叶酸对局灶性脑梗塞大鼠脑组织Notch信号通路作用的研究
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摘要
目的研究叶酸(folic acid,FA)对成年局灶性脑梗塞大鼠脑组织Notch信号通路相关基因和蛋白表达的影响,在分子水平上探讨叶酸防治脑梗塞的作用及其作用机制。
方法本实验采用成年SD大鼠48只,按体重随机分为假手术组(sham operationgroup,SO),大脑中动脉闭塞模型组(middle cerebral artery occlusion,MCAO),MCAO+叶酸低剂量组(MCAO+low dose folic acid,MCAO+LFA),MCAO+叶酸高剂量组(MCAO+high dose folic acid,MCAO+HFA),每组12只。其中SO组和MCAO组灌胃生理盐水10ml/(kg bw·d),MCAO+LFA组和MCAO+HFA组分别灌胃叶酸溶液4mg/(kg bw·d),12mg/(kg bw·d)。预防性补充叶酸28d后,除SO组外其他三组均采用线栓法制备左侧脑梗塞模型。补充叶酸前、补充28d后及脑梗塞后采取血清,化学发光免疫分析法测定血清中叶酸含量;模型建立24h后进行神经功能评分,每组各取3只大鼠断头取脑TTC染色测定脑梗塞体积;其余脑梗塞大鼠继续补充叶酸3d、7d、14d后断头处死,取出脑组织制作冰冻切片,HE染色观察脑梗塞后3d脑组织病理学变化;荧光原位杂交法测定各时间点Notch信号通路Noch1、Hes1、Hes5、Mash1、Neurogenin1、Neurogenin2mRNA的表达水平;Western blot法测定各时间点Notch1、Hes1、Hes5蛋白的表达水平。
结果脑梗塞模型建立后存活大鼠除SO组外均出现左侧Horner征,神经功能评分在1～3分之间,达到了模型成功标准。血清中叶酸含量测定结果显示:MCAO组于脑梗塞后低于SO组,叶酸补充28d及脑梗塞3d后MCAO组低于MCAO+LFA和MCAO+HFA组,且MCAO+LFA组低于MCAO+HFA组(P＜0.05),每组脑梗塞前后比较差异均有统计学意义(P＜0.05);TTC染色显示:MCAO组大鼠脑梗塞体积比值明显高于MCAO+LFA和MCAO+HFA组(P＜0.05);HE染色显示:SO组神经细胞排列整齐,形态完整;MCAO组梗塞区广泛的神经细胞坏死,细胞间隙变宽,排列紊乱,胞体缩小变形,染色加深,叶酸补充组神经细胞坏死及脑组织变性较MCAO组轻;荧光原位杂交结果显示:大鼠脑梗塞后补充叶酸3d Notch信号通路相关基因已经开始表达。其中Notch1,Hes5 mRNA的表达于梗塞7d达到高峰,14d下降,Hes1 mRNA在三个时间点间的表达呈上升趋势。三种基因阳性细胞荧光强度,各时间点SO组均低于MCAO组(P＜0.05);7d、14d点MCAO组低于MCAO+LFA组和MCAO+HFA组(P＜0.05),MCAO+LFA组低于MCAO+HFA组(P＜0.05)。Mash1,Neurogenin1,Neurogenin2 mRNA表达于梗塞后7d下降,14d上升。各时间点阳性细胞荧光强度:Mash1基因MCAO组与SO组、MCAO+LFA组、MCAO+HFA组比较差异均有统计学意义(P＜0.05);3d、14d点MCAO+LFA组高于MCAO+HFA组(P＜0.05)。Neurogenin1基因3d、14d点MCAO组高于MCAO+LFA组,各时间点均高于MCAO+HFA组(P＜0.05);7d、14d点MCAO+LFA组均高于MCAO+HFA组(P＜0.05)。Neurogenin2基因3d、14d点SO组均低于MCAO组(P＜0.05);14d点MCAO组高于MCAO+LFA组(P＜0.05),各时间点两组均高于MCAO+HFA组(P＜0.05)。Western blot结果显示:Notch1,Hes1,Hes5蛋白的表达趋势与其相应基因表达完全相同。三种蛋白表达量,7d、14d点MCAO组均低于MCAO+LFA组和MCAO+HFA组(P＜0.05);7d、14d点Notch1,Hes1蛋白MCAO+LFA组低于MCAO+HFA组;7d点Hes5蛋白表达MCAO+LFA组低于MCAO+HFA组(P＜0.05)。
结论本实验采用线栓法成功建立了大鼠局灶性脑梗塞模型,研究结果显示脑梗塞的发生可降低血清叶酸含量,补充叶酸可提高大鼠血清叶酸含量,降低脑梗塞体积,减轻梗塞造成的神经细胞损伤,并有一定的剂量反应关系。同时叶酸可能通过上调脑梗塞大鼠脑组织内Notch1、Hes1、Hes5 mRNA及其蛋白的表达,下调Mash1、Neurogenin1、Neurogenin2 mRNA的表达对大鼠脑梗塞的治疗及康复起一定的促进作用。
Objective To study the effects of folic acid on Notch signal pathway related genes and proteins in the brain tissues of adult rats with focal cerebral infarction,and to explore the effects mechanisms of folic acid on prevention and treatment of cerebral infarction at the molecular level.
