针刺对脑缺血模型大鼠突触重建促进作用的研究
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摘要
脑血管疾病已跃居人类主要死因的第二位,存活者1/3遗留残疾,给个人、家庭和社会造成沉重的负担,而脑血管疾病中缺血性脑血管病超过75%,故寻找有效的防治手段已成为脑科学领域的的重要课题。针灸对缺血性脑损伤的保护机制是一个复杂的多因素过程。近年来脑的可塑性研究为缺血性脑损伤后恢复的机制研究打开了新的研究方向,而突触是脑可塑性最强的部位。因此,本文拟从针刺对脑缺血大鼠突触重建的促进作用方面进行研究,以进一步揭示针刺治疗缺血性中风的作用机制,为临床治疗提供坚实的理论基础。本文分为文献研究、实验研究及小结三大部分。
1.文献研究
通过对中风病因病机理论的古代及现代文献研究,我们认为中风的病因繁多,病机复杂,发病急骤,变化多端,表现各异。大量的实验研究也揭示了针灸治疗缺血性中风的可能作用机制。本文还就现代医学对星形胶质细胞、突触可塑性的认识及研究进展进行了综述,认为脑可塑性的理论为脑卒中后的治疗和康复奠定了理论基础,星形胶质细胞和突触紧密相连,脑缺血后活化的星形胶质细胞在脑损伤及修复中具有重要作用,星形胶质细胞参与了对突触可塑性的调节,而针刺是中枢神经系统有效的刺激形式之一,针刺对大脑的功能重组和代偿起着重要作用。
2.实验研究
目的:观察针刺对局灶性脑缺血大鼠缺血灶周围区不同时间段突触结构参数及星形胶质细胞反应性变化的影响,进一步揭示针刺治疗脑缺血疾病的可能作用机制。
方法:雄性Wistar大鼠90只,随机分为3组:假手术组、模型组和电针组,各组又分为术后1h,1d,3d,7d及21d 5个时段组,6只/时段组。模型组和电针组采用电凝闭大脑中动脉建立局灶性脑缺血(MCAO)模型,假手术组只暴露大鼠大脑中动脉,不予凝闭。电针组术后立即给予电针治疗,取百会(GV20)、大椎(GV14)穴,选用疏密波,5-10次/s,强度以大鼠安静耐受为度,电压约2-3V,留针30min,1次/d。其他2组不予针刺处理。观察以下指标:
(1)各组大鼠神经功能缺损评分及进行HE染色观察大鼠脑缺血灶周围区病理形态学改变。
(2)透射电镜观察不同时段各组大鼠缺血灶周围区皮层的突触数密度、突触后致密物厚度、突触间隙宽度以及突触界面曲率的变化。
(3)透射电镜观察各组大鼠脑缺血灶周围区星形胶质细胞的超微结构,采用免疫组织化学法、激光共聚焦扫描显微镜观察星形胶质细胞胶质纤维酸性蛋白(GFAP)的变化。
(4)采用免疫组织化学法检测各组大鼠脑缺血灶周围区谷氨酸转运体EAAT1、EAAT2的表达。
(5)采用免疫组织化学法检测各组大鼠脑缺血灶周围区缝隙连接蛋白CX43的表达。
(6)激光共聚焦扫描显微镜观察各组大鼠脑缺血灶周围区星形胶质细胞胞浆[Ca~(2+)]i的变化。
(7)运用统计学软件PEMS3.1分别做各时间段脑缺血和电针干预后的突触结构参数x1-x4(突触数密度、突触后致密物厚度、突触间隙宽度及突触界面曲率)与星形胶质细胞参数y1-y4(CX43、EAAT2、GFAP、[Ca~(2+)]i)之间的典型相关分析。
结果:
(1)不同时段的模型组与假手术组比较均有显著差异,大鼠造模后均出现不同程度的神经缺损体征,表明脑缺血模型造模成功。1d电针组与模型组比较差异无显著性意义。3d模型组大鼠神经缺损症状加重,部分大鼠出现转圈运动,而电针组大鼠神经体征有所恢复,评分明显低于模型组(P＜0.01)。7d、21d模型组和电针组的大鼠神经功能缺损评分均较前降低,而电针组评分明显低于模型组(P＜0.01,P＜0.05)。
HE染色结果显示1h-3d模型组有神经细胞坏死征象,出现筛网状结构,部分神经细胞排列紊乱,呈三角形和多角形,细胞核固缩深染,胞浆空泡样变性等典型的脑缺血征象,说明MCAO模型造模成功,上述表现尤其以缺血3d组变性坏死较为明显。而随缺血后时间的延长,上述表现有减轻的趋势,但电针组与模型组比较,形成的液化灶较小,细胞轮廓及核仁较清晰。
(2)脑缺血后大鼠缺血灶周围区皮层的突触结构发生破坏,突触数量明显减少。模型组的突触数密度在1h、1d、3d、7d及21d时均明显低于假手术组(P＜0.01或P＜0.05),尤其在1d和3d时下降最明显,3d后逐渐升高。电针组的突触数密度在1h、1d、3d及7d时也明显低于假手术组(P＜0.01或P＜0.05)。而在1d、3d、7d及21d时,电针组的突触数密度均明显高于同时段模型组(P＜0.05或P＜0.01)。
模型组的突触后致密物(PSD)厚度在1h、1d、3d、7d及21d时均明显低于假手术组(P＜0.01),尤其在3d时PSD厚度减小最明显,3d后有所增加。电针组的PSD厚度在1h、1d、3d及7d时也明显低于假手术组(P＜0.05或P＜0.01)。而电针组于各时段PSD厚度均明显高于同时段模型组(P＜0.05或P＜0.01)。
模型组的突触问隙宽度在1h、1d、3d、7d及21d时与假手术组比较均明显减小,差异具有非常显著性意义或显著性意义(P＜0.01或P＜0.05),3d时突触间隙宽度减小最明显,3d后有所提高。电针组的突触间隙宽度在1h、1d、3d及7d时也明显低于假手术组(P＜0.01),但在21d时,与假手术组比较,差异无显著性意义(P＞0.05)。而电针组的突触间隙宽度在1d、3d及7d时均明显高于同时段模型组(P＜0.05)。
