电针预处理通过EAAT2调节NDRG2诱导脑缺血耐受的研究
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摘要
中风是世界第二大致死性第一大致残性疾病。因此需要开发有效地治疗手段来预防中风发生，同时减少缺血再灌注造成的损伤。电针是一种传统医学与现代电疗结合的新的治疗手段。由于针刺对于很多心脑疾患都有很好的疗效，电针疗法是对传统针刺的一大提升。我们近年的研究显示，电针能够发挥预处理效应，诱导脑缺血耐受。随后的机制研究显示，电针的预处理效应涉及到许多信号通路，如提高抗氧化物活性、调节内源性大麻素系统以及抑制凋亡。脑内星形胶质细胞在缺血后第一个受到损伤，并启动级联反应，影响神经元的转归。NDRG2表达于星形胶质细胞，并可能参与星形胶质细胞的功能调节，我们前期研究也证实NDRG2在脑缺血损伤后表达上调。但其在电针预处理诱导的脑缺血耐受中的作用以及上下游调节机制尚不清楚。本研究旨在探讨NDRG2在电针预处理中的作用，并研究其上下游调节机制。
实验一NDRG2在电针预处理诱导的脑缺血耐受作用的研究
目的：探讨NDRG2在电针预处理诱导的脑缺血耐受中的作用
方法：60只雄性SD大鼠，体重280-320g，随机分为3组(n=20)：假手术组(Sham)：不插入栓线，其余处理同MCAO组；对照组(Con)：建立MCAO模型，再灌注24h后处死；EA组(EA)：单次电针刺激，刺激后2h行MCAO，再灌注后24h处死动物。动物处死后取材，用免疫荧光双标法定性观察NDRG2蛋白的细胞分布，Western Blot定量检测NDRG2蛋白表达，RT-PCR半定量测NDRG2mRNA表达，免疫荧光双标法测NDRG2的细胞定位，细胞凋亡用TUNEL法检测。
结果：缺血再灌24h后，NDRG2表达上调且主要分布于缺血半影区的GFAP阳性细胞中，NDRG2mRNA的表达和蛋白表达趋势一致。NDRG2在假手术组主要定位于星形胶质细胞的胞浆，单纯缺血时则主要定位于胞核，电针预处理组NDRG2表达较缺血组减少，胞核与胞浆均存在定位。TUNEL与NDRG2双标结果显示：NDRG2信号与TUNEL阳性细胞存在共定位，电针预处理组缺血半暗区TUNEL与NDRG2双阳性细胞表达较缺血组减少。
结论：电针预处理通过逆转NDRG2表达上调减少凋亡，从而诱导脑缺血耐受。
实验二电针预处理通过EAAT2调节NDRG2表达的研究
目的：探讨电针预处理是否通过EAAT2调节NDRG2表达
方法：100只雄性SD大鼠，体重280-320g，随机分为5组(n=20)：假手术组(Sham)：不插入栓线，其余处理同MCAO组；单纯缺血组(Con)：建立MCAO模型，再灌注24h后处死；EA组(EA)：单次电针刺激，刺激后2h行MCAO，再灌注后24h处死动物；EAAT2激动剂(CXT)组；EAAT2抑制剂(DHK)组。再灌注后24h评价神经功能学评分及脑梗死容积，动物处死后取材，用免疫荧光双标法定性观察NDRG2蛋白的细胞分布，WesternBlot定量检测EAAT2及NDRG2蛋白表达。
结果：CXT组神经功能学评分明显优于MCAO组，DHK组与MCAO组组间比较无显著统计学差异。CXT组脑梗死容积明显小于MCAO组(P<0.01)，DHK组与MCAO组组间比较无显著统计学差异。CXT组EAAT2表达高于MCAO组，DHK组与MCAO组组间比较无显著统计学差异。CXT组NDRG2表达低于MCAO组，DHK组与MCAO组组间比较无显著统计学差异。NDRG2主要分布于缺血半影区的GFAP阳性细胞中，在假手术组主要定位于星形胶质细胞的胞浆，MCAO时主要定位于胞核，电针预处理组胞核与胞浆均存在定位，CXT组主要表达于胞浆，DHK组多表达于胞核。
结论：电针预处理可通过上调星形胶质细胞中EAAT2的表达，抑制NDRG2的上调，从而减轻脑缺血损伤。
实验三2-AG通过NDRG2调节STAT3在脑缺血耐受中作用的研究
目的：探讨2-AG通过NDRG2调节STAT3在脑缺血耐受中的作用
方法：培养原代星形胶质细胞细胞，构建氧糖剥夺OGD模型模拟脑缺血。细胞转染pSRL-SIH1-H1-GFP后行OGD，对照组不施行OGD，其余同实验组。MTT及LDH检测细胞活力，Western Blot检测NDRG2及STAT3表达。随后转染pSRL-CDH1-GFP细胞后加入2-AG行OGD，MTT及LDH检测细胞活力，Western Blot观察NDRG2及STAT3表达。
结果：MTT及LDH结果显示，ODG后星形胶质细胞活力较正常细胞降低，转染pSRL-SIH1-H1-GFP组细胞活力与正常细胞无差异；与正常星形胶质细胞相比，OGD后NDRG2、pSTAT3蛋白水平上调，而pSRL-SIH1-H1-GFP转染组NDRG2、pSTAT3蛋白水平低于ODG组。2-AG组细胞活力比OGD组细胞活力高，pSRL-CDH1-GFP转染细胞后，抑制了2-AG组的细胞生存；Western Blot结果显示，与OGD组相比，2-AG组NDRG2、pSTAT3表达下调，转染pSRL-CDH1-GFP后，逆转了2-AG对NDRG2、pSTAT3表达的抑制作用。
结论：2-AG通过减少NDRG2表达从而抑制STAT3磷酸化产生神经保护效应。
