实验性脑出血大鼠出血量与NSE、S100的相关性及中医药干预的影响
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摘要
目的：在“八五”攻关课题的基础上,深入研究急性ICH出血量在临界范围内(<50ml),中医内科保守治疗的依据及机制；通过研究中药干预前后NSE、S1OO血清、蛋白表达及基因调控的变化,及其与出血量和神经功能损伤程度的相关性,初步确立脑出血实质发生损害时,血清发生敏感性、特异性变化的最佳临界点,并进一步探讨中医药治疗脑出血急性期的最佳出血量,及特异性、敏感性的诊断标准范围。
方法：(1)建立稳定、可行的大鼠脑出血模型,观察中药干预前后,大鼠神经功能缺损评分的改变,应用HE染色观察大鼠脑组织病理形态学的改变。(2)运用ELISA法检测血清NSE、S100的变化；运用免疫组化法检测NSE、S100的蛋白表达；运用RT-PCR法观察脑组织局部NSE、S10O蛋白mRNA的动态改变。(3)与前期的实验进行对比,观察不同出血量、不同出血时间与血清的动态改变之间的相关性；确立脑实质发生损害时,血清变化的临界点以及中医药治疗急性脑出血的最佳出血量,最佳诊断标准。
结果：(1)造模后第5天,与假手术组相比,模型组、治疗组神经功能缺损评分有极显著性差异(p<0.01)；在出血量相同的情况下,模型组神经功能缺损评分均高于治疗组,两者相比有显著性差异(p<0.05),随出血量的逐步增加,模型组和治疗组的神经功能缺损评分均呈逐渐增高趋势。(2)镜下HE染色显示,模型组及治疗组与假手术组相比,脑组织均有不同程度的破坏,但治疗组脑组织破坏情况远较模型组大鼠轻。(3)造模后5天,模型组和治疗组的血清NSE浓度水平,均高于假手术组,存在极显著性差异(p<0.01)；随出血量的逐渐增加,模型组和治疗组血清NSE浓度水平呈逐渐增高趋势；模型组组内比较,出血量40μl、53μl、67μl组均与出血量27μl组有极显著性差异(P<0.01),40μl、53μl、67μl组之间比较无显著差别(p>0.05)；应用中药治疗后,治疗组与模型组比较,治疗组的血清NSE浓度已较模型组降低,不同血量的出血组相比,在出血量为27μl、40μl时,治疗组与模型组之间存在极显著性差异(p<0.01),出血量为53μl时,治疗组与模型组之间存在显著性差异(p<0.05),出血量为67μl时治疗组与模型组之间无统计学意义。免疫组化结果显示除治疗组27μl外,其余各组大鼠脑组织NSE光密度高于假手术组,NSE表达增强;出血量越高,NSE表达越明显；中药治疗后,治疗组NSE表达较模型组降低,治疗组与模型组比较,出血量为27μl、40μl时更为明显(P<0.01)。NSE半定量PCR结果提示脑出血后5天,与假手术组相比,各模型组NSE的转录水平明显提高,且随着出血量的增多,呈逐渐上升的趋势,在出血量相同的情况下,与相应模型组相比,中药治疗组NSE的转录水平有所下降。(4)血清S100显示造模后5天,模型组、治疗组均高于假手术组；随出血量的增加,模型组和治疗组血清S100浓度水平呈逐渐增高趋势；在中药干预之后,血清S100浓度水平下降,特别是小出血量(27μ、l40μl)时更为明显(p<0.01)。免疫组化结果显示治疗组及模型组大鼠脑组织S100表达均高于假手术组,随出血量的增加,S100表达越明显；应用中药治疗后,治疗组S100表达较模型组降低。S100半定量PCR结果提示脑出血后5天,与假手术组相比,各模型组S100的转录水平明显提高,且随着出血量的增多,呈逐渐上升的趋势,在出血量相同的情况下,与相应模型组相比,中药治疗组S100的转录水平有所下降。(5)将出血后3天、5天的模型组大鼠血清NSE、S100浓度进行比较,发现大鼠血清浓度水平在出血量为27μl时,明显低于其他各组(p<0.01或p<0.05),当出血量达到40μl后,血清浓度虽然上升但已趋于平缓,出血量为40μl、53μl、67μl各组之间并无统计学差异(p>0.05)；中药治疗前后大鼠血清浓度比较,在出血量分别为27μl、40μl时,治疗组与模型组之间存在极显著性差异(p<0.01),在出血量为53μl及67μl时两组存在显著性差异(p<0.05)或无差异(p>0.05)；对血清NSE及S100浓度水平分别做ROC曲线(受试者工作特征曲线)分析,血清NSE浓度水平范围为19.95ng/ml-21.65ng/ml,血清S100浓度水平范围为6.3ng/ml-8.16ng/ml。
结论：(1)初步证实大鼠脑出血40μl(即人脑出血的出血量30ml)是脑实质发生损害时NSE、S100表达的突变临界点,为临床诊断提供了有价值的参考数据。(2)初步确立脑出血后3天是检测]NSE、S100的最佳敏感时点,为临床治疗提供了最佳诊断时机。(3)初步确立中药干预脑出血的最佳疗效出血量应小于大鼠脑出血40μl(即人脑出血的出血量30ml),为临床选择合理有效的治疗方法提供了依据。(4)初步证实了当血清NSE浓度水平在19.95ng/ml-21.65ng/ml范围内,血清S100浓度水平在6.3ng/ml-8.16ng/ml范围内时,是中药治疗脑出血的安全有效区间,为临床治疗提供了客观化的诊断标准。
Purpose:On the basis of Eighth Five Year's Plan",this research aims to investigate the evidence and mechanism of Chinese internal medicine coNSErvative treatment on ICH within critical amount of bleeding(<50ml);Research the change of NSE, serum S100, protein expression and regulation of gene expression before and after the TCM intervention and the correlation with the bleeding amount and NDS,which to confirm the optimum critical point of the sensibility and the specific change of serum when ICH causes damage on Brain Parenchyma, and to further probe into the correlation between the Traditional Chinese medical treatment and the optimum ICH critical amount of bleeding, and the diagnostic criteria in specificity and sensibility.