Methods 48 adult male Sprague-Dawley rats were randomly divided into four groups according to body mass.They were sham operation(SO),middle cerebral artery occlusion(MCAO),MCAO+low dose folic acid(MCAO+LFA),and MCAO +high dose folic acid(MCAO+HFA).There were 12 rats in each group.SO and MCAO group were supplemented by saline for 10ml/(kg bw·d),MCAO+LFA and MCAO+HFA group were supplemented by folic acid for 4mg/(kg bw·d),12mg/(kg bw·d) respectively.The left cerebral infarction model was induced by occlusion of middle cerebral artery after 28-days folic acid supplementation.Serum folic acid concentration was measured with immune chemiluminescence before and after folic acid supplementation and after cerebral infarction.We observed the symptom and evaluated the neurological function on Zea longa five-point scale at 24h after the operation.And the brain infarction volume for the three rats of each group was detected by TTC staining method.Afler 3d,7d and 14d folic acid supplementation, the survival rats of each group were decapitated respectively and brains were rapidly removed and snap frozen in liquid nitrogen,frozen transverse sections were cut using a cryostat.The pathology change of brain was examined by hematoxylin-eosin(HE) staining at 3d.The expression levels of Notch1,Hes1,Hes5,Mash1,Neurogeninl and Neurogenin2 mRNA were detected by fluorescence in situ hybridization(FISH) method.The expression levels of Notch1,Hes1 and Hes5 proteins were detected by western blot method.
Results The survival rats with focal cerebral infarction had the symptoms of Homer in left side,and the scores of neurological function were in 1 to 3,which showed that modeling was successful.The detection results showed that the concentration of serum folic acid in MCAO group was lower than that in SO group after cerebral infarction,and significantly lower than that in MCAO+LFA and MCAO+HFA group,and MCAO+LFA was lower than MCAO+HFA group before and after cerebral infarction(P＜0.05).There was significantly different between before and after cerebral infarction in MCAO,MCAO+LFA and MCAO+HFA groups respectively(P＜0.05).TTC staining showed that the ratio of infarction volume in MCAO was significantly higher than that in MCAO+LFA and MCAO+HFA group(P＜0.05).HE staining showed that neural cells were arranged orderly and intact in shape in SO group,the neural cells of infarction zone in MCAO group were necrosis,arranged asymmetrically,the cellular interspaces widened,the volume of some cells decreased with nuclear pyknosisand dyed darkly.While the pathology changes in the groups of folic acid supplementation were lighter than that in MCAO group.The results of fluorescence in situ hybridization showed that the expressions of related genes in notch signal pathway in rats with focal cerebral infarction were all detected at 3d.The expression levels of Notch1,and Hes5 mRNA were highest at 7d,and lowest at 14d.And that of Hes1 mRNA was highest at the time point of 14d.The fluorescence