羟基红花黄色素A抗兴奋毒性神经元死亡的神经保护作用
摘要
目的
1.探讨谷氨酸(Glu)兴奋毒性损伤后,羟基红花黄色素A(HSYA)对器官型脑片海马齿状回(HDG)神经发生的影响。
2.研究Glu兴奋毒性损伤后,HSYA对器官型海马脑片神经细胞死亡的影响,以及保护线粒体功能的机制。
3.探讨Glu兴奋毒性损伤后,HSYA对大鼠皮层神经细胞凋亡的影响,以及对p38MAPK途径诱导凋亡的作用。
方法
1.制备出生后6天SD乳鼠器官型海马脑片,按随机数字表法分为4组(每组6张脑片)：(1)生理盐水对照组(3.5mM Glu+1ml生理盐水干预,CG)；(2)空白对照组(正常培养,不造模+不干预,Nor)；(3)大剂量HSYA组(3.5mMGlu+1ml0.072mg/ml HSYA干预,HG1)；(4)小剂量HSYA组(3.5mM Glu+1ml0.036mg/ml HSYA干预,HG2)。建立Glu损伤模型,造模前及造模后1d、3d和6d通过倒置显微镜及免疫荧光染色观察脑片生长情况,按常规方法分别进行BrdU与Nestin免疫荧光双标染色。计数HDG中神经干细胞(Neural stem cells, NSCs)并进行重复测量的方差分析,每个时间点各组之间的比较采用单因素方差分析,各组内不同时间之间的比较采用重复测量的方差分析,主效应不同水平间的多重比较采用LSD法,P<0.05为差异有统计学意义。
2.制备出生后6天SD乳鼠器官型海马脑片,按随机数字表法分为5组(每组5张脑片)：(1)正常对照组(正常培养基培养,Nor)；(2)大剂量HSYA干预组(3.5mM Glu+lml0.072mg/ml HSYA干预,HGl)；(3)小剂量HSYA干预组(3.5mM Glu+lml0.036mg/ml HSYA干预,HG2)；(4)生理盐水对照组(3.5mMGlu+1ml生理盐水干预,CG)；(5)大剂量HSYA对照组(1ml0.072mg/ml HSYA干预,Only)。建立Glu损伤模型,加入含有不同浓度HSYA的培养基(0.072mg/ml,0.036mg/ml)(?)化72小时,加入HSYA前、24和48小时后分别测量PI摄取量。蛋白免疫印迹分析5-LO,caspase-3, SOD2, P-Akt蛋白表达水平。各组之间PI荧光值,5-LO, caspase-3, SOD2, P-Akt蛋白表达量的比较采用单因素方差分析(One-way ANOVA),方差齐时组内两两多重比较采用LSD法,方差不齐时组内两两多重比较采用Tamhane's T2法,P<0.05为差异有统计学意义。
3.用胚胎18天(E18)SD大鼠制备前额叶皮层神经元的原代培养,在体外培养10至14天后建立Glu损伤模型。按随机数字表法将神经细胞分为5组(每组5孔)：(1)正常对照组(正常培养基培养,Nor)；(2)大剂量HSYA干预组(3.5mM Glu+0.072mg/ml HSYA干预,HG1)；(3)小剂量HSYA干预组(3.5mM Glu+0.036mg/ml HSYA干预,HG2)；(4)生理盐水对照组(3.5mM Glu+生理盐水干预,CG)；(5)大剂量HSYA对照组(0.072mg/ml HSYA干预,Only).MTT法,Hoechst33258/PI双染,流式细胞术(Annexin V-FITC/PI双染法)检测神经细胞死亡和凋亡。RT-PCR法检测caspase-3、ATF2、p38MAPK、MAPKKK的表达。不同组别之间神经细胞凋亡的比较、RT-PCR相对密度的比较采用单因素方差分析(One-way ANOVA),组内两两多重比较采用LSD法,P<0.05为差异有统计学意义。
结果
1.低倍镜下(40×)正常脑片呈褐色,颜色均匀,透光性良好,可清晰分辨皮层、海马(CA1-4及DG区)、脑室、皮层下核团,白质纤维束等结构。高倍镜下(200×)可见胞质和胞核。Glu损伤前后不同时间点之间NSCs(BrdU+, Nestin+)的差异有统计学意义(F=228.075,P<0.001),HG1, HG2, CG及Nor均如此,F值分别为31.537,181.762,248.345和52.444,均.P<0.001。各组之间神经干细胞数的差异有统计学意义(F=947.077,P<0.001)；从各时间点看,除Glu损伤前,各时间点神经干细胞数均存在下列关系：Nor>HG1>HG2>CG(均P<0.001)。Glu损伤前后与不同组别之间存在交互效应(F＝123.639,P<0.001)。
2.3.5mM Glu损伤后24和48小时主要导致海马DG区递增性细胞死亡。Glu损伤24h后各组之间PI荧光值的差异有统计学意义(F=11.305,P=0.002)；HG1HG1,Nor>HG2, Nor>CG, HG1>CG, HG2>CG,差异有统计学意义(均P<0.05)。各组之间P-Akt的差异有统计学意义(F=23.299,P=0.000)；Nor>HG2, Nor>CG, HG1>CG, HG1>HG2,差异有统计学意义(均P<0.05)。
