FGF1、FGFR1在大鼠全脑缺血预处理诱导缺血耐受的保护作用
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摘要
目的:观察成纤维生长因子-1(FGF-1)和成纤维生长因子受体-1(FGFR-1)在大鼠全脑缺血预处理诱导缺血耐受过程中不同时相的表达,探讨两者在脑保护作用中的意义。
材料与方法:采用改良四血管阻断法制作大鼠全脑缺血模型,选用健康成年SD大鼠120只随机分成A、B、C、D 4组,根据设计时间点不同每组分5亚组,每个亚组6只。A组为假手术对照组,仅进行相关血管游离后缝合切口,分别再饲养1天、3天、7天、14天及21天;B组为全脑缺血3分钟预处理对照组,B1、B3、B7、B14及B21亚组分别为全脑缺血3分钟后再灌注1天、3天、7天、14天及21天;C组为全脑缺血9分钟对照组,C1、C3、C7、C14及C21亚组分别为全脑缺血9分钟后再灌注1天、3天、7天、14天及21天;D组为试验组,均做全脑缺血3分钟预处理后,D1、D3、D7、D14及D21亚组分别灌注1天、3天、7天、14天及21天后均再次全脑缺血9分钟。A组、B组和C组均在饲养时间或再灌注时间完成后即断头取脑,D组在最后一次缺血再灌注7天后即断头取脑。在视交叉后1mm及4mm处冠状切面取切片行H-E染色、FGF-1和FGFR-1免疫组化染色,分别观察海马区神经元的存活情况及FGF-1和FGFR-1的表达,采用SPSS13.0软件对实验数据进行进行完全随机设计单因素方差分析,各组均数两两比较采用LSD-t检验。
结果:H-E染色切片于光镜下计数海马CA1区存活神经元密度,A组和B组无明显神经元坏死;C组和D1、D14、D21亚组可见大量神经元坏死;D3和D7亚组可见部分神经元坏死,其中D3亚组存活神经元数目最多,最接近A组存活神经元数目。免疫组化染色切片观察见:FGF-1和FGFR-1免疫阳性细胞均表现为棕黄着色,主要位于胞浆。(1)FGF-1免疫阳性细胞观察结果如下:A组和B1、B3、B7、C1、C3、C7亚组的FGF-1免疫阳性细胞稀疏;B14、B21、C14、C21亚组和D组免疫阳性细胞明显增多。(2)FGFR-1免疫阳性细胞观察结果如下:A组和B14、B21、C14、C21亚组免疫阳性细胞较少;B1、B3、B7、C1、C3、C7亚组及D组免疫阳性细胞明显增多。经过相应的全脑缺血处理后,各组及各亚组之间两两对比显示神经元存活数目及FGF-1和FGFR-1表达强度存在显著性差异。
结论:(1)全脑3分钟缺血预处理后,脑组织能对随后致死性的脑缺血能产生有效的保护作用;(2)无论全脑缺血3分钟还是9分钟后,FGF-1和FGFR-1在脑组织中表达均有增强,但先缺血预处理3分钟后在不同时间点再缺血9分钟,FGF-1和FGFR-1在脑组织中表达得到更进一步增强;(3)FGF-1和FGFR-1参与了缺血预处理诱导缺血耐受的过程,在此过程中,其表达的改变与缺血预处理的神经保护作用相关。
OBJECTIVE:To investigate the changes of expression of both FGF-1 and FGFR-1 in the process of ischemia tolerance induced by global cere- bral ischemia preconditioning(IP)in the adult SD rat and to explore their role in ischemic tolerance.
MATERIALS AND METHODS:Modified four-vessel occlusion rat models was used in this study.120 healthy adult Sprague-Dawley(SD) rats were divided randomly into 4 groups,and each group was divided into 5 subgroups according to different time points that were designed in advance.Group A:sham-operated control group,The subgroup A1,A3, A7,A14 and A21 were raised respectively 1 day,3 days,7 days,14 days and 21 days after sham operation;Group B:Control group to be given ischemia preconditioning for 3 minuts,subgroup B1,B3,B7,B14 and B21 were respectively reperfused for 1 day,3 days,7 days,14 days and 21 days;Group C:Control group to be given ischemia preconditioning for 9 minuts,subgroup C1,C3,C7,C14 and C21 were respectively reperfused for 1 day,3 days,7 days,14 days and 21 days;Group D:Trial group,subgroup D1,D3,D7,D14 and D21 were reperfused respectively for 1 day,3 days,7 days,14 days and 21 days followed 3 minuts' ischemia,then all be given ischemia for 9 minuts.Rats of Group A, Group B and Group C were decapitated and the brains were taken out when raise or reperfusion finished,and so did the rats of group D 7 days after 9 minuts' ischemia.The histopathological changes and ultrastructure of cerebral hippocampus CA1 subarea were exmined by HE staining and the expressions of FGF-1 and FGFR-1 were studied by immunohistochemistry. All the experimental data were analyzed to be deployed one-way analysis of variance by SPSS 13.0 software.