Stroke is the second most common cause of death and results in a largenumber of people with disability worldwide. Therefore, it is a huge and urgentmedical need to develop novel and rational strategies aimed at preventing strokeas well as reducing impairments caused by ischemia/reperfusion (I/R) injury.EAis a novel therapy based on traditional acupuncture combined with modernelectrotherapy. Due to the beneficial effects of acupuncture to different brainand heart diseases, EA has been used in treatment as an improvement ontraditional acupuncture.In recent years, numerous studies have shown that EAalso induced pretreatment effect, inducing ischemic tolerance as well. Manystudies have shown that protective mechanisms of EA preconditioning mayinvolve a series of regulatory molecular pathways including activityenhancement of antioxidant, regulation of the endocannabinoid system,inhibition of apoptosis, etc. Astrocytes is the first cell type in the central nervoussystem to encounter insult after brain ischemia, and induced initiation ofischemic cascade．NDRG2is expressed in astrocytes, and may involve in the modulation of glial cell function in the central nervous system. However, therole of NDRG2in the EA induced cerebral ischemic tolerance is unknown. Thisstudy was designed to investigate the role of NDRG2in neuroprotective effectof EA, and to explore its possible up and downstream regulation mechanism.
Experiment1
Purpose: N-myc downstream regulated gene2(NDRG2) was reported to bewidely expressed in the nervous system. However, the expression and potentialrole of NDRG2in focal cerebral ischemia brain remain unclear. Herein, weinvestigated whether or not the NDRG2was involved in the ischemic toleranceinduced by EA preconditioning in rats.
Methods: Male SD rats were radomly divided into three groups as follows:Sham, MCAO and EA groups. After24h period of reperfusion, brain sampleswere harvested to determine the expression of NDRG2in the brain by reversetranscriptase-polymerase chain reaction (RT-PCR), Western Blot analysis andimmunohistochemical staining. Cellular apoptosis was assessed by TUNELstaining.
Results: By using double immunofluorescence, NDRG2signals in astrocyteswas suppressed in EA group at24h after reperfusion, and NDRG2proteinexpression was weak in the nucleus and strong in the cytoplasm in the EA group,but strong in nucleus in the MCAO group. Triple immunofluorescent stainingfor TUNEL, NDRG2, and DAPI showed that most of NDRG2signalsco-localized with apoptotic cells. Moreover, the number of apoptotic cellsdecreased with attenuation of NDRG2-positive signals in EA group comparedwith MCAO group. Conclusion: NDRG2is involved in anti-apoptosis induced byelectroacupuncture preconditioning after focal cerebral ischemia in rats。
Experiment2
Purpose: To investigated if EAAT2regulate NDRG2involved in cerebralischemic tolerance induced by electroacupancture.