3.MTT法测得各组之间细胞存活率的差异有统计学意义(F=17.063,P=0.000); Nor 结论
1.0.072mg/ml HSYA减轻Glu兴奋毒性对NSCs的损伤,促进NSCs再生。
2.0.072mg/ml HSYA减少Glu造成的神经元死亡,这种保护作用24h出现,可持续至48h。Glu兴奋性损伤导致神经元线粒体功能障碍,0.072mg/ml HSYA通过降低5-LO和caspase-3,升高SOD2和磷酸化Akt的蛋白表达,保护线粒体功能,减少神经细胞死亡。
3. HSYA主要是通过抑制Glu诱导的细胞凋亡来保护神经细胞0.072mg/ml HSYA作用于p38MAPK通路的上游激活物MAPKKK,核心蛋白激酶p38MAPK,下游转录因子ATF2,以及最后的效应蛋白caspase-3多个位点,下调其基因表达,抑制神经元的凋亡。
Object
1. To explore the effects of hydroxysafflor yellow A (HSYA) on neurogenesis in the hippocampal dentate gyrus (HDG) of the organotypic slices after glutamate(Glu) neurotoxicity.
2. To investigated the neuroprotective effects of HSYA on Glu induced neuronal death and mitochondrium dysfunction in organotypic hippocampal slice cultures (OHSCs).
3. To approach anti-apoptotic effects of HSYA on neurotoxicity of glutamate in primary cultured rat cortical neurons along with its possible mechanism of action through p38MAPK pathway.
Materials and Methods
1. The organotypic hippocampal slices (300μm) from postnatal6th day SD rats were prepared and randomly divided into four groups(n=6brain slices):(1) saline control group (3.5mM Glu+1ml normal saline intervention, CG);(2) blank control group (normal culture, not modeling+nonintervention. Nor):(3) large doses HSYA group (3.5mM Glu+1ml0.072mg/ml HSYA intervention, HG1);(4) small doses HSYA group (3.5mM Glu+lml0.036mg/ml HSYA intervention, HG2). Each group except Nor was received the same model of Glu intervention and then cultured with different dose of HSYA for72h. Double staining of BrdU and Nestin immunofluorescence according to conventional methods. After that, Neural stem cells(NSCs) in hippocampal dentate gyrus(HDG) were observed under invert microscope or detected by immuno fluorescence staining in different time points(before.24and48h after the application of HSYA). Count NSCs and make the comparison in groups. Repeated measure analysis of NSCs was used in different time points with different intervention, so did in different time in each group; at each time point, comparisons in groups using one-way analysis of variance (One-way ANOVA), two groups'comparisons using LSD method. P<0.05was considered statistically significant.
