银杏内酯B对缺氧缺血新生大鼠脑细胞凋亡及神经发生的影响
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摘要
目的
新生儿缺氧缺血性脑损伤(Hypoxic-ischemic brain damage, HIBD)是指各种围生期疾患导致脑组织不同程度缺氧及血流减少甚至停止,从而导致中枢神经系统损伤,是新生儿死亡及儿童癫痫、智力低下和脑性瘫痪的重要原因。神经发生是指神经干细胞(neural stem cell, NSCs)在特定条件下发生增殖、迁移及进一步分化成有特定表型的神经细胞,并参与神经功能修复的过程。自从证实成体脑组织中存在NSCs以来,研究进展很大。生理情况下NSCs微量增殖,一定条件下如脑缺血、癫痫等可诱导增加,但由于增殖数量较少、迁移过程中发生凋亡及分化为神经元的比例小等原因而不足以修复受损的神经功能。因此,了解脑损伤诱导神经发生机制,寻找促进神经发生增加的措施,将为治疗中枢神经系统疾病带来新的希望。银杏内酯(ginkgolides)是从银杏叶中提取的一类萜内酯类化合物,药理作用广泛,在中枢神经系统,可通过降低损伤后神经细胞凋亡促进新生血管形成等机制保护并修复受损的神经功能。近年研究发现,银杏内酯B(ginkgolides B, GB)可促进体外培养的NSCs增殖、迁移及定向分化。本课题通过制作HIBD新生大鼠模型,应用GB进行干预,观察新生大鼠HIBD后细胞凋亡情况及内源性神经干细胞增殖分化的改变,研究GB对其发生的影响,为NSCs定向诱导分化研究及临床应用提供理论依据。
方法
清洁级新生7日龄SD大鼠200只,随机分为假手术组48只、HIBD组52只、GB低剂量组50只及GB高剂量组50只,最终纳入数据分析的大鼠每组均为48只。经典Rice法制作HIBD动物模型,在造模过程中及造模后观察动物行为学改变。GB低剂量组与GB高剂量组分别按5mg/kg、10mg/kg腹腔注射GB,其它两组注射等量生理盐水(10ml/kg体重体积注射量),每天一次共5天。各组随机选取6只分别在造模后3d,7d,14d,28d处死：(1)规定时间点断头取脑处死大鼠,荧光定量PCR法检测各时间点Caspase-3、VEGF、Foxgl mRNA的表达水平,2-△△CT法计算相对表达量,比较各组表达差异；(2)按规定时间点处死前给予腹腔注射溴脱氧尿嘧啶核苷(Bromodeoxyuridine BrdU)标记新生细胞,剂量50mg/kg,1次/12h,共5次,最后一次腹腔注射BrdU4h后处死；分别以巢蛋白(Nestin)神经元烯醇化酶(neuron special enolase, NSE)和胶质纤维酸性蛋白(glial fibrillary acidic portein, GFAP)标记神经干细胞、神经元和星形胶质细胞,免疫组化检测各时间点海马齿状回BrdU阳性细胞数,免疫荧光双标法检测各时间点皮层BrdU+Nestin+、BrdU+/GFAP+、BrdU+/NSE+细胞数,观察各组阳性细胞的定位及半定量结果的差异。定量结果数据以x±s表示,采用SPSS17.0统计软件分析,多组间计量资料比较采用单因素方差分析,差异有统计学意义者进一步以LSD-t法进行两两比较,以a=0.05为检验水准。
结果
1.各组大鼠Caspase-3mRNA的表达：Caspase-3在3d时表达最高,此后逐渐下降,28d时接近正常水平,两治疗组较HIBD组基因表达明显降低,GB高剂量组较GB低剂量组降低明显；
2.各组大鼠VEGF mRNA的表达：在3d明显增加,此后渐降,两治疗组增加较HIBD组显著,其中GB高剂量组表达较GB低剂量组表达增加,差异有统计学意义。
3.各组大鼠Foxgl mRNA的表达：HIBD后3d表达开始增加,7d达高峰,7d后逐渐下降；两治疗组表达高于HIBD组,其中,GB高剂量组在造模后7d、14d、28d表达均高于GB低剂量组,差异有统计学意义。
4.海马BrdU+细胞：假手术组海马可见少量BrdU+细胞,HIBD后BrdU+细胞数增加,7d最多,此后逐渐下降；两治疗组在各时间点BrdU+细胞数高于HIBD组,其中,GB高剂量组的BrdU+细胞数在各时间点高于GB低剂量组。
5.皮层BrdU+/nestin+细胞：HIBD后3d开始增加,7d时细胞数最多,14d、28d逐渐减少；两治疗组阳性细胞数高于HIBD组；此外,GB高剂量组在7d、14d及28d时细胞数较GB低剂量组增多。
6.皮层BrdU+/NSE+细胞：HIBD后3d开始增加,14d达高峰,28d逐渐下降；3d时,两治疗组和HIBD组细胞数无明显差异,7d后前者较后者显著增多；GB高剂量组在28d时较GB低剂量组增多,差异有统计学意义。
7.皮层BrdU+/GFAP+细胞：HIBD后3d时细胞数无明显增多,7d开始增加,14d最多,28d时降低；在7d,14d及28d时,两治疗组比HIBD组细胞数增多,其中GB高剂量组又较GB低剂量组细胞数增多,差异有统计学意义。
结论
1.HIBD后Caspase-3mRNA表达上调,脑细胞凋亡增加,上调VEGF mRNA表达,促新生血管形成修复损伤,上调Foxgl表达,诱导内源性神经干细胞增殖分化增加；
2.GB可降低HIBD后神经细胞凋亡,可进一步上调VEGF及Foxgl表达,减轻神经系统损伤,促进神经干细胞增殖并向神经元方向分化,从而减轻神经系统损伤并促进受损神经功能的修复；
3.GB高剂量组较GB低剂量组治疗作用更显著。
Objective
Neonatal hypoxic-ischemic brain damage (HIBD) is what all sorts of perinatal asphyxia caused varying degrees of hypoxia, blood flow reduced even stopped in brain, which led to foetus or new borns brain damage. HIBD is always the cause of perinatal death of fetal and newborn an, the childhood epilepsy, low intelligence as well as cerebral palsy. Neurogenesis is a process by which under certain conditions neural stem cells can proliferate,migrate and differentiate into mature neurons with specific phenotype, and be involved in the restoration process of nerve injury. After studies have demonstrated that there are neural stem cells(NSCs)in the adult mammalian brain, and they have