CREB磷酸化在电针结合重复经颅磁刺激激活脑缺血后内源性神经再生的作用机制研究
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摘要
第一部分、PKA-CREB信号通路在电针结合重复经颅磁刺激激活脑缺血后内源性神经再生中的作用及机制
研究目的：
探讨PKA-CREB信号通路在电针(electro-acupuncture，EA)结合重复经颅磁刺激(repetitive Transcranial Magnetic Stimulation，rTMS)激活脑缺血后内源性神经再生中的作用及机制。
研究方法：
取Wistar大鼠150只，采用线栓法制备大鼠大脑中动脉闭塞模型[廖维靖，刘淑红，范明，等．线栓阻断大鼠大脑中动脉制作缺血性脑损伤模型的改良．中华物理医学与康复杂志，2002，24(6)：345-349．]，随机分为正常组、模型组、EA组、rTMS组和EA+rTMS组，通过免疫组化和Western blot检测脑缺血后第7d、14d与28d三个不同时相大鼠缺血侧海马PKA、pCREB表达的变化，并观测其神经功能评分和学习记忆能力。
研究结果：
(1)EA组、rTMS组和EA+rTMS组各时相神经功能评分和电跳台实验评分均较模型组改善(p＜0．01，p＜0．05)，尤以EA+rTMS组为明显；
(2)脑缺血后不同时相缺血侧海马PKA及pCREB的阳性表达和灰度值比较，模型组在7d时高于正常组，28d时低于正常组，差异均有统计学意义(p＜0．05)，14d时与正常组相比差异无统计学意义(p＞0．05)；EA组、rTMS组和EA+rTMS组三个时相均高于模型组，7d、14d时高于正常组，差异有统计学意义(p＜0．05)，28d时与正常组相比差异无统计学意义(p＞0．05)；EA+rTMS组7d、14d时高于EA组和rTMS组，差异有统计学意义(p＜0．05)，EA组和rTMS组各时相差异均无统计学意义(p＞0．05)；
(3)pCREB阳性表达与NSCs增殖量成正相关。
研究结论：
EA结合rTMS对缺血性脑卒中后神经功能的恢复具有显著的促进作用，缺血侧海马PKA-CREB信号分子的表达增强可能是其治疗缺血性脑卒中的机制之一。
第二部分、电针结合重复经颅磁刺激对局灶性脑缺血大鼠内源性神经干细胞迁移、分化的影响
研究目的：
探讨电针(electro-acupuncture，EA)结合重复经颅磁刺激(repetitive TranscranialMagnetic Stimulation，rTMS)对局灶性脑缺血大鼠内源性神经干细胞迁移、分化的影响及其治疗缺血性脑损伤的机制。
研究方法：
取Wistar大鼠120只，采用线栓法制备大鼠大脑中动脉闭塞模型[廖维靖，刘淑红，范明，等．线栓阻断大鼠大脑中动脉制作缺血性脑损伤模型的改良．中华物理医学与康复杂志，2002，24(6)：345-349．]，随机分为正常组、模型组、EA组、rTMS组和EA+rTMS组，采用免疫组织化学方法动态检测大鼠脑缺血后第7d、14d与28d三个不同时相、不同脑区多唾液酸神经细胞粘附分子(polysiolylated neural cell adhesion molecule，PSA-NCAM)与PSA-NCAM／5-嗅脱氧尿嘧啶(5-bromodeoxyuridine，BrdU)、神经核抗原(neuronalnuclear antigen，NeuN)与NeuN／BrdU、钙结合蛋白(Calbindin)等标志物的免疫阳性表达。
研究结果：
(1)PSA-NCAM在正常组仅有少量稀疏表达，染色淡；缺血后7d其阳性细胞表达明显增加(P＜0．05)，成簇状分布，突起短，14d表达达到高峰，胞体变大，突起变长，28d表达开始下降；PSA-NCAM／BrdU标记细胞在正常组少量表达，缺血后7d表达增加(P＜0．05)，14d表达达到高峰，28d表达下降，仍高于正常组(P＜0．05)。EA组、rTMS组、EA+rTMS组与模型组在7d、14d时差异均有统计学意义(P＜0．05)，EA+rTMS组与EA组、rTMS组在7d、14d时差异也有统计学意义(P＜0．05)，EA组、rTMS组、EA+rTMS组与模型组在28d相比PSA-NCAM与PSA-NCAM／BrdU阳性细胞数目之间的差异均无统计学意义(P＞0．05)；
