罂粟碱在兔蛛网膜下腔出血后脑血管痉挛中的作用
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摘要
目的：研究罂粟碱在兔蛛网膜下腔出血后脑血管痉挛中的作用。
材料与方法：采用单侧颈总动脉结扎后枕大池二次注血法制备兔蛛网膜下腔出血模型,选用健康成年新西兰兔72只随机分成A、B、C、D 4组,根据设计时间点不同每组分24h、72h、7天3个亚组,每个亚组6只。A组为假手术对照组,分别以A1、A2、A3代表假手术后饲养24h、72h、7天三个亚组；B组为SAH对照组,分别以B1、B2、B3代表SAH模型制作成功后饲养24h、72h、7天三个亚组；C组为SAH+PPA组,分别以C1、C2、C3代表SAH+PPA干预后饲养24h、72h、7天三个亚组；D组为SAH+PPA明胶海绵组,分别以D1、D2、D3代表SAH+PPA明胶海绵干预后饲养24h、72h、7天三个亚组,各组在其对应的饲养时间点断头取脑,于视交叉后1.4cm、2.0cm处取冠状面切片行HE染色、Bcl-2免疫组化染色及bax免疫组化染色,分别观察兔海马CA1区存活神经元密度及Bcl-2、bax的表达。本实验数据采用SPSS17.0软件进行统计学分析。
结果：光镜下观察H-E染色切片,可以见到A组基底动脉血管管壁平滑,结构完整,未见增厚,B组血管管径狭窄,血管内皮细胞肿胀明显,内弹力板皱折,部分内皮细胞脱落,平滑肌细胞变性,C、D组血管管径轻度狭窄,内皮细胞肿胀轻微。光镜下对HE染色切片中海马CA1区神经元密度进行计数, A组见散在神经元凋亡；B组可见大量海马锥体细胞凋亡；同时间点上,C、D组切片中海马CA1区神经元细胞凋亡数目较B组少。各组免疫组化染色切片观察结果示:Bcl-2和bax染色阳性细胞表现为胞质被染成棕黄色,并且均匀弥漫染色。(1)Bcl-2免疫组化染色阳性神经元细胞观察结果：在A组海马CA1区Bcl-2染色较浅,而在B、C、D组中,海马CA1区的Bcl-2染色明显,且相较于B组,C、D组阳性细胞数更多且染色更深。(2)bax免疫组化染色阳性神经元细胞观察结果：在A海马CA1区bax染色较浅,而在B、C、D组中,海马CA1区bax染色明显。B组与C、D两组相比,阳性细胞数更多且染色更深。统计学处理分析结果显示各组之间存活神经元密度、Bcl-2及bax表达强度进行两两对比存在显著性差异。
结论：
1.SAH能够使海马CA1区神经元细胞中Bcl-2、bax的表达升高。
2.罂粟碱(PPV)对SAH后CVS有舒张血管作用,可升高海马CA1区神经元细胞中的Bcl-2的表达,降低bax的表达,发挥抗凋亡作用。
3.罂粟碱(PPV)的缓释制剂在SAH后CVS的扩血管作用显著,但明胶海绵仍不是理想的缓释载体。
OBJECTIVE:To investigate the role of papaverine in rabbit cerebral vasospasm after subarachnoid hemorrhage
METHODS:In this study, model of subarachnoid hemorrhage that is established by injecting autologous arterial blood to cisterna magna of unilateral carotid artery ligated rabbit.72 healthy adult rabbits were divided randomly into 4 groups, and each group was divided into 4 subgroups according to different time points pre-designed with 6 adult rabbits in each subgroup. Group A:sham-operated control group includes subgroup A1, A2, A3, which were raised respectively 24hour,72hours, 7days after sham operation; Group B:SAH control group, includes subgroup B1, B2, B3, which were raised respectively 24hours,72hours, 7days after the establishment of SAH model; Group C:SAH+PPV group, included subgroups of C1, C2, C3, which were raised respectively 24hours,72hours,7days after the establishment of SAH+PPV model; Group D:SAH+PPV gelfoam (sustained-release preparations) group, subgroups D1, D2, D3 were raised respectively 24hours,48hours, 7days after establishment of SAH+PPV gelfoam model. Rabbits of Group A, Group B, Group C and group D were decapitated and the brains were harvested according to different time points designed in advance. Coronal sections of brain tissue were taken post to the optic chiasm for respectively 1.4 and 2.0cm. The histopathological changes and ultrastructure of cerebral hippocampus CA1 subarea as well as the live neurons density were exmined by HE staining and the expressions of Bcl-2 and bax were studied by immunohistochemistry. All the experimental datas were analyzed by SPSS 17.0 software.