2. The organotypic hippocampal slices (300μm) from postnatal6th day SD rats were prepared and randomly divided into five groups(n=5brain slices):(1) normal control group (normal culture, not modeling+nonintervention, Nor);(2) large doses HSYA group (3.5mM Glu+1ml0.072mg/ml HSYA intervention, HG1);(3) small doses HSYA group (3.5mM Glu+1ml0.036mg/ml HSYA intervention, HG2);(4) saline control group (3.5mM Glu+1ml normal saline intervention, CG);(5) large doses HSYA control group(1ml0.072mg/ml HSYA intervention, OnlyHGl). Each group except Nor and OnlyHG1was received the same model of Glu intervention and then cultured with different dose of HSYA for72h. PI uptake was measured before,24and48h after the application of HSYA. Protein expressions of5-LO, caspase-3, the SOD2and phospho-Akt(P-Akt) were deteced by using western blot analysis. Each of these indicators was compared in groups using one-way analysis of variance (One-way ANOVA). If homogeneity of variance, pairwise multiple comparisons using LSD method within groups, and if not, using Tamhane's T2method. P<0.05was considered statistically significant.
3. Primary cultures of prefrontal cortical neurons were prepared from embryonic18days old (E18) Sprague-Dawley rats. Cultures were used for challenge with Glu between10and14days in vitro (DIV). Cultures were randomly divided into five groups(n=5walls):(1) normal control group (normal culture, not modeling+nonintervention, Nor);(2) large doses HSYA group (3.5mM Glu+0.072mg/ml HSYA intervention, HG1);(3) small doses HSYA group (3.5mM Glu+0.036mg/ml HSYA intervention, HG2);(4) saline control group (3.5mM Glu+normal saline intervention, CG);(5) large doses HSYA control group(0.072mg/ml HSYA intervention, OnlyHG1). Cell death and apoptosis were detected with MTT assay, Hoechst33258/PI double staining and flow cytometry (Annexin V-FITC/PI double staining). mRNA expressions of caspase-3, ATF2, p38MAPK and MAPKKK were detected by RT-PCR. Each of these indicators was compared in groups using one-way analysis of variance (One-way ANOVA), two groups' comparisons using LSD method. P<0.05was considered statistically significant.
Results
1. Low power lens (40x):normal brain slices were brown, uniform and good light transmission, can be clearly distinguished between the cortex, hippocampus (CA1-4and DG District), intraventricular, subcortical nuclei and white matter fiber bundle structure. High power lens (200x):visible cytoplasm and nuclei. NSCs (BrdU+, Nestin+) difference was statistically significant in different time points before or after Glu intervention (F=228.075, P<0.001), HG1, HG2, CG and Nor, F value31.537,181.762,248.345and52.444respectively, all P<0.001. Neural stem cell numbers between the groups there were statistically significant differences (F=947.077, P<0.001); except Glu intervention before, from the time point of view, each time point the number of neural stem cells have the following relationship: Nor>HG1>HG2>CG (P<0.001). Glu intervention different time points and different groups there is interactive effect (F=123.639, P<0.001).
2.3.5mM Glu damage after24and48hours caused increasing cell death in hippocampal DG area.Glu damage after24h PI fluorescence values between the groups had significant difference (F=11.305; P=0.002); HG1HG1, Nor>HG2, Nor>CG, HG1>CG, HG2>CG the differences were statistically significant (all P<0.05). Phospho-Akt had a significant difference (F=23.299, P=0.000); Nor>HG2, Nor>CG, HG1>CG, HG1> HG2, the differences were statistically significant (all P<0.05).
3. The MTT measuring method of cell survival rate differences between the groups was statistically significant (F=17.063, P=0.000); Nor Conclusions
1.0.072mg/ml HSYA alleviated Glu intervention on NSCs damage, promoted the regeneration of NSCs.
2.0.072mg/ml HSYA reduced Glu induced neuronal death, this protective effect of24h to48h, sustainable. Glu excitotoxicity led to mitochondrial dysfunction,0.072mg/ml HSYA protected mitochondrial function and reduced neuronal cell death through reducing of5-LO and caspase-3, increasing SOD2and phospho-Akt protein expression.