RESULTS:HE-stained slices were observed by microscope,all results showed:There were no significant changes of cellular necrosis in subgroups of A1,A3,A7,A14,A21,B1,B3,B7,B14 andB21;Mass cellular necrosis were observed in subgroups of C1,C3,C7,C14,C21, D1,D14 and D21,part of neurons of D3 and D7 were necrotic,and neuronal survival of D3 was highest among all subgroups of group D. immunohistochemical staining of FGF-1 showed:Positive stains were rare inhippocampusinsubgroupsofA1,A3,A7,A 14,A21,B1, B3,B7,C1,C3 and C7;Positive stains were abundant in hippocampus in subgroups of B14,B21,C14,C21,D3,D7,D14 and D21. immunohistochemical staining of FGF-1 showed:Positive stains were rare inhippocampus in subgroups of A1,A3,A7,A14,A21,B14, B21,C14,C21;Positive stains were abundant in hippocampus in subgroups of B1,B3,B7,C1,C3,C7,D1,D3,D7,D14,D21.Compared with each other of groups,due to IP,the quantum of survive neuron and expression ofFGF-1 and FGFR-1 were different significantly.
CONCLUSIONS:(1)after single cerebral ischemia for 3 minutes, brain can got the protective effect against the following deadly cerebral ischemia;especially in the third day;(2)single cerebral ischemia for both 3 minutes and 9 minutes,the expression of FGF-1 and FGFR-1 had a strengthen tendency,after single cerebral ischemia for 3 minutes and respective reperfusion for 1 day,3 days,7 days,14 days and 21 days, then all for cerebral ischemia once more for 9 minuts,the expression of FGF-1 and FGFR-1 have a further expression;(3)FGF-1 and FGFR-1 played a role in the mechanism of ischemic tolerant effect,and the level of FGF-1 and FGFR-1 's expression was related to the protective effect on brain.
材料与方法:采用改良四血管阻断法制作大鼠全脑缺血模型,选用健康成年SD大鼠120只随机分成A、B、C、D 4组,根据设计时间点不同每组分5亚组,每个亚组6只。A组为假手术对照组,仅进行相关血管游离后缝合切口,分别再饲养1天、3天、7天、14天及21天;B组为全脑缺血3分钟预处理对照组,B1、B3、B7、B14及B21亚组分别为全脑缺血3分钟后再灌注1天、3天、7天、14天及21天;C组为全脑缺血9分钟对照组,C1、C3、C7、C14及C21亚组分别为全脑缺血9分钟后再灌注1天、3天、7天、14天及21天;D组为试验组,均做全脑缺血3分钟预处理后,D1、D3、D7、D14及D21亚组分别灌注1天、3天、7天、14天及21天后均再次全脑缺血9分钟。A组、B组和C组均在饲养时间或再灌注时间完成后即断头取脑,D组在最后一次缺血再灌注7天后即断头取脑。在视交叉后1mm及4mm处冠状切面取切片行H-E染色、FGF-1和FGFR-1免疫组化染色,分别观察海马区神经元的存活情况及FGF-1和FGFR-1的表达,采用SPSS13.0软件对实验数据进行进行完全随机设计单因素方差分析,各组均数两两比较采用LSD-t检验。
结果:H-E染色切片于光镜下计数海马CA1区存活神经元密度,A组和B组无明显神经元坏死;C组和D1、D14、D21亚组可见大量神经元坏死;D3和D7亚组可见部分神经元坏死,其中D3亚组存活神经元数目最多,最接近A组存活神经元数目。免疫组化染色切片观察见:FGF-1和FGFR-1免疫阳性细胞均表现为棕黄着色,主要位于胞浆。(1)FGF-1免疫阳性细胞观察结果如下:A组和B1、B3、B7、C1、C3、C7亚组的FGF-1免疫阳性细胞稀疏;B14、B21、C14、C21亚组和D组免疫阳性细胞明显增多。(2)FGFR-1免疫阳性细胞观察结果如下:A组和B14、B21、C14、C21亚组免疫阳性细胞较少;B1、B3、B7、C1、C3、C7亚组及D组免疫阳性细胞明显增多。经过相应的全脑缺血处理后,各组及各亚组之间两两对比显示神经元存活数目及FGF-1和FGFR-1表达强度存在显著性差异。
结论:(1)全脑3分钟缺血预处理后,脑组织能对随后致死性的脑缺血能产生有效的保护作用;(2)无论全脑缺血3分钟还是9分钟后,FGF-1和FGFR-1在脑组织中表达均有增强,但先缺血预处理3分钟后在不同时间点再缺血9分钟,FGF-1和FGFR-1在脑组织中表达得到更进一步增强;(3)FGF-1和FGFR-1参与了缺血预处理诱导缺血耐受的过程,在此过程中,其表达的改变与缺血预处理的神经保护作用相关。
OBJECTIVE:To investigate the changes of expression of both FGF-1 and FGFR-1 in the process of ischemia tolerance induced by global cere- bral ischemia preconditioning(IP)in the adult SD rat and to explore their role in ischemic tolerance.