(2)NeuN在正常组仅有少量稀疏表达，缺血后7d其阳性细胞的表达明显增加(P＜0．05)，14d表达达到高峰，28d表达开始下降；NeuN／BrdU标记细胞在正常组几乎没有表达，缺血后7d表达增加(P＜0．05)，14d表达达到高峰，28d表达下降，仍高于正常组(P＜0．05)。增加最明显的为EA+rTMS组，EA组和rTMS组也有明显增加，模型组增加最少；从组间比较看，EA组、rTMS组、EA+rTMS组与模型组在7d、14d时差异均有统计学意义(P＜0．05)，EA+rTMS组在7d、14d时均高于EA组和rTMS组(P＜0．05)，EA组、rTMS组、EA+rTMS组与模型组在28d相比NeuN及NeuN／BrdU阳性细胞数目之间的差异均无统计学意义(P＞0．05)；
(3)正常组大鼠脑组织切片可见Calbindin-D28k阳性神经元表达清晰，神经元层排列整齐而致密，形态正常，神经元表达多，染色深。模型组切片可见Calbindin-D28k阳性神经元胞体缩小，神经元排列紊乱而疏松，染色较浅，表达较少。EA+rTMS组切片Calbindin-D28k阳性神经元有较多表达，形态基本正常，细胞染色较深。EA组、rTMS组切片显示Calbindin-D28k阳性神经元表达欠清晰，细胞形态不规则，呈缺血坏死改变，阳性细胞表达较少，染色较浅。EA组、rTMS组各时相及EA+rTMS组第7d、14d时Calbindin-D28k阳性表达均少于正常组(P＜0．05)，EA+rTMS组第28d与正常组差异无统计学意义(P＞0．05)，EA组、rTMS组、EA+rTMS组各时相Calbindin-D28k阳性表达均高于模型组(P＜0．05)，EA+rTMS组各时相Calbindin-D28k阳性表达均高于EA组、rTMS组(P＜0．05)，EA组与rTMS组之间各时相差异均无统计学意义(P＞0．05)。各组SVZ、SGZ各时相Calbindin-D28k阳性表达均高于梗死灶周围皮质。
研究结论：
EA结合rTMS促进缺血侧不同脑区内源性神经干细胞的增殖、迁移和分化及整合，促进神经再生及损伤后神经功能的恢复，可能是其治疗缺血性脑卒中的重要作用机制之一。
PartⅠStudy on the role and mechanism of PKA-CREB SignalTransduction System in neurogenesis activated by electro-acupuncturecombined with repetitive Transcranial Magnetic Stimulation after focalcerebral ischemia in adult rats
Objective:
To investigate the role and mechanism of PKA-CREB Signal Transduction System inneurogenesis activated by electro-acupuncture combined with rTMS after focal cerebralischemia in adult rats.
Methods:
The model of transient focal ischemia was made by the middle cerebral arteryocclusion.One hundred and fifty Wistar rats were randomly divided into normal group,model group,EA group,rTMS group and EA combined with rTMS group.To observe theneurologic impairment rating,ability of learning and memory at the 7th、14th and 28th dayafter infarction respectively.Meanwhile,Immunohistochemistry and Western blot wereconducted to detect the expression of PKA and pCREB in hippocampus of ipsilateralhemispheres.