3. HSYA mainly by inhibiting the apoptosis induced by Glu to protect nerve cells.0.072mg/ml HSYA inhibited neuronal apoptosis through down-regulating p38MAPK pathway gene expression of MAPKKK, p38MAPK, ATF2, caspase-3multiple loci.
1.探讨谷氨酸(Glu)兴奋毒性损伤后,羟基红花黄色素A(HSYA)对器官型脑片海马齿状回(HDG)神经发生的影响。
2.研究Glu兴奋毒性损伤后,HSYA对器官型海马脑片神经细胞死亡的影响,以及保护线粒体功能的机制。
3.探讨Glu兴奋毒性损伤后,HSYA对大鼠皮层神经细胞凋亡的影响,以及对p38MAPK途径诱导凋亡的作用。
方法
1.制备出生后6天SD乳鼠器官型海马脑片,按随机数字表法分为4组(每组6张脑片)：(1)生理盐水对照组(3.5mM Glu+1ml生理盐水干预,CG)；(2)空白对照组(正常培养,不造模+不干预,Nor)；(3)大剂量HSYA组(3.5mMGlu+1ml0.072mg/ml HSYA干预,HG1)；(4)小剂量HSYA组(3.5mM Glu+1ml0.036mg/ml HSYA干预,HG2)。建立Glu损伤模型,造模前及造模后1d、3d和6d通过倒置显微镜及免疫荧光染色观察脑片生长情况,按常规方法分别进行BrdU与Nestin免疫荧光双标染色。计数HDG中神经干细胞(Neural stem cells, NSCs)并进行重复测量的方差分析,每个时间点各组之间的比较采用单因素方差分析,各组内不同时间之间的比较采用重复测量的方差分析,主效应不同水平间的多重比较采用LSD法,P<0.05为差异有统计学意义。
2.制备出生后6天SD乳鼠器官型海马脑片,按随机数字表法分为5组(每组5张脑片)：(1)正常对照组(正常培养基培养,Nor)；(2)大剂量HSYA干预组(3.5mM Glu+lml0.072mg/ml HSYA干预,HGl)；(3)小剂量HSYA干预组(3.5mM Glu+lml0.036mg/ml HSYA干预,HG2)；(4)生理盐水对照组(3.5mMGlu+1ml生理盐水干预,CG)；(5)大剂量HSYA对照组(1ml0.072mg/ml HSYA干预,Only)。建立Glu损伤模型,加入含有不同浓度HSYA的培养基(0.072mg/ml,0.036mg/ml)(?)化72小时,加入HSYA前、24和48小时后分别测量PI摄取量。蛋白免疫印迹分析5-LO,caspase-3, SOD2, P-Akt蛋白表达水平。各组之间PI荧光值,5-LO, caspase-3, SOD2, P-Akt蛋白表达量的比较采用单因素方差分析(One-way ANOVA),方差齐时组内两两多重比较采用LSD法,方差不齐时组内两两多重比较采用Tamhane's T2法,P<0.05为差异有统计学意义。
3.用胚胎18天(E18)SD大鼠制备前额叶皮层神经元的原代培养,在体外培养10至14天后建立Glu损伤模型。按随机数字表法将神经细胞分为5组(每组5孔)：(1)正常对照组(正常培养基培养,Nor)；(2)大剂量HSYA干预组(3.5mM Glu+0.072mg/ml HSYA干预,HG1)；(3)小剂量HSYA干预组(3.5mM Glu+0.036mg/ml HSYA干预,HG2)；(4)生理盐水对照组(3.5mM Glu+生理盐水干预,CG)；(5)大剂量HSYA对照组(0.072mg/ml HSYA干预,Only).MTT法,Hoechst33258/PI双染,流式细胞术(Annexin V-FITC/PI双染法)检测神经细胞死亡和凋亡。RT-PCR法检测caspase-3、ATF2、p38MAPK、MAPKKK的表达。不同组别之间神经细胞凋亡的比较、RT-PCR相对密度的比较采用单因素方差分析(One-way ANOVA),组内两两多重比较采用LSD法,P<0.05为差异有统计学意义。
结果
1.低倍镜下(40×)正常脑片呈褐色,颜色均匀,透光性良好,可清晰分辨皮层、海马(CA1-4及DG区)、脑室、皮层下核团,白质纤维束等结构。高倍镜下(200×)可见胞质和胞核。Glu损伤前后不同时间点之间NSCs(BrdU+, Nestin+)的差异有统计学意义(F=228.075,P<0.001),HG1, HG2, CG及Nor均如此,F值分别为31.537,181.762,248.345和52.444,均.P<0.001。各组之间神经干细胞数的差异有统计学意义(F=947.077,P<0.001)；从各时间点看,除Glu损伤前,各时间点神经干细胞数均存在下列关系：Nor>HG1>HG2>CG(均P<0.001)。Glu损伤前后与不同组别之间存在交互效应(F＝123.639,P<0.001)。
2.3.5mM Glu损伤后24和48小时主要导致海马DG区递增性细胞死亡。Glu损伤24h后各组之间PI荧光值的差异有统计学意义(F=11.305,P=0.002)；HG1