Method:(1) A stable and feasible ICH rats model is built to observe the NIHSS and brain tissue pathomorphology change before and after the intervention of Traditional Chinese Medicine. (2) By means of ELIS A to detect NSE and S100 serum values; By means of SP to detect the protein expression n brain tissue of NSE and S100 in brain tissue of positive expression; By means of RT-PCR to detect a dynamic change of mRNA regulation in brain tissue NSE、S100. (3)By comparing with the preliminary experiment, the amount of bleeding, the time of bleeding and the dynamic change can be observed and the critical point of serum change when the brain parenchyma is damaged, and the optimum amount of bleeding and the best diagnostic criteria with the treatment of Traditional Chinese Medicine can be confirmed.
Results:(1) Five days after the modeling,the model group,there is significant difference(p<0.01) in NIHSS between the model group and the treatment group with sham group. When the amount of bleeding are the same,the model group's NIHSS is higher than the treatment group and the difference is significant(P<0.05).With the gradual increasing of the amount of bleeding,NIHSS of model group and treatment group both have the trend of increasing. (2) The microscopic HE stain reveals that the brain tissues in the model group and the treatment group have been damaged when comparing with the sham group,but the level of the brain damage in treatment group is far less than that in model group.(3)Five days after the modeling,the serum NSE levels of model group and treatment group are higher than that of sham group.and the difference is significant (p<0.01).With the increase of bleeding amount, the serum level of the former two groups also increases. A comparison has been made inside the model group and there is significant difference (P<0.01) in the amount of bleeding between 40μl.53μl.67μl and 27μl, while there is no significant difference (P>0.05) betweer 40μl.53μl and 67μl.After using Traditional Chinese Medicine.when compared with the model group.the serum NSE level of the treatment group has been decreased;and in comparison with the different bleeding amount,there is significant difference (p<0.01) between model group and treatment group in 27μl> 40μl.When the bleeding amount is 53μl,there is significant difference(P<0.05)between model group and treatment group,and when the bleeding amount is 67μl,there is no statistic point between model group and treatment group.The result of immunohistochemistry shows that except 27μl in treatment group,the rats' brain tissue NSE optical density in other groups are higher than sham group.and NSE is increased;the more the bleeding amount is,the stronger the NSE;after using the Traditional Chinese Medicine.the NSE in treatment group is weaker than that of model group.when compared between model group and treatment group.the bleeding amount with 27μl>40μl is more significant(P<0.01). NSE semiquantitative PCR result indicates that five days after ICH,the levels of transcription of NSE in model groups increase significantly,with the increase of bleeding