Methods: Male SD rats were radomly divided into three groups as follows:Sham, MCAO, EA, CXT and DHK groups. After24h period of reperfusion,the animals were examined for neurological scores and then killed to measuredinfarct volumes, brain samples were harvested to determine the expression ofNDRG2in the brain by Western Blot analysis and immunohistochemicalstaining.
Results: The neurological scores were higher in EA and CXT groups than thatin MCAO group, no statistical difference was found between DHK group andMCAO group.The infarct volumes in EA and CXT groups were significantlysmaller than that in MCAO group, no statistical difference was found betweenDHK and MCAO group. EAAT2signals was suppressed in DHK group andactivated in EA and CXT groups.The expression of NDRG2protein expressionwas weak in the EA and CXT groups, but strong in the DHK group.Conclusion: Electroacupancture preconditioning suppressed NDRG2viaupregulated the expression of EAAT2involved in cerebral ischemic tolerance.
Experiment3
Purpose: To investigated the role of NDRG2regulate STAT3in protectiveeffect induced by2-AG in primary astrocytes after OGD.
Methods: After transfecting the NDRG2pSRL-SIH1-H1-GFP vector, OGD4h, reoxygenation was subjected to primary astrocytes in24h. The cell growth wasmonitored by MTT and LDH assay, NDRG2and STAT3protein level wasdetected by Western Blot and immunocytochemistry. Then ransfecting theNDRG2pSRL-CDH1-GFP and add2-AG. After OGD was subjected to primaryastrocytes, the cell growth was monitored by MTT and LDH assay, NDRG2andSTAT3protein were detected by Western Blot and immunocytochemistry.
Results: The cell viability was inhibited after OGD, no statistical difference wasfound between pSRL-SIH1-H1-GFP and Sham groups. The level of NDRG2,pSTAT3in ODG group were higher than those in sham group, and comparedto OGD group, the upregulation of NDRG2, pSTAT3in pSRL-SIH1-H1-GFPgroup were supressed. The cell viability in2-AG group was higher thanthat inOGD group, and ransfecting the NDRG2pSRL-CDH1-GFP vector reversed theprotective effects of2-AG. no statistical difference was found betweenpSRL-SIH1-H1-GFP and OGD groups. The level of NDRG2, pSTAT3in2-AGgroup were loeer than those in OGD group, no statistical difference was foundbetween pSRL-SIH1-H1-GFP and OGD groups.
Conclusion:2-AG suppressed phosphorylation of STAT3by decreasedexpression of NDRG2induced neuroprotection.
实验一NDRG2在电针预处理诱导的脑缺血耐受作用的研究
目的：探讨NDRG2在电针预处理诱导的脑缺血耐受中的作用
方法：60只雄性SD大鼠，体重280-320g，随机分为3组(n=20)：假手术组(Sham)：不插入栓线，其余处理同MCAO组；对照组(Con)：建立MCAO模型，再灌注24h后处死；EA组(EA)：单次电针刺激，刺激后2h行MCAO，再灌注后24h处死动物。动物处死后取材，用免疫荧光双标法定性观察NDRG2蛋白的细胞分布，Western Blot定量检测NDRG2蛋白表达，RT-PCR半定量测NDRG2mRNA表达，免疫荧光双标法测NDRG2的细胞定位，细胞凋亡用TUNEL法检测。