3.MTT法测得各组之间细胞存活率的差异有统计学意义(F=17.063,P=0.000); Nor
1.0.072mg/ml HSYA减轻Glu兴奋毒性对NSCs的损伤,促进NSCs再生。
2.0.072mg/ml HSYA减少Glu造成的神经元死亡,这种保护作用24h出现,可持续至48h。Glu兴奋性损伤导致神经元线粒体功能障碍,0.072mg/ml HSYA通过降低5-LO和caspase-3,升高SOD2和磷酸化Akt的蛋白表达,保护线粒体功能,减少神经细胞死亡。
3. HSYA主要是通过抑制Glu诱导的细胞凋亡来保护神经细胞0.072mg/ml HSYA作用于p38MAPK通路的上游激活物MAPKKK,核心蛋白激酶p38MAPK,下游转录因子ATF2,以及最后的效应蛋白caspase-3多个位点,下调其基因表达,抑制神经元的凋亡。
Object
1. To explore the effects of hydroxysafflor yellow A (HSYA) on neurogenesis in the hippocampal dentate gyrus (HDG) of the organotypic slices after glutamate(Glu) neurotoxicity.
2. To investigated the neuroprotective effects of HSYA on Glu induced neuronal death and mitochondrium dysfunction in organotypic hippocampal slice cultures (OHSCs).
3. To approach anti-apoptotic effects of HSYA on neurotoxicity of glutamate in primary cultured rat cortical neurons along with its possible mechanism of action through p38MAPK pathway.
Materials and Methods
1. The organotypic hippocampal slices (300μm) from postnatal6th day SD rats were prepared and randomly divided into four groups(n=6brain slices):(1) saline control group (3.5mM Glu+1ml normal saline intervention, CG);(2) blank control group (normal culture, not modeling+nonintervention. Nor):(3) large doses HSYA group (3.5mM Glu+1ml0.072mg/ml HSYA intervention, HG1);(4) small doses HSYA group (3.5mM Glu+lml0.036mg/ml HSYA intervention, HG2). Each group except Nor was received the same model of Glu intervention and then cultured with different dose of HSYA for72h. Double staining of BrdU and Nestin immunofluorescence according to conventional methods. After that, Neural stem cells(NSCs) in hippocampal dentate gyrus(HDG) were observed under invert microscope or detected by immuno fluorescence staining in different time points(before.24and48h after the application of HSYA). Count NSCs and make the comparison in groups. Repeated measure analysis of NSCs was used in different time points with different intervention, so did in different time in each group; at each time point, comparisons in groups using one-way analysis of variance (One-way ANOVA), two groups'comparisons using LSD method. P<0.05was considered statistically significant.