the capability of neurogenesis, research of NSCs is progressing rapidly in recent years. Normally Neurogenesis is a small amount and increases in such conditions as ischemia and seizure,but is not enough to repair damaged brain tissue for some reason such as lower multiplied quantity, apoptosis and a smaller proportion of divided into neurons.So,it will be a new hope for treating many diseases of the central nervous system to study the process of neurogenesis after brain damage and to search methods toinduce NSCs proliferation and differentiation. Ginkgolides is a terpene lactones compound extracted from ginkgo biloba, which has wide pharmacological functions and neuroprotective and repair functions by lowing the apoptosis of nerve cells and promoting neovascularization after injuries in central nervous system. It has recently reported that GB can accelerate the proliferation,migration and differentiation directionally of the NSCs cultured in vitro. The present study is proposed to observe apoptosis and changes of neurogenesis following injur by the HIBD model of neonatal rats, to study the the effect of GB on these,and it is hoped to provide a basis for future studies.
Methods
A total of200cleaning grade healthy neonatal aged7-day-old SD rats were randomly divided into sham operated group with48rats, HIBD group with52rats, low dose GB group with50rats and high dose GB group with50rats and duplicated a model of HIBD in the neonatal rat by by the classical Rice. The behaviour of rats were observed in and after modeling process, Low dose GB group and high dose GB group were intraperitoneally injected with GB in dose of5mg/kg、10mg/kg respectively while the other groups was given equal normal saline, once daily for5days.6rats were randomly selected each group and sacrificed on3d,7d,14d,28d respectively. Rats were killed on scheduled time and expression of Caspase-3and VEGF were detected at various points by real-time PCR(RT-PCR).1.Relative expression were calculated with the method of2-△△CT then the difference of each group was compared.2. Rats marked with5bromodeoxyuridine (BrdU) before execution in dose of50mg/kg, once12h for5times and the rats were put to death after4hours of last injection. Nestin, neuron special enolase(NSE) glial fibrillary acidic protein(GFAP) were seen as markers of NSCs, neurons and astrocytes. Then the number of BrdU positive cell were measured by immunohistochemistry and the number of BrdU-Nestin positive cells of double staining in SGZ and BrdU-NSE、 BrdU-NSE double positive cells cortex were investigated by immunofluorescent double staining. The difference of positive cells among each group were compared. Quantitative data presented in a form of x±s were analyzed by SPSS17.0.The measurement data of multiple group were compared with single factor analysis of variance, and any two of several groups was performed with LSD-t West. Pearson's correlation was used in analyzing the relation of two parameters. To consider P<0.05as statistically significant.