结果：缺血再灌24h后，NDRG2表达上调且主要分布于缺血半影区的GFAP阳性细胞中，NDRG2mRNA的表达和蛋白表达趋势一致。NDRG2在假手术组主要定位于星形胶质细胞的胞浆，单纯缺血时则主要定位于胞核，电针预处理组NDRG2表达较缺血组减少，胞核与胞浆均存在定位。TUNEL与NDRG2双标结果显示：NDRG2信号与TUNEL阳性细胞存在共定位，电针预处理组缺血半暗区TUNEL与NDRG2双阳性细胞表达较缺血组减少。
结论：电针预处理通过逆转NDRG2表达上调减少凋亡，从而诱导脑缺血耐受。
实验二电针预处理通过EAAT2调节NDRG2表达的研究
目的：探讨电针预处理是否通过EAAT2调节NDRG2表达
方法：100只雄性SD大鼠，体重280-320g，随机分为5组(n=20)：假手术组(Sham)：不插入栓线，其余处理同MCAO组；单纯缺血组(Con)：建立MCAO模型，再灌注24h后处死；EA组(EA)：单次电针刺激，刺激后2h行MCAO，再灌注后24h处死动物；EAAT2激动剂(CXT)组；EAAT2抑制剂(DHK)组。再灌注后24h评价神经功能学评分及脑梗死容积，动物处死后取材，用免疫荧光双标法定性观察NDRG2蛋白的细胞分布，WesternBlot定量检测EAAT2及NDRG2蛋白表达。
结果：CXT组神经功能学评分明显优于MCAO组，DHK组与MCAO组组间比较无显著统计学差异。CXT组脑梗死容积明显小于MCAO组(P<0.01)，DHK组与MCAO组组间比较无显著统计学差异。CXT组EAAT2表达高于MCAO组，DHK组与MCAO组组间比较无显著统计学差异。CXT组NDRG2表达低于MCAO组，DHK组与MCAO组组间比较无显著统计学差异。NDRG2主要分布于缺血半影区的GFAP阳性细胞中，在假手术组主要定位于星形胶质细胞的胞浆，MCAO时主要定位于胞核，电针预处理组胞核与胞浆均存在定位，CXT组主要表达于胞浆，DHK组多表达于胞核。
结论：电针预处理可通过上调星形胶质细胞中EAAT2的表达，抑制NDRG2的上调，从而减轻脑缺血损伤。
实验三2-AG通过NDRG2调节STAT3在脑缺血耐受中作用的研究
目的：探讨2-AG通过NDRG2调节STAT3在脑缺血耐受中的作用
方法：培养原代星形胶质细胞细胞，构建氧糖剥夺OGD模型模拟脑缺血。细胞转染pSRL-SIH1-H1-GFP后行OGD，对照组不施行OGD，其余同实验组。MTT及LDH检测细胞活力，Western Blot检测NDRG2及STAT3表达。随后转染pSRL-CDH1-GFP细胞后加入2-AG行OGD，MTT及LDH检测细胞活力，Western Blot观察NDRG2及STAT3表达。
结果：MTT及LDH结果显示，ODG后星形胶质细胞活力较正常细胞降低，转染pSRL-SIH1-H1-GFP组细胞活力与正常细胞无差异；与正常星形胶质细胞相比，OGD后NDRG2、pSTAT3蛋白水平上调，而pSRL-SIH1-H1-GFP转染组NDRG2、pSTAT3蛋白水平低于ODG组。2-AG组细胞活力比OGD组细胞活力高，pSRL-CDH1-GFP转染细胞后，抑制了2-AG组的细胞生存；Western Blot结果显示，与OGD组相比，2-AG组NDRG2、pSTAT3表达下调，转染pSRL-CDH1-GFP后，逆转了2-AG对NDRG2、pSTAT3表达的抑制作用。
结论：2-AG通过减少NDRG2表达从而抑制STAT3磷酸化产生神经保护效应。
Stroke is the second most common cause of death and results in a largenumber of people with disability worldwide. Therefore, it is a huge and urgentmedical need to develop novel and rational strategies aimed at preventing strokeas well as reducing impairments caused by ischemia/reperfusion (I/R) injury.EAis a novel therapy based on traditional acupuncture combined with modernelectrotherapy. Due to the beneficial effects of acupuncture to different brainand heart diseases, EA has been used in treatment as an improvement ontraditional acupuncture.In recent years, numerous studies have shown that EAalso induced pretreatment effect, inducing ischemic tolerance as well. Manystudies have shown that protective mechanisms of EA preconditioning mayinvolve a series of regulatory molecular pathways including activityenhancement of antioxidant, regulation of the endocannabinoid system,inhibition of apoptosis, etc. Astrocytes is the first cell type in the central nervoussystem to encounter insult after brain ischemia, and induced initiation ofischemic cascade．NDRG2is expressed in astrocytes, and may involve in the modulation of glial cell function in the central nervous system. However, therole of NDRG2in the EA induced cerebral ischemic tolerance is unknown. Thisstudy was designed to investigate the role of NDRG2in neuroprotective effectof EA, and to explore its possible up and downstream regulation mechanism.
