The model of rats'Papez loop morphologic changed,which hinted at the internal mechanism at the evolution course of groups of mental symptoms after stroke disease for Papez loop.And Yinao Jieyu prescription may mitigate such already cerebral pathologic changes.
4 The model rats exists abnormal expression of GAP-43, Nogo-A and NgR in Papez loop.So raising such factors'expression maybe one of the link in the role of evolution intervention.
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