模型组的突触界面曲率在1d、3d、7d及21d时与假手术组比较均明显下降(P＜0.01)。电针组的突触界面曲率在1d和3d时也明显低于假手术组(P＜0.05,P＜0.01),至7d和21d时,与假手术组比较,差异无显著性意义(P＞0.05),而电针组的突触界面曲率在1d、3d、7d及21d时均明显高于同时段模型组(P＜0.05或P＜0.01)。
(3)大鼠缺血灶周围区皮层的星形胶质细胞在缺血的早期表现为肿胀、肥大,术后1-3d以细胞肿胀、破溃为主,7d后星形胶质细胞明显增多,而电针组星形胶质细胞肿胀程度较模型组轻。模型组和电针组GFAP表达在1h时与假手术组比较,差异无显著性意义(P＞0.05);在1d、3d、7d及21d时,模型组和电针组GFAP表达都明显增高,与假手术组比较,差异均有非常显著性意义(P＜0.01),尤其是在7d时表达最强,而电针组GFAP表达均明显低于同时段模型组,差异具有显著性意义或非常显著性意义(P＜0.05或P＜0.01)。
(4)模型组EAAT1的表达在1d、3d时较假手术组显著升高(P＜0.05,P＜0.01),随后持续下降,7d、21d时仍显著高于同时段假手术组(P＜0.01,P＜0.05)。电针组EAAT1的表达于1h即开始增加,与假手术组比较,差异有显著性(P＜0.05),在1d、3d、7d及21d时,电针组EAAT1的变化趋势与模型组基本相仿,但均显著高于同时段模型组的表达(P＜0.01)。
模型组EAAT2的表达在1h、1d、3d及7d时均高于同时段的假手术组(P＜0.01),电针组EAAT2的变化趋势与模型组基本一致,但在21d时仍显著高于假手术组(P＜0.01),且在各时段均高于模型组的表达(P＜0.01,P＜0.05)。
(5)在缺血后1d、3d及7d,模型组和电针组CX43的表达均明显低于假手术组,差异均有非常显著性意义(P＜0.01),其中3d时下降最明显,而电针组CX43的表达在缺血后3d和7d均明显高于同时段模型组CX43的表达(P＜0.01,P＜0.05)。在缺血后21d,模型组CX43的表达仍低于假手术组,差异有非常显著性意义(P＜0.01),而电针组CX43的表达与假手术组比较,差异无显著性意义(P＞0.05)。
(6)模型组和电针组星形胶质细胞胞浆Ca~(2+)的平均荧光强度值从1h开始于各时段均明显高于假手术组,差异有非常显著性意义或显著性意义(P＜0.01或P＜0.05),于1d、3d时表达最强,3d后逐渐降低;而在1h、1d、3d及7d时,电针组Ca~(2+)的平均荧光强度值均明显低于同时段模型组,差异具有显著性意义或非常显著性意义(P＜0.05或P＜0.01)。
(7)从脑缺血早期开始突触结构参数的变化与星形胶质细胞CX43、EAAT2、GFAP和[Ca~(2+)]i的变化有密切的联系,且这种相关性主要表现在脑缺血后3周以前。电针治疗后,突触结构参数的变化与星形胶质细胞CX43、EAAT2、GFAP和[Ca~(2+)]i的变化仍具有相关性,且由于电针的干预,在脑缺血后3周突触结构参数的变化与星形胶质细胞仍密切相关。
结论:
(1)缺血性脑损伤后,大鼠神经功能缺损、病理形态变化也有向好发展的趋势,并且其本身存在突触可塑性变化,以及星形胶质细胞出现反应性增生活化,并通过高亲和力谷氨酸转运体、细胞间缝隙连接和钙波等,影响脑损伤的发展和转归,说明脑损伤后具有可塑性变化。
(2)缺血性脑损伤后,电针可促进大鼠突触结构的修复,提高突触界面结构参数,可能促进了残存神经元突触形态可塑性代偿效应的发挥。因此,我们认为电针治疗缺血性脑血管病的机理与其促进突触重建有关。
(3)缺血性脑损伤后,电针可干预星形胶质细胞的活化状态,抑制星形胶质细胞的过度增殖,增强星形胶质细胞清除细胞外间隙谷氨酸的能力,稳定缝隙连接蛋白的表达,维持星形胶质细胞胞浆Ca~(2+)稳态,从而可能下调了星形胶质细胞活化后的一系列损伤反应,更有利于发挥星形胶质细胞对神经元的保护效应。
(4)缺血性脑损伤后,大鼠突触结构参数的变化与星形胶质细胞CX43、EAAT2、GFAP和[Ca~(2+)]i的变化密切相关,电针可能通过干预星形胶质细胞的活化状态,促进星形胶质细胞与突触的良性相互作用,从而影响突触的结构重塑和传递功能,达到促进突触重建的目的。
(5)结合本研究的实验结果,我们认为针刺启动神经-胶质网络调节,促进突触重建是其治疗脑缺血的关键作用机制。
Cerebrovascular disease has ranked the second of the leading cause of death for human. One third of the people who survive this disease will be disabled.It is important to search for effective prevention and treatment on ischemic cerebrovascular disease.The synaptic is one of the key positions in the brain plasticity on the treated and recovered mechanism of ischemic brain damage.We try to explore the underlying mechanism of acupuncture on the improvement of synaptic reorganization in rats with cerebral ischemia.