amount.it gradually increases.When the bleeding amount is the same,compared with the corresponding model group,NSE transcriptional level of TCM treatment group has been in decrease. (4)Five days after modeling.the serum S100 in model group and treatment group is higher than the sham group;with the increase of bleeding amount.the level of the serum S100 in model group and treatment group gradually increases.With the intervention of TCM, the level of serum S100 decreases,especially significant (P<0.01) in less bleeding amount (27μl、40μl).The result of SP shows that the rats'brain tissue S100 in treatment group and model group is higher than sham group. With the increase of bleeding amount.S100 is stronger;after TCM treatment 100 in treatment group decreased relatively compared with model group;S100 semiquantitative PCR result indicates that five days after ICH.S100 transcriptional level in model groups is stronger compared with sham group. With the increase of bleeding amount,it gradually increases. When the bleeding amount is the same, compared with the corresponding model group.S 100 transcriptional level of TCM treatment group has been in decrease. (5) Compared between NSE and S100 density level three days and five days after rats' ICH in model group,it is found that when the rats' bleeding amount is 27μl,the serum density level is lower than the other groups(P<0.01或P<0.05),when the bleeding amount reaches 40μl,the serum density level has been leveled off.And there is no statistic point in the bleeding amount between 40μL 53μl, and 67μl.There is significant difference (p<0.01) in rats'serum density level between treatment group and model group when the bleeding amount is 27μl and 40μl before and after TCM treatment.There is significant difference (p<0.05) or no significant difference (p>0.05) when the bleeding amount is 53μl and 67μl.When the ROC curve analysis is made in serum NSE and S100 density level,serum NSE density level ranges from 19.95ng/ml to 21.65ng/ml,and the serum S100 density level ranges from 6.3ng/ml to 8.16ng/ml.
Conclusion:(1) It preliminarily deduced that 40μl in ICH rats (i.e.30ml in human ICH) is the critical point of specificity and sensitivity of NSE and S100 when the brain parenchyma has been damaged, which provides the valuable reference data for clinical diagnosis. (2) It preliminarily established that the optimum sensitive point of Detection of NSE and S100 is three days after ICH. which provides the best treatment for clinical diagnosis of opportunity. (3) It preliminarily deduced that less than 40μl in ICH rats (i.e.30ml in human ICH) is the best curative effect with TCM on ICH, which provides the basis for clinical choose reasonable and effective treatment methods. (4) It preliminarily deduced that when the serum NSE density level is between 19.95ng/ml-21.65ng/ml and the serum S100 density level is between 6.3ng/ml-8.16ng/ml, that is the safe and effective interval with TCM on ICH and which provides the objective diagnostic criteria for clinical treatments.