RESULTS:HE-stained slides were observed under Optical microscope:vessel wall of basilar arteries in Group A are smooth, the structure of vessel walls was integral, and not thickened. Blood vessel diameters of Group B are obviously diminished, and endothelial cells of basilar arteries in Group B are manifested engorged. The internal elastic laminae ruffled, parts of the endothelial cells ecclasis, the smooth muscle cells degenerated. Blood vessel wall of Group C and D are little shrinked, and endothelial cells of vessels in these two groups are less engorgemented than Group B. The observation of hippocampus CA1 subarea and counting of survival neuron dense under microscope showed: Apoptosis of neurones in Group A are rarely observed; Apoptosis of neurones in larger number are observed in Group B. Group C and D showed obviously reduce of apoptosis of neurones compared to Group B of the same time points. Immunohistochemical staining of Bcl-2 and bax positive cells manifested:homogeneous diffuse brown color in cell plasm. (1)Positive stained cells of Bcl-2 are very rare in hippocampus in subgroups of Group A with shallow stain; Positive stained cells are abundant in subgroups of Group B、C and D. Positive stained cells in groups C and D are greater in number and deeply stained compared to the subgroups in Group B. (2) The same result can be found with respect to the expression of bax. Positive stained cells of bax are very rare in hippocampus in subgroups of Group A with shallow stain; Positive stained cells are abundant in subgroups of Group B、C and D. Positive stained cells in groups C and D are greater in number and deeply stained compared to the subgroups in Group B. After statistical analysis and through comparison among the groups and subgroups, we found the survival neuron dense and expression of Bcl-2 and bax significantly different.
CONCLUSION:
1、The expression of Bcl-2 and bax in neuronal cells is enhanced by subarachnoid hemorrhage.
2、Papaverion paly an vasodilative role in cerebral vasospasm after subarachnoid hemorrhage. It enhance the expression of Bcl-2 and inhibit the expression of bax and play a role of anti-apoptosis.
3、Papaverion sustained-release preparation play an significant vasodilative role in cerebral vasospasm after subarachnoid hemorrhage, but gelfoam is still not the ideal carrier.
材料与方法：采用单侧颈总动脉结扎后枕大池二次注血法制备兔蛛网膜下腔出血模型,选用健康成年新西兰兔72只随机分成A、B、C、D 4组,根据设计时间点不同每组分24h、72h、7天3个亚组,每个亚组6只。A组为假手术对照组,分别以A1、A2、A3代表假手术后饲养24h、72h、7天三个亚组；B组为SAH对照组,分别以B1、B2、B3代表SAH模型制作成功后饲养24h、72h、7天三个亚组；C组为SAH+PPA组,分别以C1、C2、C3代表SAH+PPA干预后饲养24h、72h、7天三个亚组；D组为SAH+PPA明胶海绵组,分别以D1、D2、D3代表SAH+PPA明胶海绵干预后饲养24h、72h、7天三个亚组,各组在其对应的饲养时间点断头取脑,于视交叉后1.4cm、2.0cm处取冠状面切片行HE染色、Bcl-2免疫组化染色及bax免疫组化染色,分别观察兔海马CA1区存活神经元密度及Bcl-2、bax的表达。本实验数据采用SPSS17.0软件进行统计学分析。
结果：光镜下观察H-E染色切片,可以见到A组基底动脉血管管壁平滑,结构完整,未见增厚,B组血管管径狭窄,血管内皮细胞肿胀明显,内弹力板皱折,部分内皮细胞脱落,平滑肌细胞变性,C、D组血管管径轻度狭窄,内皮细胞肿胀轻微。光镜下对HE染色切片中海马CA1区神经元密度进行计数, A组见散在神经元凋亡；B组可见大量海马锥体细胞凋亡；同时间点上,C、D组切片中海马CA1区神经元细胞凋亡数目较B组少。各组免疫组化染色切片观察结果示:Bcl-2和bax染色阳性细胞表现为胞质被染成棕黄色,并且均匀弥漫染色。(1)Bcl-2免疫组化染色阳性神经元细胞观察结果：在A组海马CA1区Bcl-2染色较浅,而在B、C、D组中,海马CA1区的Bcl-2染色明显,且相较于B组,C、D组阳性细胞数更多且染色更深。(2)bax免疫组化染色阳性神经元细胞观察结果：在A海马CA1区bax染色较浅,而在B、C、D组中,海马CA1区bax染色明显。B组与C、D两组相比,阳性细胞数更多且染色更深。统计学处理分析结果显示各组之间存活神经元密度、Bcl-2及bax表达强度进行两两对比存在显著性差异。
结论：
1.SAH能够使海马CA1区神经元细胞中Bcl-2、bax的表达升高。
2.罂粟碱(PPV)对SAH后CVS有舒张血管作用,可升高海马CA1区神经元细胞中的Bcl-2的表达,降低bax的表达,发挥抗凋亡作用。
3.罂粟碱(PPV)的缓释制剂在SAH后CVS的扩血管作用显著,但明胶海绵仍不是理想的缓释载体。
OBJECTIVE:To investigate the role of papaverine in rabbit cerebral vasospasm after subarachnoid hemorrhage