2. The organotypic hippocampal slices (300μm) from postnatal6th day SD rats were prepared and randomly divided into five groups(n=5brain slices):(1) normal control group (normal culture, not modeling+nonintervention, Nor);(2) large doses HSYA group (3.5mM Glu+1ml0.072mg/ml HSYA intervention, HG1);(3) small doses HSYA group (3.5mM Glu+1ml0.036mg/ml HSYA intervention, HG2);(4) saline control group (3.5mM Glu+1ml normal saline intervention, CG);(5) large doses HSYA control group(1ml0.072mg/ml HSYA intervention, OnlyHGl). Each group except Nor and OnlyHG1was received the same model of Glu intervention and then cultured with different dose of HSYA for72h. PI uptake was measured before,24and48h after the application of HSYA. Protein expressions of5-LO, caspase-3, the SOD2and phospho-Akt(P-Akt) were deteced by using western blot analysis. Each of these indicators was compared in groups using one-way analysis of variance (One-way ANOVA). If homogeneity of variance, pairwise multiple comparisons using LSD method within groups, and if not, using Tamhane's T2method. P<0.05was considered statistically significant.
3. Primary cultures of prefrontal cortical neurons were prepared from embryonic18days old (E18) Sprague-Dawley rats. Cultures were used for challenge with Glu between10and14days in vitro (DIV). Cultures were randomly divided into five groups(n=5walls):(1) normal control group (normal culture, not modeling+nonintervention, Nor);(2) large doses HSYA group (3.5mM Glu+0.072mg/ml HSYA intervention, HG1);(3) small doses HSYA group (3.5mM Glu+0.036mg/ml HSYA intervention, HG2);(4) saline control group (3.5mM Glu+normal saline intervention, CG);(5) large doses HSYA control group(0.072mg/ml HSYA intervention, OnlyHG1). Cell death and apoptosis were detected with MTT assay, Hoechst33258/PI double staining and flow cytometry (Annexin V-FITC/PI double staining). mRNA expressions of caspase-3, ATF2, p38MAPK and MAPKKK were detected by RT-PCR. Each of these indicators was compared in groups using one-way analysis of variance (One-way ANOVA), two groups' comparisons using LSD method. P<0.05was considered statistically significant.
Results
1. Low power lens (40x):normal brain slices were brown, uniform and good light transmission, can be clearly distinguished between the cortex, hippocampus (CA1-4and DG District), intraventricular, subcortical nuclei and white matter fiber bundle structure. High power lens (200x):visible cytoplasm and nuclei. NSCs (BrdU+, Nestin+) difference was statistically significant in different time points before or after Glu intervention (F=228.075, P<0.001), HG1, HG2, CG and Nor, F value31.537,181.762,248.345and52.444respectively, all P<0.001. Neural stem cell numbers between the groups there were statistically significant differences (F=947.077, P<0.001); except Glu intervention before, from the time point of view, each time point the number of neural stem cells have the following relationship: Nor>HG1>HG2>CG (P<0.001). Glu intervention different time points and different groups there is interactive effect (F=123.639, P<0.001).
2.3.5mM Glu damage after24and48hours caused increasing cell death in hippocampal DG area.Glu damage after24h PI fluorescence values between the groups had significant difference (F=11.305; P=0.002); HG1
3. The MTT measuring method of cell survival rate differences between the groups was statistically significant (F=17.063, P=0.000); Nor
1.0.072mg/ml HSYA alleviated Glu intervention on NSCs damage, promoted the regeneration of NSCs.
2.0.072mg/ml HSYA reduced Glu induced neuronal death, this protective effect of24h to48h, sustainable. Glu excitotoxicity led to mitochondrial dysfunction,0.072mg/ml HSYA protected mitochondrial function and reduced neuronal cell death through reducing of5-LO and caspase-3, increasing SOD2and phospho-Akt protein expression.
3. HSYA mainly by inhibiting the apoptosis induced by Glu to protect nerve cells.0.072mg/ml HSYA inhibited neuronal apoptosis through down-regulating p38MAPK pathway gene expression of MAPKKK, p38MAPK, ATF2, caspase-3multiple loci.
引文
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