Results:
(1) The improvement of neural motor function deficits as well as the indexes oflearning and memory were more obvious in EA group,rTMS,EA combined with rTMS group compared with the model group (p＜0.01,p＜0.05),and the improvement were themost obvious in the EA combined with rTMS group.
(2) The number of positive cells and the average gray density of PKA and pCREBexpression in hippocampus of ipsilateral hemispheres in the model group were higher at the7th day,lower at the 28th day than that of nomal group (p＜0.05),higher in EA group,rTMS,EA combined with rTMS group than that of model group in every time point andnomal group at 7th and 14th day (p＜0.05),higher in EA combined with rTMS group thanthat in EA group,rTMS group at 7th and 14th day,and there was no difference between EAgroup and rTMS group.
(3) Positive correlation existed between pCREB positive expression with NSCsproliferation.
Conclusion:
EA combined with rTMS can conspicuously promote the functional recovery aftercerebral arterial thrombosis,upregulate the expression of related signaling molecule ofPKA-CREB transduction system in hippocampus of ipsilateral hemispheres,which mightbe one of the important mechanisms of EA combined with rTMS in treating ischemic braininjury.
PartⅡEffects of electro-acupuncture combined with repetitiveTranscranial Magnetic Stimulation on migration and differentiation ofinherent neural stem cells after focal cerebral ischemia in adult rats
Objective:
To investigate the effects of electro-acupuncture(EA) combined with repetitive Transcranial Magnetic Stimulation (rTMS) on migration and differentiation of inherentneural stem cells after focal cerebral ischemia in adult rats and to explore the mechanism ofEA combined with rTMS in treating ischemic brain injury.
Methods:
The model of transient focal ischemia was made by the middle cerebral arteryocclusion.One hundred and twenty Wistar rats were randomly divided into normal group,model group,EA group,rTMS group and EA combined with rTMS group.To observe theexpression of polysiolylated neural cell adhesion molecule(PSA-NCAM) andPSA-NCAM/5-bromodeoxyuridine (BrdU),NeuN and NeuN/BrdU,Calbindin in differentencephalic regions of ipsilateral hemispheres by immunohistochemical andimmunofluorescence staining at the 7th、14th and 28th day after infarction respectively.
Results:
(1) The number of PSA-NCAM-positive cells and PSA-NCAM/BrdU positive cells indifferent encephalic regions of ipsilateral hemispheres increased at day 7after MCAO(p＜0.05),reached maximum at day 14 (p＜0.05),and decreased markedly at day 28,but itwas still elevated compared with that in normal group.There were significant differences inEA group,rTMS group and EA combined with rTMS group when compared with that ofmodel group at day 7 and 14 (P＜0.05).There were significant differences in EA combinedwith rTMS group when compared with that of EA group and rTMS group at day 7 and 14(P＜0.05).However,there were no statistic differences in EA group,rTMS group and EAcombined with rTMS group when compared with that of model group at day 28(P＞0.05).
(2) The number of NeuN-positive cells and NeuN/BrdU positive cells in hippocampusincreased at day 7after MCAO (p＜0.05),reached maximum at day 14 (p＜0.05),anddecreased markedly at day 28,but it was still elevated compared with that of normalgroup.There were significant differences in EA group,rTMS group and EA combined withrTMS group when compared with that of model group at day 7 and 14 (P＜0.05).Therewere significant differences in EA combined with rTMS group when compared with that of EA group and rTMS group at day 7 and 14 (P＜0.05).However,there were no statisticdifferences in EA group,rTMS group and EA combined with rTMS group when comparedwith that of model group at day 28(P＞0.05).
(3) In EA combined with rTMS group,the neuron arrangement in peripheral cortex ofinfarction was regular just with mild cell loss and some darken dyeing nucleus.The averageoptical density of Calbindin in EA combined with rTMS group were higher than that inmodel group,EA group and rTMS group (P＜0.05).
Conclusion:
EA combined with rTMS can promote the proliferation,migration and differentiationof inherent neural stem cells in different encephalic regions of ipsilateral hemispheres,promote the neural regeneration and neurofunctional restoration,which might be one of theimportant mechanisms of EA combined with rTMS in treating ischemic brain injury.