Results
1. The expression of Caspase-3:The expression of Caspase-3reached the peak at3d, then declined gradually, approaches the contrast values at28d. Compared with the model group, the level of the expression was decreased in the two trial groups, but it reduced dramatically in high-dose group.
2. The expression of VEGF:The expression of VEGF significantly increases at3d after HIBD, then declined gradually.The level of the expression were higher in the two trial groups compared with the model group but it was added dramatically in high-dose group.
3. The expression of Foxgl:expression were observed at3d after HIBD, peaked at7d, then declined gradually; The level in the two treatment groups are higher than that of the HIBD group; The expression of Foxgl in high-dose group is higher than that in low-dose group, with statistical significance.
4. The BrdU positive cells in hippocampus:A few histamine positive cells were found in hippocampus; The number of BrdU+cells increased after HIBD, reached the peak at7d then declined; The number of positive cells were higher in the two trial groups compared with it in the model group; It was higher in high-dose group than in low-dose group.
5. BrdU+/nestin+cells in cortex:BrdU+/nestin+cells appeared at3d peaked on7d, then declined gradually;The number of positive cells were higher in the two trial groups compared with it in the model group; The numbers of BrdU+/nestin+cell in high-dose group were increased than those in low-dose group at7d,14d,28d.
6. BrdU+/NSE+cell in cortex:There is no significant difference among the four groups at3d; The number of positive cells appeared at3d,peaked on14d, then declined gradually; Those were higher in the two trial groups compared with those in the model group at7d; The numbers of BrdU+/NSE+cell in high-dose group were increased than those in low-dose group at28d, with statistical significance.
7. BrdU+/GFAP+cell in cortex:Among all the groups, there was no significant difference of positive cells3d; the positive cells increased at7d,peaked on14d, declined at28d after HIBD; The number of positive cells were higher in the two trial groups compared with it in the model group at7d,14d,28d; The numbers of BrdU+/NSE+cell in high-dose group were increased than those in low-dose group at14d and28d, with statistical significance.
Conclusions
1. HIBD can induce the apoptosis of cells, promote neovascularization, induce upregulation of Foxgl expression and reduce neurogenesis in brain.
2. GB can lower the expression of Caspase-3increase VEGF, facilitate the expression of Foxgl, the proliferation of neural stem cells, the differentiate from stem cell into neuron and finally improve the functional recovery of nervous system.
3. There are more significant efficacy in high-dose group than in low-dose group.
新生儿缺氧缺血性脑损伤(Hypoxic-ischemic brain damage, HIBD)是指各种围生期疾患导致脑组织不同程度缺氧及血流减少甚至停止,从而导致中枢神经系统损伤,是新生儿死亡及儿童癫痫、智力低下和脑性瘫痪的重要原因。神经发生是指神经干细胞(neural stem cell, NSCs)在特定条件下发生增殖、迁移及进一步分化成有特定表型的神经细胞,并参与神经功能修复的过程。自从证实成体脑组织中存在NSCs以来,研究进展很大。生理情况下NSCs微量增殖,一定条件下如脑缺血、癫痫等可诱导增加,但由于增殖数量较少、迁移过程中发生凋亡及分化为神经元的比例小等原因而不足以修复受损的神经功能。因此,了解脑损伤诱导神经发生机制,寻找促进神经发生增加的措施,将为治疗中枢神经系统疾病带来新的希望。银杏内酯(ginkgolides)是从银杏叶中提取的一类萜内酯类化合物,药理作用广泛,在中枢神经系统,可通过降低损伤后神经细胞凋亡促进新生血管形成等机制保护并修复受损的神经功能。近年研究发现,银杏内酯B(ginkgolides B, GB)可促进体外培养的NSCs增殖、迁移及定向分化。本课题通过制作HIBD新生大鼠模型,应用GB进行干预,观察新生大鼠HIBD后细胞凋亡情况及内源性神经干细胞增殖分化的改变,研究GB对其发生的影响,为NSCs定向诱导分化研究及临床应用提供理论依据。
方法