1.Literature research
We found that stroke has various etiological factors,complicated pathogenesis,sudden onset and different clinical manifestations through researched on the etiology and pathogenesis theory of stroke from ancient to modern literatures.Lots of experimental studies have showed the underlying mechanism of acupuncture in the treatment of cerebral ischemia.It was reviewed of the research progress on astrocyte and synaptic plasticity in modern medicine,and found that the theory of brain plasticity laid a theoretical foundation for the treatment and recovery of stroke,and astrocyte connect closely with synapses,so reactive astrocyte has played an important role in restoration of brain injured and participation in the regulation to synaptic plasticity.Moreover,acupuncture is one of effective stimulating methods to central nervous system,which has played an important role in functional reorganization of cerebra.
2.Experiments research Purpose
To observe the effects of electroacupuncture(EA) on structure parameters of synapse and reactive changes of astrocyte in the marginal zone of focal cerebral ischemia in rats at different time courses so as to further explores its underlying mechanism in the treatment of cerebral ischemia.
Methods
A total of 90 male Wistar rats were divided randomly into sham group,model group and EA group.According to different drawing materials time there was 1 hour,1 day,3days, 7days,and 21days time point after cerebral ischemia in each group,with 6 cases in each time point.Heat-coagulation-induced occlusion of the middle cerebral artery was performed to establish the model of focal cerebral ischemia in model group and EA group, but the middle cerebral arteries were exposed without occlusion in sham group.EA was immediately applied to Baihui(GV20) and Dazhui(GV14) for 30min in EA group.The treatment was given once daily.The sham and model groups did not receive acupuncture. Main outcome measures are following:
(1) Neurological deficit scores and pathomorphology changes dyed by the way of HE were observed in every group.
(2) Synaptic number density(Nv),the thickness of postsynaptic density(PSD),the width of synaptic cleft,and the curvature of synaptic interface were observed by using transmission electronic microscope in the marginal zone of focal cerebral ischemia in rats at different time points.
(3) In the marginal zone of focal cerebral ischemia in rats at different time points,the ultrastructure changes of astrocytes were observed by using transmission electronic microscope,and glial fibrillary acidic protein(GFAP) expression of astrocytes were detected by using immunohistochemical method and laser confocal scanning microscope (LCSM).
(4) In the marginal zone of focal cerebral ischemia in rats at different time points, excitatory amino acid transporters-1(EAAT 1 ) and excitatory amino acid transporters-2(EAAT2) expression of astrocytes were assayed with immunohistochemical method in different groups.
(5) In the marginal zone of focal cerebral ischemia in rats at different time points, connexin 43(Cx43) expressions were measured by using immunohistochemical method.
(6) In the marginal zone of focal cerebral ischemia in rats at different time points, [Ca~(2+)]i of astrocytes were detected by using LCSM.
(7) Canonical correlation analysis was taken between structure parameters of synapse x1- x4(Nv,PSD,the width of synaptic cleft,and the curvature of synaptic interface) and parameters of astrocyte y1- y4(CX43、EAAT2、GFAP、[Ca~(2+)]i) in the same time and group by PEMS3.1.
Results
(1) There had significant differences in the neurological deficit scores of model group and sham group at all stages,which showed that the models were made successfully.There had no obvious difference between EA and model group at 1 day.Neurological deficit symptoms were aggravated in model group at 3days,and compared with that in model group,neurological deficit scores of EA group significantly decreased(P＜0.01).At 7days and 21days,neurological deficit scores of EA group obviously lower than those in model group(P＜0.01,P＜0.05).
The results of HE staining showed that neuronal necrosis appeared.The models were made successfully according to signs of cerebral ischemia such as neural cells arranged in disorder,reticular formation,cell nuclear pyknosis and anachromasis,cytoplasm degeneration appeared,especially at 3days the neuron degeneration and necrosis most obviously.With the prolongation of ischemia,the lesion reduced.But in comparison with that in model group,smaller liquefaction lesion,cell outline and nucleolus could be seen clearly in EA group.
(2) Synaptic structure of cortex in the marginal zone of focal cerebral ischemia in rats was broke,and the number of synapse was decreased obviously.The Nv in model group were significantly lower than those in sham group at 1 hour,1day,3days,7days,and 21days post-surgery(P＜0.01,P＜0.05),especially at 1day and 3days the Nv decreased most obviously,increased gradually after 3days.The Nv in EA group were significantly lower than those in sham group at 1 hour,1day,3days and 7days(P＜0.01,P＜0.05),but the Nv in EA group were significantly higher than those in model group at 1day,3days, 7days,and 21days(P＜0.05,P＜0.01).