研究目的：
探讨PKA-CREB信号通路在电针(electro-acupuncture，EA)结合重复经颅磁刺激(repetitive Transcranial Magnetic Stimulation，rTMS)激活脑缺血后内源性神经再生中的作用及机制。
研究方法：
取Wistar大鼠150只，采用线栓法制备大鼠大脑中动脉闭塞模型[廖维靖，刘淑红，范明，等．线栓阻断大鼠大脑中动脉制作缺血性脑损伤模型的改良．中华物理医学与康复杂志，2002，24(6)：345-349．]，随机分为正常组、模型组、EA组、rTMS组和EA+rTMS组，通过免疫组化和Western blot检测脑缺血后第7d、14d与28d三个不同时相大鼠缺血侧海马PKA、pCREB表达的变化，并观测其神经功能评分和学习记忆能力。
研究结果：
(1)EA组、rTMS组和EA+rTMS组各时相神经功能评分和电跳台实验评分均较模型组改善(p＜0．01，p＜0．05)，尤以EA+rTMS组为明显；
(2)脑缺血后不同时相缺血侧海马PKA及pCREB的阳性表达和灰度值比较，模型组在7d时高于正常组，28d时低于正常组，差异均有统计学意义(p＜0．05)，14d时与正常组相比差异无统计学意义(p＞0．05)；EA组、rTMS组和EA+rTMS组三个时相均高于模型组，7d、14d时高于正常组，差异有统计学意义(p＜0．05)，28d时与正常组相比差异无统计学意义(p＞0．05)；EA+rTMS组7d、14d时高于EA组和rTMS组，差异有统计学意义(p＜0．05)，EA组和rTMS组各时相差异均无统计学意义(p＞0．05)；
(3)pCREB阳性表达与NSCs增殖量成正相关。
研究结论：
EA结合rTMS对缺血性脑卒中后神经功能的恢复具有显著的促进作用，缺血侧海马PKA-CREB信号分子的表达增强可能是其治疗缺血性脑卒中的机制之一。
第二部分、电针结合重复经颅磁刺激对局灶性脑缺血大鼠内源性神经干细胞迁移、分化的影响
研究目的：
探讨电针(electro-acupuncture，EA)结合重复经颅磁刺激(repetitive TranscranialMagnetic Stimulation，rTMS)对局灶性脑缺血大鼠内源性神经干细胞迁移、分化的影响及其治疗缺血性脑损伤的机制。
研究方法：
取Wistar大鼠120只，采用线栓法制备大鼠大脑中动脉闭塞模型[廖维靖，刘淑红，范明，等．线栓阻断大鼠大脑中动脉制作缺血性脑损伤模型的改良．中华物理医学与康复杂志，2002，24(6)：345-349．]，随机分为正常组、模型组、EA组、rTMS组和EA+rTMS组，采用免疫组织化学方法动态检测大鼠脑缺血后第7d、14d与28d三个不同时相、不同脑区多唾液酸神经细胞粘附分子(polysiolylated neural cell adhesion molecule，PSA-NCAM)与PSA-NCAM／5-嗅脱氧尿嘧啶(5-bromodeoxyuridine，BrdU)、神经核抗原(neuronalnuclear antigen，NeuN)与NeuN／BrdU、钙结合蛋白(Calbindin)等标志物的免疫阳性表达。
研究结果：
(1)PSA-NCAM在正常组仅有少量稀疏表达，染色淡；缺血后7d其阳性细胞表达明显增加(P＜0．05)，成簇状分布，突起短，14d表达达到高峰，胞体变大，突起变长，28d表达开始下降；PSA-NCAM／BrdU标记细胞在正常组少量表达，缺血后7d表达增加(P＜0．05)，14d表达达到高峰，28d表达下降，仍高于正常组(P＜0．05)。EA组、rTMS组、EA+rTMS组与模型组在7d、14d时差异均有统计学意义(P＜0．05)，EA+rTMS组与EA组、rTMS组在7d、14d时差异也有统计学意义(P＜0．05)，EA组、rTMS组、EA+rTMS组与模型组在28d相比PSA-NCAM与PSA-NCAM／BrdU阳性细胞数目之间的差异均无统计学意义(P＞0．05)；
(2)NeuN在正常组仅有少量稀疏表达，缺血后7d其阳性细胞的表达明显增加(P＜0．05)，14d表达达到高峰，28d表达开始下降；NeuN／BrdU标记细胞在正常组几乎没有表达，缺血后7d表达增加(P＜0．05)，14d表达达到高峰，28d表达下降，仍高于正常组(P＜0．05)。增加最明显的为EA+rTMS组，EA组和rTMS组也有明显增加，模型组增加最少；从组间比较看，EA组、rTMS组、EA+rTMS组与模型组在7d、14d时差异均有统计学意义(P＜0．05)，EA+rTMS组在7d、14d时均高于EA组和rTMS组(P＜0．05)，EA组、rTMS组、EA+rTMS组与模型组在28d相比NeuN及NeuN／BrdU阳性细胞数目之间的差异均无统计学意义(P＞0．05)；