清洁级新生7日龄SD大鼠200只,随机分为假手术组48只、HIBD组52只、GB低剂量组50只及GB高剂量组50只,最终纳入数据分析的大鼠每组均为48只。经典Rice法制作HIBD动物模型,在造模过程中及造模后观察动物行为学改变。GB低剂量组与GB高剂量组分别按5mg/kg、10mg/kg腹腔注射GB,其它两组注射等量生理盐水(10ml/kg体重体积注射量),每天一次共5天。各组随机选取6只分别在造模后3d,7d,14d,28d处死：(1)规定时间点断头取脑处死大鼠,荧光定量PCR法检测各时间点Caspase-3、VEGF、Foxgl mRNA的表达水平,2-△△CT法计算相对表达量,比较各组表达差异；(2)按规定时间点处死前给予腹腔注射溴脱氧尿嘧啶核苷(Bromodeoxyuridine BrdU)标记新生细胞,剂量50mg/kg,1次/12h,共5次,最后一次腹腔注射BrdU4h后处死；分别以巢蛋白(Nestin)神经元烯醇化酶(neuron special enolase, NSE)和胶质纤维酸性蛋白(glial fibrillary acidic portein, GFAP)标记神经干细胞、神经元和星形胶质细胞,免疫组化检测各时间点海马齿状回BrdU阳性细胞数,免疫荧光双标法检测各时间点皮层BrdU+Nestin+、BrdU+/GFAP+、BrdU+/NSE+细胞数,观察各组阳性细胞的定位及半定量结果的差异。定量结果数据以x±s表示,采用SPSS17.0统计软件分析,多组间计量资料比较采用单因素方差分析,差异有统计学意义者进一步以LSD-t法进行两两比较,以a=0.05为检验水准。
结果
1.各组大鼠Caspase-3mRNA的表达：Caspase-3在3d时表达最高,此后逐渐下降,28d时接近正常水平,两治疗组较HIBD组基因表达明显降低,GB高剂量组较GB低剂量组降低明显；
2.各组大鼠VEGF mRNA的表达：在3d明显增加,此后渐降,两治疗组增加较HIBD组显著,其中GB高剂量组表达较GB低剂量组表达增加,差异有统计学意义。
3.各组大鼠Foxgl mRNA的表达：HIBD后3d表达开始增加,7d达高峰,7d后逐渐下降；两治疗组表达高于HIBD组,其中,GB高剂量组在造模后7d、14d、28d表达均高于GB低剂量组,差异有统计学意义。
4.海马BrdU+细胞：假手术组海马可见少量BrdU+细胞,HIBD后BrdU+细胞数增加,7d最多,此后逐渐下降；两治疗组在各时间点BrdU+细胞数高于HIBD组,其中,GB高剂量组的BrdU+细胞数在各时间点高于GB低剂量组。
5.皮层BrdU+/nestin+细胞：HIBD后3d开始增加,7d时细胞数最多,14d、28d逐渐减少；两治疗组阳性细胞数高于HIBD组；此外,GB高剂量组在7d、14d及28d时细胞数较GB低剂量组增多。
6.皮层BrdU+/NSE+细胞：HIBD后3d开始增加,14d达高峰,28d逐渐下降；3d时,两治疗组和HIBD组细胞数无明显差异,7d后前者较后者显著增多；GB高剂量组在28d时较GB低剂量组增多,差异有统计学意义。
7.皮层BrdU+/GFAP+细胞：HIBD后3d时细胞数无明显增多,7d开始增加,14d最多,28d时降低；在7d,14d及28d时,两治疗组比HIBD组细胞数增多,其中GB高剂量组又较GB低剂量组细胞数增多,差异有统计学意义。
结论
1.HIBD后Caspase-3mRNA表达上调,脑细胞凋亡增加,上调VEGF mRNA表达,促新生血管形成修复损伤,上调Foxgl表达,诱导内源性神经干细胞增殖分化增加；
2.GB可降低HIBD后神经细胞凋亡,可进一步上调VEGF及Foxgl表达,减轻神经系统损伤,促进神经干细胞增殖并向神经元方向分化,从而减轻神经系统损伤并促进受损神经功能的修复；
3.GB高剂量组较GB低剂量组治疗作用更显著。
Objective
Neonatal hypoxic-ischemic brain damage (HIBD) is what all sorts of perinatal asphyxia caused varying degrees of hypoxia, blood flow reduced even stopped in brain, which led to foetus or new borns brain damage. HIBD is always the cause of perinatal death of fetal and newborn an, the childhood epilepsy, low intelligence as well as cerebral palsy. Neurogenesis is a process by which under certain conditions neural stem cells can proliferate,migrate and differentiate into mature neurons with specific phenotype, and be involved in the restoration process of nerve injury. After studies have demonstrated that there are neural stem cells(NSCs)in the adult mammalian brain, and they have the capability of neurogenesis, research of NSCs is progressing rapidly in recent years. Normally Neurogenesis is a small amount and increases in such conditions as ischemia and seizure,but is not enough to repair damaged brain tissue for some reason such as lower multiplied quantity, apoptosis and a smaller proportion of divided into neurons.So,it will be a new hope for treating many diseases of the central nervous system to study the process of neurogenesis after brain damage and to search methods toinduce NSCs proliferation and differentiation. Ginkgolides is a terpene lactones compound extracted from ginkgo biloba, which has wide pharmacological functions and neuroprotective and repair functions by lowing the apoptosis of nerve cells and promoting neovascularization after injuries in central nervous system. It has recently reported that GB can accelerate the proliferation,migration and differentiation directionally of the NSCs cultured in vitro. The present study is proposed to observe apoptosis and changes of neurogenesis following injur by the HIBD model of neonatal rats, to study the the effect of GB on these,and it is hoped to provide a basis for future studies.