方法：(1)建立稳定、可行的大鼠脑出血模型,观察中药干预前后,大鼠神经功能缺损评分的改变,应用HE染色观察大鼠脑组织病理形态学的改变。(2)运用ELISA法检测血清NSE、S100的变化；运用免疫组化法检测NSE、S100的蛋白表达；运用RT-PCR法观察脑组织局部NSE、S10O蛋白mRNA的动态改变。(3)与前期的实验进行对比,观察不同出血量、不同出血时间与血清的动态改变之间的相关性；确立脑实质发生损害时,血清变化的临界点以及中医药治疗急性脑出血的最佳出血量,最佳诊断标准。
结果：(1)造模后第5天,与假手术组相比,模型组、治疗组神经功能缺损评分有极显著性差异(p<0.01)；在出血量相同的情况下,模型组神经功能缺损评分均高于治疗组,两者相比有显著性差异(p<0.05),随出血量的逐步增加,模型组和治疗组的神经功能缺损评分均呈逐渐增高趋势。(2)镜下HE染色显示,模型组及治疗组与假手术组相比,脑组织均有不同程度的破坏,但治疗组脑组织破坏情况远较模型组大鼠轻。(3)造模后5天,模型组和治疗组的血清NSE浓度水平,均高于假手术组,存在极显著性差异(p<0.01)；随出血量的逐渐增加,模型组和治疗组血清NSE浓度水平呈逐渐增高趋势；模型组组内比较,出血量40μl、53μl、67μl组均与出血量27μl组有极显著性差异(P<0.01),40μl、53μl、67μl组之间比较无显著差别(p>0.05)；应用中药治疗后,治疗组与模型组比较,治疗组的血清NSE浓度已较模型组降低,不同血量的出血组相比,在出血量为27μl、40μl时,治疗组与模型组之间存在极显著性差异(p<0.01),出血量为53μl时,治疗组与模型组之间存在显著性差异(p<0.05),出血量为67μl时治疗组与模型组之间无统计学意义。免疫组化结果显示除治疗组27μl外,其余各组大鼠脑组织NSE光密度高于假手术组,NSE表达增强;出血量越高,NSE表达越明显；中药治疗后,治疗组NSE表达较模型组降低,治疗组与模型组比较,出血量为27μl、40μl时更为明显(P<0.01)。NSE半定量PCR结果提示脑出血后5天,与假手术组相比,各模型组NSE的转录水平明显提高,且随着出血量的增多,呈逐渐上升的趋势,在出血量相同的情况下,与相应模型组相比,中药治疗组NSE的转录水平有所下降。(4)血清S100显示造模后5天,模型组、治疗组均高于假手术组；随出血量的增加,模型组和治疗组血清S100浓度水平呈逐渐增高趋势；在中药干预之后,血清S100浓度水平下降,特别是小出血量(27μ、l40μl)时更为明显(p<0.01)。免疫组化结果显示治疗组及模型组大鼠脑组织S100表达均高于假手术组,随出血量的增加,S100表达越明显；应用中药治疗后,治疗组S100表达较模型组降低。S100半定量PCR结果提示脑出血后5天,与假手术组相比,各模型组S100的转录水平明显提高,且随着出血量的增多,呈逐渐上升的趋势,在出血量相同的情况下,与相应模型组相比,中药治疗组S100的转录水平有所下降。(5)将出血后3天、5天的模型组大鼠血清NSE、S100浓度进行比较,发现大鼠血清浓度水平在出血量为27μl时,明显低于其他各组(p<0.01或p<0.05),当出血量达到40μl后,血清浓度虽然上升但已趋于平缓,出血量为40μl、53μl、67μl各组之间并无统计学差异(p>0.05)；中药治疗前后大鼠血清浓度比较,在出血量分别为27μl、40μl时,治疗组与模型组之间存在极显著性差异(p<0.01),在出血量为53μl及67μl时两组存在显著性差异(p<0.05)或无差异(p>0.05)；对血清NSE及S100浓度水平分别做ROC曲线(受试者工作特征曲线)分析,血清NSE浓度水平范围为19.95ng/ml-21.65ng/ml,血清S100浓度水平范围为6.3ng/ml-8.16ng/ml。
结论：(1)初步证实大鼠脑出血40μl(即人脑出血的出血量30ml)是脑实质发生损害时NSE、S100表达的突变临界点,为临床诊断提供了有价值的参考数据。(2)初步确立脑出血后3天是检测]NSE、S100的最佳敏感时点,为临床治疗提供了最佳诊断时机。(3)初步确立中药干预脑出血的最佳疗效出血量应小于大鼠脑出血40μl(即人脑出血的出血量30ml),为临床选择合理有效的治疗方法提供了依据。(4)初步证实了当血清NSE浓度水平在19.95ng/ml-21.65ng/ml范围内,血清S100浓度水平在6.3ng/ml-8.16ng/ml范围内时,是中药治疗脑出血的安全有效区间,为临床治疗提供了客观化的诊断标准。
Purpose:On the basis of Eighth Five Year's Plan",this research aims to investigate the evidence and mechanism of Chinese internal medicine coNSErvative treatment on ICH within critical amount of bleeding(<50ml);Research the change of NSE, serum S100, protein expression and regulation of gene expression before and after the TCM intervention and the correlation with the bleeding amount and NDS,which to confirm the optimum critical point of the sensibility and the specific change of serum when ICH causes damage on Brain Parenchyma, and to further probe into the correlation between the Traditional Chinese medical treatment and the optimum ICH critical amount of bleeding, and the diagnostic criteria in specificity and sensibility.