intensity of positive cells of the three genes in SO group were lower than that in MCAO group at each time point(P＜0.05),MCAO was lower than that in MCAO +LFA and MCAO+LFA group,and MCAO+LFA was lower than that in MCAO+LFA group at 7d and 14d(P＜0.05).The expression levels of Mash1,Neurogenin1 and Neurogenin2 mRNA in rats with focal cerebral infarction were lowest at 7d and highest at 14d.The fluorescence intensity of positive cells of Mash1 mRNA in MCAO group was significantly different from SO,MCAO+LFA and MCAO+HFA group(P＜0.05),and MCAO+LFA group was higher than that in MCAO+HFA group at 3d and 14d(P＜0.05).The fluorescence intensity of positive cells of Neurogenin1 mRNA in MCAO group were higher than that in MCAO+LFA group at 3d and 14d,and higher than that in MCAO+HFA group at each time point (P＜0.05),the MCAO+LFA group was higher than that in MCAO+HFA group at 7d and 14d(P＜0.05).The fluorescence intensity of positive cells of Neurogenin2 mRNA in SO group was lower than that in MCAO group at 3d and 14d,and MCAO group was higher than that in MCAO+LFA group(P＜0.05),and both of the two groups were all higher than that in MCAO+HFA group(P＜0.05).The results of western blot showed that the expression levels of Notch1,Hes1,Hes5 proteins were consistent with that of their genes respectively.And the expression levels of these three proteins in MCAO group were all lower than that in MCAO+LFA and MCAO+HFA group at 7d and 14d(P＜0.05),the expression levels of Notch1 and Hes1 proteins in MCAO+LFA group were all lower than that in MCAO+HFA group at the same time points(P＜0.05),the expression level of Hes5 protein in MCAO+LFA group was lower than that in MCAO+HFA group at 7d.
Conclusion The focal cerebral infarction model of rats was established successfully by thread method.It showed that cerebral infarction can decrease the concentration of serum folic acid,and folic acid supplementation can increase the concentration of serum folic acid of rats,decrease the volume of cerebral infarction, and protect the neuron from necrosis,there was a dose-dependent relation. Supplementation of folic acid can promote the mRNA and protein expressions of Notch1,Hes1 and Hes5,decrease the mRNA expressions of Mash1,Neurogenin1 and Neurogenin2.Folic acid can enhance the therapy and recovery of cerebral infarction.
方法本实验采用成年SD大鼠48只,按体重随机分为假手术组(sham operationgroup,SO),大脑中动脉闭塞模型组(middle cerebral artery occlusion,MCAO),MCAO+叶酸低剂量组(MCAO+low dose folic acid,MCAO+LFA),MCAO+叶酸高剂量组(MCAO+high dose folic acid,MCAO+HFA),每组12只。其中SO组和MCAO组灌胃生理盐水10ml/(kg bw·d),MCAO+LFA组和MCAO+HFA组分别灌胃叶酸溶液4mg/(kg bw·d),12mg/(kg bw·d)。预防性补充叶酸28d后,除SO组外其他三组均采用线栓法制备左侧脑梗塞模型。补充叶酸前、补充28d后及脑梗塞后采取血清,化学发光免疫分析法测定血清中叶酸含量;模型建立24h后进行神经功能评分,每组各取3只大鼠断头取脑TTC染色测定脑梗塞体积;其余脑梗塞大鼠继续补充叶酸3d、7d、14d后断头处死,取出脑组织制作冰冻切片,HE染色观察脑梗塞后3d脑组织病理学变化;荧光原位杂交法测定各时间点Notch信号通路Noch1、Hes1、Hes5、Mash1、Neurogenin1、Neurogenin2mRNA的表达水平;Western blot法测定各时间点Notch1、Hes1、Hes5蛋白的表达水平。