(3)正常组大鼠脑组织切片可见Calbindin-D28k阳性神经元表达清晰，神经元层排列整齐而致密，形态正常，神经元表达多，染色深。模型组切片可见Calbindin-D28k阳性神经元胞体缩小，神经元排列紊乱而疏松，染色较浅，表达较少。EA+rTMS组切片Calbindin-D28k阳性神经元有较多表达，形态基本正常，细胞染色较深。EA组、rTMS组切片显示Calbindin-D28k阳性神经元表达欠清晰，细胞形态不规则，呈缺血坏死改变，阳性细胞表达较少，染色较浅。EA组、rTMS组各时相及EA+rTMS组第7d、14d时Calbindin-D28k阳性表达均少于正常组(P＜0．05)，EA+rTMS组第28d与正常组差异无统计学意义(P＞0．05)，EA组、rTMS组、EA+rTMS组各时相Calbindin-D28k阳性表达均高于模型组(P＜0．05)，EA+rTMS组各时相Calbindin-D28k阳性表达均高于EA组、rTMS组(P＜0．05)，EA组与rTMS组之间各时相差异均无统计学意义(P＞0．05)。各组SVZ、SGZ各时相Calbindin-D28k阳性表达均高于梗死灶周围皮质。
研究结论：
EA结合rTMS促进缺血侧不同脑区内源性神经干细胞的增殖、迁移和分化及整合，促进神经再生及损伤后神经功能的恢复，可能是其治疗缺血性脑卒中的重要作用机制之一。
PartⅠStudy on the role and mechanism of PKA-CREB SignalTransduction System in neurogenesis activated by electro-acupuncturecombined with repetitive Transcranial Magnetic Stimulation after focalcerebral ischemia in adult rats
Objective:
To investigate the role and mechanism of PKA-CREB Signal Transduction System inneurogenesis activated by electro-acupuncture combined with rTMS after focal cerebralischemia in adult rats.
Methods:
The model of transient focal ischemia was made by the middle cerebral arteryocclusion.One hundred and fifty Wistar rats were randomly divided into normal group,model group,EA group,rTMS group and EA combined with rTMS group.To observe theneurologic impairment rating,ability of learning and memory at the 7th、14th and 28th dayafter infarction respectively.Meanwhile,Immunohistochemistry and Western blot wereconducted to detect the expression of PKA and pCREB in hippocampus of ipsilateralhemispheres.
Results:
(1) The improvement of neural motor function deficits as well as the indexes oflearning and memory were more obvious in EA group,rTMS,EA combined with rTMS group compared with the model group (p＜0.01,p＜0.05),and the improvement were themost obvious in the EA combined with rTMS group.