MATERIALS AND METHODS:Modified four-vessel occlusion rat models was used in this study.120 healthy adult Sprague-Dawley(SD) rats were divided randomly into 4 groups,and each group was divided into 5 subgroups according to different time points that were designed in advance.Group A:sham-operated control group,The subgroup A1,A3, A7,A14 and A21 were raised respectively 1 day,3 days,7 days,14 days and 21 days after sham operation;Group B:Control group to be given ischemia preconditioning for 3 minuts,subgroup B1,B3,B7,B14 and B21 were respectively reperfused for 1 day,3 days,7 days,14 days and 21 days;Group C:Control group to be given ischemia preconditioning for 9 minuts,subgroup C1,C3,C7,C14 and C21 were respectively reperfused for 1 day,3 days,7 days,14 days and 21 days;Group D:Trial group,subgroup D1,D3,D7,D14 and D21 were reperfused respectively for 1 day,3 days,7 days,14 days and 21 days followed 3 minuts' ischemia,then all be given ischemia for 9 minuts.Rats of Group A, Group B and Group C were decapitated and the brains were taken out when raise or reperfusion finished,and so did the rats of group D 7 days after 9 minuts' ischemia.The histopathological changes and ultrastructure of cerebral hippocampus CA1 subarea were exmined by HE staining and the expressions of FGF-1 and FGFR-1 were studied by immunohistochemistry. All the experimental data were analyzed to be deployed one-way analysis of variance by SPSS 13.0 software.
RESULTS:HE-stained slices were observed by microscope,all results showed:There were no significant changes of cellular necrosis in subgroups of A1,A3,A7,A14,A21,B1,B3,B7,B14 andB21;Mass cellular necrosis were observed in subgroups of C1,C3,C7,C14,C21, D1,D14 and D21,part of neurons of D3 and D7 were necrotic,and neuronal survival of D3 was highest among all subgroups of group D. immunohistochemical staining of FGF-1 showed:Positive stains were rare inhippocampusinsubgroupsofA1,A3,A7,A 14,A21,B1, B3,B7,C1,C3 and C7;Positive stains were abundant in hippocampus in subgroups of B14,B21,C14,C21,D3,D7,D14 and D21. immunohistochemical staining of FGF-1 showed:Positive stains were rare inhippocampus in subgroups of A1,A3,A7,A14,A21,B14, B21,C14,C21;Positive stains were abundant in hippocampus in subgroups of B1,B3,B7,C1,C3,C7,D1,D3,D7,D14,D21.Compared with each other of groups,due to IP,the quantum of survive neuron and expression ofFGF-1 and FGFR-1 were different significantly.
CONCLUSIONS:(1)after single cerebral ischemia for 3 minutes, brain can got the protective effect against the following deadly cerebral ischemia;especially in the third day;(2)single cerebral ischemia for both 3 minutes and 9 minutes,the expression of FGF-1 and FGFR-1 had a strengthen tendency,after single cerebral ischemia for 3 minutes and respective reperfusion for 1 day,3 days,7 days,14 days and 21 days, then all for cerebral ischemia once more for 9 minuts,the expression of FGF-1 and FGFR-1 have a further expression;(3)FGF-1 and FGFR-1 played a role in the mechanism of ischemic tolerant effect,and the level of FGF-1 and FGFR-1 's expression was related to the protective effect on brain.
引文
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