结果脑梗塞模型建立后存活大鼠除SO组外均出现左侧Horner征,神经功能评分在1～3分之间,达到了模型成功标准。血清中叶酸含量测定结果显示:MCAO组于脑梗塞后低于SO组,叶酸补充28d及脑梗塞3d后MCAO组低于MCAO+LFA和MCAO+HFA组,且MCAO+LFA组低于MCAO+HFA组(P＜0.05),每组脑梗塞前后比较差异均有统计学意义(P＜0.05);TTC染色显示:MCAO组大鼠脑梗塞体积比值明显高于MCAO+LFA和MCAO+HFA组(P＜0.05);HE染色显示:SO组神经细胞排列整齐,形态完整;MCAO组梗塞区广泛的神经细胞坏死,细胞间隙变宽,排列紊乱,胞体缩小变形,染色加深,叶酸补充组神经细胞坏死及脑组织变性较MCAO组轻;荧光原位杂交结果显示:大鼠脑梗塞后补充叶酸3d Notch信号通路相关基因已经开始表达。其中Notch1,Hes5 mRNA的表达于梗塞7d达到高峰,14d下降,Hes1 mRNA在三个时间点间的表达呈上升趋势。三种基因阳性细胞荧光强度,各时间点SO组均低于MCAO组(P＜0.05);7d、14d点MCAO组低于MCAO+LFA组和MCAO+HFA组(P＜0.05),MCAO+LFA组低于MCAO+HFA组(P＜0.05)。Mash1,Neurogenin1,Neurogenin2 mRNA表达于梗塞后7d下降,14d上升。各时间点阳性细胞荧光强度:Mash1基因MCAO组与SO组、MCAO+LFA组、MCAO+HFA组比较差异均有统计学意义(P＜0.05);3d、14d点MCAO+LFA组高于MCAO+HFA组(P＜0.05)。Neurogenin1基因3d、14d点MCAO组高于MCAO+LFA组,各时间点均高于MCAO+HFA组(P＜0.05);7d、14d点MCAO+LFA组均高于MCAO+HFA组(P＜0.05)。Neurogenin2基因3d、14d点SO组均低于MCAO组(P＜0.05);14d点MCAO组高于MCAO+LFA组(P＜0.05),各时间点两组均高于MCAO+HFA组(P＜0.05)。Western blot结果显示:Notch1,Hes1,Hes5蛋白的表达趋势与其相应基因表达完全相同。三种蛋白表达量,7d、14d点MCAO组均低于MCAO+LFA组和MCAO+HFA组(P＜0.05);7d、14d点Notch1,Hes1蛋白MCAO+LFA组低于MCAO+HFA组;7d点Hes5蛋白表达MCAO+LFA组低于MCAO+HFA组(P＜0.05)。
结论本实验采用线栓法成功建立了大鼠局灶性脑梗塞模型,研究结果显示脑梗塞的发生可降低血清叶酸含量,补充叶酸可提高大鼠血清叶酸含量,降低脑梗塞体积,减轻梗塞造成的神经细胞损伤,并有一定的剂量反应关系。同时叶酸可能通过上调脑梗塞大鼠脑组织内Notch1、Hes1、Hes5 mRNA及其蛋白的表达,下调Mash1、Neurogenin1、Neurogenin2 mRNA的表达对大鼠脑梗塞的治疗及康复起一定的促进作用。
Objective To study the effects of folic acid on Notch signal pathway related genes and proteins in the brain tissues of adult rats with focal cerebral infarction,and to explore the effects mechanisms of folic acid on prevention and treatment of cerebral infarction at the molecular level.
Methods 48 adult male Sprague-Dawley rats were randomly divided into four groups according to body mass.They were sham operation(SO),middle cerebral artery occlusion(MCAO),MCAO+low dose folic acid(MCAO+LFA),and MCAO +high dose folic acid(MCAO+HFA).There were 12 rats in each group.SO and MCAO group were supplemented by saline for 10ml/(kg bw·d),MCAO+LFA and MCAO+HFA group were supplemented by folic acid for 4mg/(kg bw·d),12mg/(kg bw·d) respectively.The left cerebral infarction model was induced by occlusion of middle cerebral artery after 28-days folic acid supplementation.Serum folic acid concentration was measured with immune chemiluminescence before and after folic acid supplementation and after cerebral infarction.We observed the symptom and evaluated the neurological function on Zea longa five-point scale at 24h after the operation.And the brain infarction volume for the three rats of each group was detected by TTC staining method.Afler 3d,7d and 14d folic acid supplementation, the survival rats of each group were decapitated respectively and brains were rapidly removed and snap frozen in liquid nitrogen,frozen transverse sections were cut using a cryostat.The pathology change of brain was examined by hematoxylin-eosin(HE) staining at 3d.The expression levels of Notch1,Hes1,Hes5,Mash1,Neurogeninl and Neurogenin2 mRNA were detected by fluorescence in situ hybridization(FISH) method.The expression levels of Notch1,Hes1 and Hes5 proteins were detected by western blot method.