(2) The number of positive cells and the average gray density of PKA and pCREBexpression in hippocampus of ipsilateral hemispheres in the model group were higher at the7th day,lower at the 28th day than that of nomal group (p＜0.05),higher in EA group,rTMS,EA combined with rTMS group than that of model group in every time point andnomal group at 7th and 14th day (p＜0.05),higher in EA combined with rTMS group thanthat in EA group,rTMS group at 7th and 14th day,and there was no difference between EAgroup and rTMS group.
(3) Positive correlation existed between pCREB positive expression with NSCsproliferation.
Conclusion:
EA combined with rTMS can conspicuously promote the functional recovery aftercerebral arterial thrombosis,upregulate the expression of related signaling molecule ofPKA-CREB transduction system in hippocampus of ipsilateral hemispheres,which mightbe one of the important mechanisms of EA combined with rTMS in treating ischemic braininjury.
PartⅡEffects of electro-acupuncture combined with repetitiveTranscranial Magnetic Stimulation on migration and differentiation ofinherent neural stem cells after focal cerebral ischemia in adult rats
Objective:
To investigate the effects of electro-acupuncture(EA) combined with repetitive Transcranial Magnetic Stimulation (rTMS) on migration and differentiation of inherentneural stem cells after focal cerebral ischemia in adult rats and to explore the mechanism ofEA combined with rTMS in treating ischemic brain injury.
Methods:
The model of transient focal ischemia was made by the middle cerebral arteryocclusion.One hundred and twenty Wistar rats were randomly divided into normal group,model group,EA group,rTMS group and EA combined with rTMS group.To observe theexpression of polysiolylated neural cell adhesion molecule(PSA-NCAM) andPSA-NCAM/5-bromodeoxyuridine (BrdU),NeuN and NeuN/BrdU,Calbindin in differentencephalic regions of ipsilateral hemispheres by immunohistochemical andimmunofluorescence staining at the 7th、14th and 28th day after infarction respectively.
Results:
(1) The number of PSA-NCAM-positive cells and PSA-NCAM/BrdU positive cells indifferent encephalic regions of ipsilateral hemispheres increased at day 7after MCAO(p＜0.05),reached maximum at day 14 (p＜0.05),and decreased markedly at day 28,but itwas still elevated compared with that in normal group.There were significant differences inEA group,rTMS group and EA combined with rTMS group when compared with that ofmodel group at day 7 and 14 (P＜0.05).There were significant differences in EA combinedwith rTMS group when compared with that of EA group and rTMS group at day 7 and 14(P＜0.05).However,there were no statistic differences in EA group,rTMS group and EAcombined with rTMS group when compared with that of model group at day 28(P＞0.05).
(2) The number of NeuN-positive cells and NeuN/BrdU positive cells in hippocampusincreased at day 7after MCAO (p＜0.05),reached maximum at day 14 (p＜0.05),anddecreased markedly at day 28,but it was still elevated compared with that of normalgroup.There were significant differences in EA group,rTMS group and EA combined withrTMS group when compared with that of model group at day 7 and 14 (P＜0.05).Therewere significant differences in EA combined with rTMS group when compared with that of EA group and rTMS group at day 7 and 14 (P＜0.05).However,there were no statisticdifferences in EA group,rTMS group and EA combined with rTMS group when comparedwith that of model group at day 28(P＞0.05).
(3) In EA combined with rTMS group,the neuron arrangement in peripheral cortex ofinfarction was regular just with mild cell loss and some darken dyeing nucleus.The averageoptical density of Calbindin in EA combined with rTMS group were higher than that inmodel group,EA group and rTMS group (P＜0.05).
Conclusion:
EA combined with rTMS can promote the proliferation,migration and differentiationof inherent neural stem cells in different encephalic regions of ipsilateral hemispheres,promote the neural regeneration and neurofunctional restoration,which might be one of theimportant mechanisms of EA combined with rTMS in treating ischemic brain injury.
引文
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