METHODS:In this study, model of subarachnoid hemorrhage that is established by injecting autologous arterial blood to cisterna magna of unilateral carotid artery ligated rabbit.72 healthy adult rabbits were divided randomly into 4 groups, and each group was divided into 4 subgroups according to different time points pre-designed with 6 adult rabbits in each subgroup. Group A:sham-operated control group includes subgroup A1, A2, A3, which were raised respectively 24hour,72hours, 7days after sham operation; Group B:SAH control group, includes subgroup B1, B2, B3, which were raised respectively 24hours,72hours, 7days after the establishment of SAH model; Group C:SAH+PPV group, included subgroups of C1, C2, C3, which were raised respectively 24hours,72hours,7days after the establishment of SAH+PPV model; Group D:SAH+PPV gelfoam (sustained-release preparations) group, subgroups D1, D2, D3 were raised respectively 24hours,48hours, 7days after establishment of SAH+PPV gelfoam model. Rabbits of Group A, Group B, Group C and group D were decapitated and the brains were harvested according to different time points designed in advance. Coronal sections of brain tissue were taken post to the optic chiasm for respectively 1.4 and 2.0cm. The histopathological changes and ultrastructure of cerebral hippocampus CA1 subarea as well as the live neurons density were exmined by HE staining and the expressions of Bcl-2 and bax were studied by immunohistochemistry. All the experimental datas were analyzed by SPSS 17.0 software.
RESULTS:HE-stained slides were observed under Optical microscope:vessel wall of basilar arteries in Group A are smooth, the structure of vessel walls was integral, and not thickened. Blood vessel diameters of Group B are obviously diminished, and endothelial cells of basilar arteries in Group B are manifested engorged. The internal elastic laminae ruffled, parts of the endothelial cells ecclasis, the smooth muscle cells degenerated. Blood vessel wall of Group C and D are little shrinked, and endothelial cells of vessels in these two groups are less engorgemented than Group B. The observation of hippocampus CA1 subarea and counting of survival neuron dense under microscope showed: Apoptosis of neurones in Group A are rarely observed; Apoptosis of neurones in larger number are observed in Group B. Group C and D showed obviously reduce of apoptosis of neurones compared to Group B of the same time points. Immunohistochemical staining of Bcl-2 and bax positive cells manifested:homogeneous diffuse brown color in cell plasm. (1)Positive stained cells of Bcl-2 are very rare in hippocampus in subgroups of Group A with shallow stain; Positive stained cells are abundant in subgroups of Group B、C and D. Positive stained cells in groups C and D are greater in number and deeply stained compared to the subgroups in Group B. (2) The same result can be found with respect to the expression of bax. Positive stained cells of bax are very rare in hippocampus in subgroups of Group A with shallow stain; Positive stained cells are abundant in subgroups of Group B、C and D. Positive stained cells in groups C and D are greater in number and deeply stained compared to the subgroups in Group B. After statistical analysis and through comparison among the groups and subgroups, we found the survival neuron dense and expression of Bcl-2 and bax significantly different.
CONCLUSION:
1、The expression of Bcl-2 and bax in neuronal cells is enhanced by subarachnoid hemorrhage.
2、Papaverion paly an vasodilative role in cerebral vasospasm after subarachnoid hemorrhage. It enhance the expression of Bcl-2 and inhibit the expression of bax and play a role of anti-apoptosis.
3、Papaverion sustained-release preparation play an significant vasodilative role in cerebral vasospasm after subarachnoid hemorrhage, but gelfoam is still not the ideal carrier.
引文
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