In comparison with that in sham group at 1 hour,1day,3days,7days,and 21days post-surgery,the thickness of PSD in model group were decreased obviously(P＜0.01 ).The thickness of PSD in EA group were significantly lower than those in sham group at 1 hour, 1 day,3days and 7days(P＜0.05,P＜0.01),while which were significantly higher than those in model group at the same time point post-surgery(P＜0.05,P＜0.01).
In comparison with that in sham group at 1 hour,1day,3days,7days,and 21days post-surgery,the width of synaptic cleft in model group were decreased obviously(P＜0.01, P＜0.05).The width of synaptic cleft in EA group were significantly lower than those in sham group at 1 hour,1day,3days and 7days(P＜0.01),but the width of synaptic cleft in EA group were higher than those in model group at lday,3days and 7days(P＜0.05).
The curvature of synaptic interface in model group were significantly lower than those in sham group at 1day,3days,7days,and 21days post-surgery(P＜0.01).The curvature of synaptic interface in EA group were significantly lower than those in sham group at 1day and 3days(P＜0.05,P＜0.01),while there have no significant differences in EA group and in sham group at 7days and 21days(P＞0.05).Compared with that in model group,The curvature of synaptic interface in EA group increased significantly at 1day,3days,7days, and 21days(P＜0.05,P＜0.01).
(3) Swollen and increasing astrocytes were observed after cerebral ischemia,while compared with that in model group,the degree of swelling of astrocytes was decreased obviously in EA group.In comparison with that in sham group at 1 hour post-surgery,there have no significant differences of the expression of average fluorescence intensity of GFAP in EA group and model group(P＞0.05),while the expression of GFAP in EA group and model group both increased significantly at 1 day,3days,7days,and 21days post-surgery(P＜0.01),and the expression of GFAP in EA group were significantly lower than those in model group(P＜0.05,P＜0.01).
(4) In comparison with that in sham group,Optical Density(OD) values of EAAT1 in model group increased obviously at 1 day,3days,7days,and 21days post-surgery(P＜0.05, P＜0.01),while compared with that in sham group,the OD value of EAAT1 in EA group increased significantly at 1 hour(P＜0.05),and the change of EAAT1 expression in EA group was similar to that in model group at 1day,3days,7days,and 21days,but OD values of EAAT1 in EA group were significantly higher than those in model group(P＜0.01 ).
In comparison with those in sham group,OD values of EAAT2 in model group increased obviously at 1 hour,1day,3days and 7days(P＜0.01),and the change of EAAT2 expression in EA group was similar to that in model group,however,in comparison with that in sham group,the OD values of EAAT2 in EA group still increased significantly at 21days(P＜0.01),and OD values of EAAT2 in EA group were significantly higher than those in model group(P＜0.01,P＜0.05).
(5) Compared with that in sham group,the expression of CX43 in model and EA group both decreased obviously at 1day,3days and 7days post-surgery(P＜0.01),especially at 3days decreased most obviously.While compared with that in model group,the expression of CX43 in EA group increased significantly at 3days and 7days(P＜0.01,P＜0.05).The expression of CX43 in model group still lower than those in sham group at 21days(P＜0.01),but there have no significant differences of the expression of CX43 in EA group and sham group(P＞0.05).
(6)In comparison with that in sham group at 1 hour,1day,3days,7days,and 21days post-surgery,Ca~(2+) average fluorescence intensity of astrocytes were increased significantly in model and EA group(P＜0.01,P＜0.05),especially at 1day and 3days the expression increased most obviously,decreased gradually after 3days.While Ca~(2+) average fluorescence intensity of astrocytes in EA group were significantly lower than those in model group at 1 hour,1day,3days and 7days(P＜0.05,P＜0.01).
(7) There have closely correlation between the changes of structure parameters of synapses and CX43、EAAT2、GFAP、[Ca~(2+)]i of astrocytes at 1 hour,1day,3days and 7days after cerebral ischemia.The changes of structure parameters of synapse were still closely related to the changes of CX43、EAAT2、GFAP、[Ca~(2+)]i of astrocytes by EA treatment at 1 hour,1day,3days,7days,and 21days after cerebral ischemia.
Conclusion
(1)Neurologic impairment and pathomorphology changes of rats have the trend of self-repair after ischemic brain damage.The development and outcome of brain damage is affected by synaptic plasticity,reactive changes of astrocyte,the changes of glumatic acid transporters,the changes of intercellular gap junction and[ca~(2+)]i,which indicate that brain plasticity is taken place after brain damage.
(2)EA can promote the repair of synaptic structure and improve structure parameters of synapses after ischemic brain damage,which may stimulate compensatory effect of synaptic morphology plasticity in survival neurons.Therefore,we consider that EA can treat cerebral ischemia,which may be related to its effect in promoting synaptic reorganization.
(3) After ischemic brain damage,EA can intervene the activation state of astrocytes, inhibit excessive hyperplasy of astrocytes,strengthen uptake ability of glutamic acid,keep stable expression of connexin in gap junctions,and reduce the reactive changes of intracellular[Ca~(2+)]i of astrocytes,which may contribute to regeneration and reparation of cerebral neurons.