Experiment1
Purpose: N-myc downstream regulated gene2(NDRG2) was reported to bewidely expressed in the nervous system. However, the expression and potentialrole of NDRG2in focal cerebral ischemia brain remain unclear. Herein, weinvestigated whether or not the NDRG2was involved in the ischemic toleranceinduced by EA preconditioning in rats.
Methods: Male SD rats were radomly divided into three groups as follows:Sham, MCAO and EA groups. After24h period of reperfusion, brain sampleswere harvested to determine the expression of NDRG2in the brain by reversetranscriptase-polymerase chain reaction (RT-PCR), Western Blot analysis andimmunohistochemical staining. Cellular apoptosis was assessed by TUNELstaining.
Results: By using double immunofluorescence, NDRG2signals in astrocyteswas suppressed in EA group at24h after reperfusion, and NDRG2proteinexpression was weak in the nucleus and strong in the cytoplasm in the EA group,but strong in nucleus in the MCAO group. Triple immunofluorescent stainingfor TUNEL, NDRG2, and DAPI showed that most of NDRG2signalsco-localized with apoptotic cells. Moreover, the number of apoptotic cellsdecreased with attenuation of NDRG2-positive signals in EA group comparedwith MCAO group. Conclusion: NDRG2is involved in anti-apoptosis induced byelectroacupuncture preconditioning after focal cerebral ischemia in rats。
Experiment2
Purpose: To investigated if EAAT2regulate NDRG2involved in cerebralischemic tolerance induced by electroacupancture.
Methods: Male SD rats were radomly divided into three groups as follows:Sham, MCAO, EA, CXT and DHK groups. After24h period of reperfusion,the animals were examined for neurological scores and then killed to measuredinfarct volumes, brain samples were harvested to determine the expression ofNDRG2in the brain by Western Blot analysis and immunohistochemicalstaining.
Results: The neurological scores were higher in EA and CXT groups than thatin MCAO group, no statistical difference was found between DHK group andMCAO group.The infarct volumes in EA and CXT groups were significantlysmaller than that in MCAO group, no statistical difference was found betweenDHK and MCAO group. EAAT2signals was suppressed in DHK group andactivated in EA and CXT groups.The expression of NDRG2protein expressionwas weak in the EA and CXT groups, but strong in the DHK group.Conclusion: Electroacupancture preconditioning suppressed NDRG2viaupregulated the expression of EAAT2involved in cerebral ischemic tolerance.
Experiment3
Purpose: To investigated the role of NDRG2regulate STAT3in protectiveeffect induced by2-AG in primary astrocytes after OGD.
Methods: After transfecting the NDRG2pSRL-SIH1-H1-GFP vector, OGD4h, reoxygenation was subjected to primary astrocytes in24h. The cell growth wasmonitored by MTT and LDH assay, NDRG2and STAT3protein level wasdetected by Western Blot and immunocytochemistry. Then ransfecting theNDRG2pSRL-CDH1-GFP and add2-AG. After OGD was subjected to primaryastrocytes, the cell growth was monitored by MTT and LDH assay, NDRG2andSTAT3protein were detected by Western Blot and immunocytochemistry.
Results: The cell viability was inhibited after OGD, no statistical difference wasfound between pSRL-SIH1-H1-GFP and Sham groups. The level of NDRG2,pSTAT3in ODG group were higher than those in sham group, and comparedto OGD group, the upregulation of NDRG2, pSTAT3in pSRL-SIH1-H1-GFPgroup were supressed. The cell viability in2-AG group was higher thanthat inOGD group, and ransfecting the NDRG2pSRL-CDH1-GFP vector reversed theprotective effects of2-AG. no statistical difference was found betweenpSRL-SIH1-H1-GFP and OGD groups. The level of NDRG2, pSTAT3in2-AGgroup were loeer than those in OGD group, no statistical difference was foundbetween pSRL-SIH1-H1-GFP and OGD groups.
Conclusion:2-AG suppressed phosphorylation of STAT3by decreasedexpression of NDRG2induced neuroprotection.
引文
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