Methods
A total of200cleaning grade healthy neonatal aged7-day-old SD rats were randomly divided into sham operated group with48rats, HIBD group with52rats, low dose GB group with50rats and high dose GB group with50rats and duplicated a model of HIBD in the neonatal rat by by the classical Rice. The behaviour of rats were observed in and after modeling process, Low dose GB group and high dose GB group were intraperitoneally injected with GB in dose of5mg/kg、10mg/kg respectively while the other groups was given equal normal saline, once daily for5days.6rats were randomly selected each group and sacrificed on3d,7d,14d,28d respectively. Rats were killed on scheduled time and expression of Caspase-3and VEGF were detected at various points by real-time PCR(RT-PCR).1.Relative expression were calculated with the method of2-△△CT then the difference of each group was compared.2. Rats marked with5bromodeoxyuridine (BrdU) before execution in dose of50mg/kg, once12h for5times and the rats were put to death after4hours of last injection. Nestin, neuron special enolase(NSE) glial fibrillary acidic protein(GFAP) were seen as markers of NSCs, neurons and astrocytes. Then the number of BrdU positive cell were measured by immunohistochemistry and the number of BrdU-Nestin positive cells of double staining in SGZ and BrdU-NSE、 BrdU-NSE double positive cells cortex were investigated by immunofluorescent double staining. The difference of positive cells among each group were compared. Quantitative data presented in a form of x±s were analyzed by SPSS17.0.The measurement data of multiple group were compared with single factor analysis of variance, and any two of several groups was performed with LSD-t West. Pearson's correlation was used in analyzing the relation of two parameters. To consider P<0.05as statistically significant.
Results
1. The expression of Caspase-3:The expression of Caspase-3reached the peak at3d, then declined gradually, approaches the contrast values at28d. Compared with the model group, the level of the expression was decreased in the two trial groups, but it reduced dramatically in high-dose group.
2. The expression of VEGF:The expression of VEGF significantly increases at3d after HIBD, then declined gradually.The level of the expression were higher in the two trial groups compared with the model group but it was added dramatically in high-dose group.
3. The expression of Foxgl:expression were observed at3d after HIBD, peaked at7d, then declined gradually; The level in the two treatment groups are higher than that of the HIBD group; The expression of Foxgl in high-dose group is higher than that in low-dose group, with statistical significance.
4. The BrdU positive cells in hippocampus:A few histamine positive cells were found in hippocampus; The number of BrdU+cells increased after HIBD, reached the peak at7d then declined; The number of positive cells were higher in the two trial groups compared with it in the model group; It was higher in high-dose group than in low-dose group.
5. BrdU+/nestin+cells in cortex:BrdU+/nestin+cells appeared at3d peaked on7d, then declined gradually;The number of positive cells were higher in the two trial groups compared with it in the model group; The numbers of BrdU+/nestin+cell in high-dose group were increased than those in low-dose group at7d,14d,28d.
6. BrdU+/NSE+cell in cortex:There is no significant difference among the four groups at3d; The number of positive cells appeared at3d,peaked on14d, then declined gradually; Those were higher in the two trial groups compared with those in the model group at7d; The numbers of BrdU+/NSE+cell in high-dose group were increased than those in low-dose group at28d, with statistical significance.
7. BrdU+/GFAP+cell in cortex:Among all the groups, there was no significant difference of positive cells3d; the positive cells increased at7d,peaked on14d, declined at28d after HIBD; The number of positive cells were higher in the two trial groups compared with it in the model group at7d,14d,28d; The numbers of BrdU+/NSE+cell in high-dose group were increased than those in low-dose group at14d and28d, with statistical significance.
Conclusions
1. HIBD can induce the apoptosis of cells, promote neovascularization, induce upregulation of Foxgl expression and reduce neurogenesis in brain.
2. GB can lower the expression of Caspase-3increase VEGF, facilitate the expression of Foxgl, the proliferation of neural stem cells, the differentiate from stem cell into neuron and finally improve the functional recovery of nervous system.
3. There are more significant efficacy in high-dose group than in low-dose group.
引文
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