(4)The changes of structure parameters of synapse were closely related to the changes ofCX43、EAAT2、GFAP、[Ca~(2+)]i ofastrocytes in rats after ischemic brain damage.EA is helpful to synaptic reorganization,which may be related to its effect in intervening the activation state of astrocytes and promoting the beneficial interaction between astrocytes and synapses.
(5)The results support that acupuncture can start the adjustment of neuron-glial network so to promote the synaptic reorganization,which may be the key mechanisms of treating cerebral ischemia.
1.文献研究
通过对中风病因病机理论的古代及现代文献研究,我们认为中风的病因繁多,病机复杂,发病急骤,变化多端,表现各异。大量的实验研究也揭示了针灸治疗缺血性中风的可能作用机制。本文还就现代医学对星形胶质细胞、突触可塑性的认识及研究进展进行了综述,认为脑可塑性的理论为脑卒中后的治疗和康复奠定了理论基础,星形胶质细胞和突触紧密相连,脑缺血后活化的星形胶质细胞在脑损伤及修复中具有重要作用,星形胶质细胞参与了对突触可塑性的调节,而针刺是中枢神经系统有效的刺激形式之一,针刺对大脑的功能重组和代偿起着重要作用。
2.实验研究
目的:观察针刺对局灶性脑缺血大鼠缺血灶周围区不同时间段突触结构参数及星形胶质细胞反应性变化的影响,进一步揭示针刺治疗脑缺血疾病的可能作用机制。
方法:雄性Wistar大鼠90只,随机分为3组:假手术组、模型组和电针组,各组又分为术后1h,1d,3d,7d及21d 5个时段组,6只/时段组。模型组和电针组采用电凝闭大脑中动脉建立局灶性脑缺血(MCAO)模型,假手术组只暴露大鼠大脑中动脉,不予凝闭。电针组术后立即给予电针治疗,取百会(GV20)、大椎(GV14)穴,选用疏密波,5-10次/s,强度以大鼠安静耐受为度,电压约2-3V,留针30min,1次/d。其他2组不予针刺处理。观察以下指标:
(1)各组大鼠神经功能缺损评分及进行HE染色观察大鼠脑缺血灶周围区病理形态学改变。
(2)透射电镜观察不同时段各组大鼠缺血灶周围区皮层的突触数密度、突触后致密物厚度、突触间隙宽度以及突触界面曲率的变化。
(3)透射电镜观察各组大鼠脑缺血灶周围区星形胶质细胞的超微结构,采用免疫组织化学法、激光共聚焦扫描显微镜观察星形胶质细胞胶质纤维酸性蛋白(GFAP)的变化。
(4)采用免疫组织化学法检测各组大鼠脑缺血灶周围区谷氨酸转运体EAAT1、EAAT2的表达。
(5)采用免疫组织化学法检测各组大鼠脑缺血灶周围区缝隙连接蛋白CX43的表达。
(6)激光共聚焦扫描显微镜观察各组大鼠脑缺血灶周围区星形胶质细胞胞浆[Ca~(2+)]i的变化。
(7)运用统计学软件PEMS3.1分别做各时间段脑缺血和电针干预后的突触结构参数x1-x4(突触数密度、突触后致密物厚度、突触间隙宽度及突触界面曲率)与星形胶质细胞参数y1-y4(CX43、EAAT2、GFAP、[Ca~(2+)]i)之间的典型相关分析。
结果:
(1)不同时段的模型组与假手术组比较均有显著差异,大鼠造模后均出现不同程度的神经缺损体征,表明脑缺血模型造模成功。1d电针组与模型组比较差异无显著性意义。3d模型组大鼠神经缺损症状加重,部分大鼠出现转圈运动,而电针组大鼠神经体征有所恢复,评分明显低于模型组(P＜0.01)。7d、21d模型组和电针组的大鼠神经功能缺损评分均较前降低,而电针组评分明显低于模型组(P＜0.01,P＜0.05)。
HE染色结果显示1h-3d模型组有神经细胞坏死征象,出现筛网状结构,部分神经细胞排列紊乱,呈三角形和多角形,细胞核固缩深染,胞浆空泡样变性等典型的脑缺血征象,说明MCAO模型造模成功,上述表现尤其以缺血3d组变性坏死较为明显。而随缺血后时间的延长,上述表现有减轻的趋势,但电针组与模型组比较,形成的液化灶较小,细胞轮廓及核仁较清晰。
(2)脑缺血后大鼠缺血灶周围区皮层的突触结构发生破坏,突触数量明显减少。模型组的突触数密度在1h、1d、3d、7d及21d时均明显低于假手术组(P＜0.01或P＜0.05),尤其在1d和3d时下降最明显,3d后逐渐升高。电针组的突触数密度在1h、1d、3d及7d时也明显低于假手术组(P＜0.01或P＜0.05)。而在1d、3d、7d及21d时,电针组的突触数密度均明显高于同时段模型组(P＜0.05或P＜0.01)。
模型组的突触后致密物(PSD)厚度在1h、1d、3d、7d及21d时均明显低于假手术组(P＜0.01),尤其在3d时PSD厚度减小最明显,3d后有所增加。电针组的PSD厚度在1h、1d、3d及7d时也明显低于假手术组(P＜0.05或P＜0.01)。而电针组于各时段PSD厚度均明显高于同时段模型组(P＜0.05或P＜0.01)。
模型组的突触问隙宽度在1h、1d、3d、7d及21d时与假手术组比较均明显减小,差异具有非常显著性意义或显著性意义(P＜0.01或P＜0.05),3d时突触间隙宽度减小最明显,3d后有所提高。电针组的突触间隙宽度在1h、1d、3d及7d时也明显低于假手术组(P＜0.01),但在21d时,与假手术组比较,差异无显著性意义(P＞0.05)。而电针组的突触间隙宽度在1d、3d及7d时均明显高于同时段模型组(P＜0.05)。