Results The survival rats with focal cerebral infarction had the symptoms of Homer in left side,and the scores of neurological function were in 1 to 3,which showed that modeling was successful.The detection results showed that the concentration of serum folic acid in MCAO group was lower than that in SO group after cerebral infarction,and significantly lower than that in MCAO+LFA and MCAO+HFA group,and MCAO+LFA was lower than MCAO+HFA group before and after cerebral infarction(P＜0.05).There was significantly different between before and after cerebral infarction in MCAO,MCAO+LFA and MCAO+HFA groups respectively(P＜0.05).TTC staining showed that the ratio of infarction volume in MCAO was significantly higher than that in MCAO+LFA and MCAO+HFA group(P＜0.05).HE staining showed that neural cells were arranged orderly and intact in shape in SO group,the neural cells of infarction zone in MCAO group were necrosis,arranged asymmetrically,the cellular interspaces widened,the volume of some cells decreased with nuclear pyknosisand dyed darkly.While the pathology changes in the groups of folic acid supplementation were lighter than that in MCAO group.The results of fluorescence in situ hybridization showed that the expressions of related genes in notch signal pathway in rats with focal cerebral infarction were all detected at 3d.The expression levels of Notch1,and Hes5 mRNA were highest at 7d,and lowest at 14d.And that of Hes1 mRNA was highest at the time point of 14d.The fluorescence intensity of positive cells of the three genes in SO group were lower than that in MCAO group at each time point(P＜0.05),MCAO was lower than that in MCAO +LFA and MCAO+LFA group,and MCAO+LFA was lower than that in MCAO+LFA group at 7d and 14d(P＜0.05).The expression levels of Mash1,Neurogenin1 and Neurogenin2 mRNA in rats with focal cerebral infarction were lowest at 7d and highest at 14d.The fluorescence intensity of positive cells of Mash1 mRNA in MCAO group was significantly different from SO,MCAO+LFA and MCAO+HFA group(P＜0.05),and MCAO+LFA group was higher than that in MCAO+HFA group at 3d and 14d(P＜0.05).The fluorescence intensity of positive cells of Neurogenin1 mRNA in MCAO group were higher than that in MCAO+LFA group at 3d and 14d,and higher than that in MCAO+HFA group at each time point (P＜0.05),the MCAO+LFA group was higher than that in MCAO+HFA group at 7d and 14d(P＜0.05).The fluorescence intensity of positive cells of Neurogenin2 mRNA in SO group was lower than that in MCAO group at 3d and 14d,and MCAO group was higher than that in MCAO+LFA group(P＜0.05),and both of the two groups were all higher than that in MCAO+HFA group(P＜0.05).The results of western blot showed that the expression levels of Notch1,Hes1,Hes5 proteins were consistent with that of their genes respectively.And the expression levels of these three proteins in MCAO group were all lower than that in MCAO+LFA and MCAO+HFA group at 7d and 14d(P＜0.05),the expression levels of Notch1 and Hes1 proteins in MCAO+LFA group were all lower than that in MCAO+HFA group at the same time points(P＜0.05),the expression level of Hes5 protein in MCAO+LFA group was lower than that in MCAO+HFA group at 7d.
Conclusion The focal cerebral infarction model of rats was established successfully by thread method.It showed that cerebral infarction can decrease the concentration of serum folic acid,and folic acid supplementation can increase the concentration of serum folic acid of rats,decrease the volume of cerebral infarction, and protect the neuron from necrosis,there was a dose-dependent relation. Supplementation of folic acid can promote the mRNA and protein expressions of Notch1,Hes1 and Hes5,decrease the mRNA expressions of Mash1,Neurogenin1 and Neurogenin2.Folic acid can enhance the therapy and recovery of cerebral infarction.
引文
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