模型组的突触界面曲率在1d、3d、7d及21d时与假手术组比较均明显下降(P＜0.01)。电针组的突触界面曲率在1d和3d时也明显低于假手术组(P＜0.05,P＜0.01),至7d和21d时,与假手术组比较,差异无显著性意义(P＞0.05),而电针组的突触界面曲率在1d、3d、7d及21d时均明显高于同时段模型组(P＜0.05或P＜0.01)。
(3)大鼠缺血灶周围区皮层的星形胶质细胞在缺血的早期表现为肿胀、肥大,术后1-3d以细胞肿胀、破溃为主,7d后星形胶质细胞明显增多,而电针组星形胶质细胞肿胀程度较模型组轻。模型组和电针组GFAP表达在1h时与假手术组比较,差异无显著性意义(P＞0.05);在1d、3d、7d及21d时,模型组和电针组GFAP表达都明显增高,与假手术组比较,差异均有非常显著性意义(P＜0.01),尤其是在7d时表达最强,而电针组GFAP表达均明显低于同时段模型组,差异具有显著性意义或非常显著性意义(P＜0.05或P＜0.01)。
(4)模型组EAAT1的表达在1d、3d时较假手术组显著升高(P＜0.05,P＜0.01),随后持续下降,7d、21d时仍显著高于同时段假手术组(P＜0.01,P＜0.05)。电针组EAAT1的表达于1h即开始增加,与假手术组比较,差异有显著性(P＜0.05),在1d、3d、7d及21d时,电针组EAAT1的变化趋势与模型组基本相仿,但均显著高于同时段模型组的表达(P＜0.01)。
模型组EAAT2的表达在1h、1d、3d及7d时均高于同时段的假手术组(P＜0.01),电针组EAAT2的变化趋势与模型组基本一致,但在21d时仍显著高于假手术组(P＜0.01),且在各时段均高于模型组的表达(P＜0.01,P＜0.05)。
(5)在缺血后1d、3d及7d,模型组和电针组CX43的表达均明显低于假手术组,差异均有非常显著性意义(P＜0.01),其中3d时下降最明显,而电针组CX43的表达在缺血后3d和7d均明显高于同时段模型组CX43的表达(P＜0.01,P＜0.05)。在缺血后21d,模型组CX43的表达仍低于假手术组,差异有非常显著性意义(P＜0.01),而电针组CX43的表达与假手术组比较,差异无显著性意义(P＞0.05)。
(6)模型组和电针组星形胶质细胞胞浆Ca~(2+)的平均荧光强度值从1h开始于各时段均明显高于假手术组,差异有非常显著性意义或显著性意义(P＜0.01或P＜0.05),于1d、3d时表达最强,3d后逐渐降低;而在1h、1d、3d及7d时,电针组Ca~(2+)的平均荧光强度值均明显低于同时段模型组,差异具有显著性意义或非常显著性意义(P＜0.05或P＜0.01)。
(7)从脑缺血早期开始突触结构参数的变化与星形胶质细胞CX43、EAAT2、GFAP和[Ca~(2+)]i的变化有密切的联系,且这种相关性主要表现在脑缺血后3周以前。电针治疗后,突触结构参数的变化与星形胶质细胞CX43、EAAT2、GFAP和[Ca~(2+)]i的变化仍具有相关性,且由于电针的干预,在脑缺血后3周突触结构参数的变化与星形胶质细胞仍密切相关。
结论:
(1)缺血性脑损伤后,大鼠神经功能缺损、病理形态变化也有向好发展的趋势,并且其本身存在突触可塑性变化,以及星形胶质细胞出现反应性增生活化,并通过高亲和力谷氨酸转运体、细胞间缝隙连接和钙波等,影响脑损伤的发展和转归,说明脑损伤后具有可塑性变化。
(2)缺血性脑损伤后,电针可促进大鼠突触结构的修复,提高突触界面结构参数,可能促进了残存神经元突触形态可塑性代偿效应的发挥。因此,我们认为电针治疗缺血性脑血管病的机理与其促进突触重建有关。
(3)缺血性脑损伤后,电针可干预星形胶质细胞的活化状态,抑制星形胶质细胞的过度增殖,增强星形胶质细胞清除细胞外间隙谷氨酸的能力,稳定缝隙连接蛋白的表达,维持星形胶质细胞胞浆Ca~(2+)稳态,从而可能下调了星形胶质细胞活化后的一系列损伤反应,更有利于发挥星形胶质细胞对神经元的保护效应。
(4)缺血性脑损伤后,大鼠突触结构参数的变化与星形胶质细胞CX43、EAAT2、GFAP和[Ca~(2+)]i的变化密切相关,电针可能通过干预星形胶质细胞的活化状态,促进星形胶质细胞与突触的良性相互作用,从而影响突触的结构重塑和传递功能,达到促进突触重建的目的。
(5)结合本研究的实验结果,我们认为针刺启动神经-胶质网络调节,促进突触重建是其治疗脑缺血的关键作用机制。
Cerebrovascular disease has ranked the second of the leading cause of death for human. One third of the people who survive this disease will be disabled.It is important to search for effective prevention and treatment on ischemic cerebrovascular disease.The synaptic is one of the key positions in the brain plasticity on the treated and recovered mechanism of ischemic brain damage.We try to explore the underlying mechanism of acupuncture on the improvement of synaptic reorganization in rats with cerebral ischemia.
1.Literature research
We found that stroke has various etiological factors,complicated pathogenesis,sudden onset and different clinical manifestations through researched on the etiology and pathogenesis theory of stroke from ancient to modern literatures.Lots of experimental studies have showed the underlying mechanism of acupuncture in the treatment of cerebral ischemia.It was reviewed of the research progress on astrocyte and synaptic plasticity in modern medicine,and found that the theory of brain plasticity laid a theoretical foundation for the treatment and recovery of stroke,and astrocyte connect closely with synapses,so reactive astrocyte has played an important role in restoration of brain injured and participation in the regulation to synaptic plasticity.Moreover,acupuncture is one of effective stimulating methods to central nervous system,which has played an important role in functional reorganization of cerebra.
2.Experiments research Purpose
To observe the effects of electroacupuncture(EA) on structure parameters of synapse and reactive changes of astrocyte in the marginal zone of focal cerebral ischemia in rats at different time courses so as to further explores its underlying mechanism in the treatment of cerebral ischemia.
Methods
A total of 90 male Wistar rats were divided randomly into sham group,model group and EA group.According to different drawing materials time there was 1 hour,1 day,3days, 7days,and 21days time point after cerebral ischemia in each group,with 6 cases in each time point.Heat-coagulation-induced occlusion of the middle cerebral artery was performed to establish the model of focal cerebral ischemia in model group and EA group, but the middle cerebral arteries were exposed without occlusion in sham group.EA was immediately applied to Baihui(GV20) and Dazhui(GV14) for 30min in EA group.The treatment was given once daily.The sham and model groups did not receive acupuncture. Main outcome measures are following:
(1) Neurological deficit scores and pathomorphology changes dyed by the way of HE were observed in every group.
(2) Synaptic number density(Nv),the thickness of postsynaptic density(PSD),the width of synaptic cleft,and the curvature of synaptic interface were observed by using transmission electronic microscope in the marginal zone of focal cerebral ischemia in rats at different time points.
(3) In the marginal zone of focal cerebral ischemia in rats at different time points,the ultrastructure changes of astrocytes were observed by using transmission electronic microscope,and glial fibrillary acidic protein(GFAP) expression of astrocytes were detected by using immunohistochemical method and laser confocal scanning microscope (LCSM).
(4) In the marginal zone of focal cerebral ischemia in rats at different time points, excitatory amino acid transporters-1(EAAT 1 ) and excitatory amino acid transporters-2(EAAT2) expression of astrocytes were assayed with immunohistochemical method in different groups.
(5) In the marginal zone of focal cerebral ischemia in rats at different time points, connexin 43(Cx43) expressions were measured by using immunohistochemical method.
(6) In the marginal zone of focal cerebral ischemia in rats at different time points, [Ca~(2+)]i of astrocytes were detected by using LCSM.
(7) Canonical correlation analysis was taken between structure parameters of synapse x1- x4(Nv,PSD,the width of synaptic cleft,and the curvature of synaptic interface) and parameters of astrocyte y1- y4(CX43、EAAT2、GFAP、[Ca~(2+)]i) in the same time and group by PEMS3.1.
Results
(1) There had significant differences in the neurological deficit scores of model group and sham group at all stages,which showed that the models were made successfully.There had no obvious difference between EA and model group at 1 day.Neurological deficit symptoms were aggravated in model group at 3days,and compared with that in model group,neurological deficit scores of EA group significantly decreased(P＜0.01).At 7days and 21days,neurological deficit scores of EA group obviously lower than those in model group(P＜0.01,P＜0.05).
The results of HE staining showed that neuronal necrosis appeared.The models were made successfully according to signs of cerebral ischemia such as neural cells arranged in disorder,reticular formation,cell nuclear pyknosis and anachromasis,cytoplasm degeneration appeared,especially at 3days the neuron degeneration and necrosis most obviously.With the prolongation of ischemia,the lesion reduced.But in comparison with that in model group,smaller liquefaction lesion,cell outline and nucleolus could be seen clearly in EA group.
(2) Synaptic structure of cortex in the marginal zone of focal cerebral ischemia in rats was broke,and the number of synapse was decreased obviously.The Nv in model group were significantly lower than those in sham group at 1 hour,1day,3days,7days,and 21days post-surgery(P＜0.01,P＜0.05),especially at 1day and 3days the Nv decreased most obviously,increased gradually after 3days.The Nv in EA group were significantly lower than those in sham group at 1 hour,1day,3days and 7days(P＜0.01,P＜0.05),but the Nv in EA group were significantly higher than those in model group at 1day,3days, 7days,and 21days(P＜0.05,P＜0.01).
In comparison with that in sham group at 1 hour,1day,3days,7days,and 21days post-surgery,the thickness of PSD in model group were decreased obviously(P＜0.01 ).The thickness of PSD in EA group were significantly lower than those in sham group at 1 hour, 1 day,3days and 7days(P＜0.05,P＜0.01),while which were significantly higher than those in model group at the same time point post-surgery(P＜0.05,P＜0.01).
In comparison with that in sham group at 1 hour,1day,3days,7days,and 21days post-surgery,the width of synaptic cleft in model group were decreased obviously(P＜0.01, P＜0.05).The width of synaptic cleft in EA group were significantly lower than those in sham group at 1 hour,1day,3days and 7days(P＜0.01),but the width of synaptic cleft in EA group were higher than those in model group at lday,3days and 7days(P＜0.05).
The curvature of synaptic interface in model group were significantly lower than those in sham group at 1day,3days,7days,and 21days post-surgery(P＜0.01).The curvature of synaptic interface in EA group were significantly lower than those in sham group at 1day and 3days(P＜0.05,P＜0.01),while there have no significant differences in EA group and in sham group at 7days and 21days(P＞0.05).Compared with that in model group,The curvature of synaptic interface in EA group increased significantly at 1day,3days,7days, and 21days(P＜0.05,P＜0.01).
(3) Swollen and increasing astrocytes were observed after cerebral ischemia,while compared with that in model group,the degree of swelling of astrocytes was decreased obviously in EA group.In comparison with that in sham group at 1 hour post-surgery,there have no significant differences of the expression of average fluorescence intensity of GFAP in EA group and model group(P＞0.05),while the expression of GFAP in EA group and model group both increased significantly at 1 day,3days,7days,and 21days post-surgery(P＜0.01),and the expression of GFAP in EA group were significantly lower than those in model group(P＜0.05,P＜0.01).
(4) In comparison with that in sham group,Optical Density(OD) values of EAAT1 in model group increased obviously at 1 day,3days,7days,and 21days post-surgery(P＜0.05, P＜0.01),while compared with that in sham group,the OD value of EAAT1 in EA group increased significantly at 1 hour(P＜0.05),and the change of EAAT1 expression in EA group was similar to that in model group at 1day,3days,7days,and 21days,but OD values of EAAT1 in EA group were significantly higher than those in model group(P＜0.01 ).
In comparison with those in sham group,OD values of EAAT2 in model group increased obviously at 1 hour,1day,3days and 7days(P＜0.01),and the change of EAAT2 expression in EA group was similar to that in model group,however,in comparison with that in sham group,the OD values of EAAT2 in EA group still increased significantly at 21days(P＜0.01),and OD values of EAAT2 in EA group were significantly higher than those in model group(P＜0.01,P＜0.05).
(5) Compared with that in sham group,the expression of CX43 in model and EA group both decreased obviously at 1day,3days and 7days post-surgery(P＜0.01),especially at 3days decreased most obviously.While compared with that in model group,the expression of CX43 in EA group increased significantly at 3days and 7days(P＜0.01,P＜0.05).The expression of CX43 in model group still lower than those in sham group at 21days(P＜0.01),but there have no significant differences of the expression of CX43 in EA group and sham group(P＞0.05).
(6)In comparison with that in sham group at 1 hour,1day,3days,7days,and 21days post-surgery,Ca~(2+) average fluorescence intensity of astrocytes were increased significantly in model and EA group(P＜0.01,P＜0.05),especially at 1day and 3days the expression increased most obviously,decreased gradually after 3days.While Ca~(2+) average fluorescence intensity of astrocytes in EA group were significantly lower than those in model group at 1 hour,1day,3days and 7days(P＜0.05,P＜0.01).
(7) There have closely correlation between the changes of structure parameters of synapses and CX43、EAAT2、GFAP、[Ca~(2+)]i of astrocytes at 1 hour,1day,3days and 7days after cerebral ischemia.The changes of structure parameters of synapse were still closely related to the changes of CX43、EAAT2、GFAP、[Ca~(2+)]i of astrocytes by EA treatment at 1 hour,1day,3days,7days,and 21days after cerebral ischemia.
Conclusion
(1)Neurologic impairment and pathomorphology changes of rats have the trend of self-repair after ischemic brain damage.The development and outcome of brain damage is affected by synaptic plasticity,reactive changes of astrocyte,the changes of glumatic acid transporters,the changes of intercellular gap junction and[ca~(2+)]i,which indicate that brain plasticity is taken place after brain damage.
(2)EA can promote the repair of synaptic structure and improve structure parameters of synapses after ischemic brain damage,which may stimulate compensatory effect of synaptic morphology plasticity in survival neurons.Therefore,we consider that EA can treat cerebral ischemia,which may be related to its effect in promoting synaptic reorganization.
(3) After ischemic brain damage,EA can intervene the activation state of astrocytes, inhibit excessive hyperplasy of astrocytes,strengthen uptake ability of glutamic acid,keep stable expression of connexin in gap junctions,and reduce the reactive changes of intracellular[Ca~(2+)]i of astrocytes,which may contribute to regeneration and reparation of cerebral neurons.
(4)The changes of structure parameters of synapse were closely related to the changes ofCX43、EAAT2、GFAP、[Ca~(2+)]i ofastrocytes in rats after ischemic brain damage.EA is helpful to synaptic reorganization,which may be related to its effect in intervening the activation state of astrocytes and promoting the beneficial interaction between astrocytes and synapses.
(5)The results support that acupuncture can start the adjustment of neuron-glial network so to promote the synaptic reorganization,which may be the key mechanisms of treating cerebral ischemia.
引文
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