Method:(1) A stable and feasible ICH rats model is built to observe the NIHSS and brain tissue pathomorphology change before and after the intervention of Traditional Chinese Medicine. (2) By means of ELIS A to detect NSE and S100 serum values; By means of SP to detect the protein expression n brain tissue of NSE and S100 in brain tissue of positive expression; By means of RT-PCR to detect a dynamic change of mRNA regulation in brain tissue NSE、S100. (3)By comparing with the preliminary experiment, the amount of bleeding, the time of bleeding and the dynamic change can be observed and the critical point of serum change when the brain parenchyma is damaged, and the optimum amount of bleeding and the best diagnostic criteria with the treatment of Traditional Chinese Medicine can be confirmed.
Results:(1) Five days after the modeling,the model group,there is significant difference(p<0.01) in NIHSS between the model group and the treatment group with sham group. When the amount of bleeding are the same,the model group's NIHSS is higher than the treatment group and the difference is significant(P<0.05).With the gradual increasing of the amount of bleeding,NIHSS of model group and treatment group both have the trend of increasing. (2) The microscopic HE stain reveals that the brain tissues in the model group and the treatment group have been damaged when comparing with the sham group,but the level of the brain damage in treatment group is far less than that in model group.(3)Five days after the modeling,the serum NSE levels of model group and treatment group are higher than that of sham group.and the difference is significant (p<0.01).With the increase of bleeding amount, the serum level of the former two groups also increases. A comparison has been made inside the model group and there is significant difference (P<0.01) in the amount of bleeding between 40μl.53μl.67μl and 27μl, while there is no significant difference (P>0.05) betweer 40μl.53μl and 67μl.After using Traditional Chinese Medicine.when compared with the model group.the serum NSE level of the treatment group has been decreased;and in comparison with the different bleeding amount,there is significant difference (p<0.01) between model group and treatment group in 27μl> 40μl.When the bleeding amount is 53μl,there is significant difference(P<0.05)between model group and treatment group,and when the bleeding amount is 67μl,there is no statistic point between model group and treatment group.The result of immunohistochemistry shows that except 27μl in treatment group,the rats' brain tissue NSE optical density in other groups are higher than sham group.and NSE is increased;the more the bleeding amount is,the stronger the NSE;after using the Traditional Chinese Medicine.the NSE in treatment group is weaker than that of model group.when compared between model group and treatment group.the bleeding amount with 27μl>40μl is more significant(P<0.01). NSE semiquantitative PCR result indicates that five days after ICH,the levels of transcription of NSE in model groups increase significantly,with the increase of bleeding amount.it gradually increases.When the bleeding amount is the same,compared with the corresponding model group,NSE transcriptional level of TCM treatment group has been in decrease. (4)Five days after modeling.the serum S100 in model group and treatment group is higher than the sham group;with the increase of bleeding amount.the level of the serum S100 in model group and treatment group gradually increases.With the intervention of TCM, the level of serum S100 decreases,especially significant (P<0.01) in less bleeding amount (27μl、40μl).The result of SP shows that the rats'brain tissue S100 in treatment group and model group is higher than sham group. With the increase of bleeding amount.S100 is stronger;after TCM treatment 100 in treatment group decreased relatively compared with model group;S100 semiquantitative PCR result indicates that five days after ICH.S100 transcriptional level in model groups is stronger compared with sham group. With the increase of bleeding amount,it gradually increases. When the bleeding amount is the same, compared with the corresponding model group.S 100 transcriptional level of TCM treatment group has been in decrease. (5) Compared between NSE and S100 density level three days and five days after rats' ICH in model group,it is found that when the rats' bleeding amount is 27μl,the serum density level is lower than the other groups(P<0.01或P<0.05),when the bleeding amount reaches 40μl,the serum density level has been leveled off.And there is no statistic point in the bleeding amount between 40μL 53μl, and 67μl.There is significant difference (p<0.01) in rats'serum density level between treatment group and model group when the bleeding amount is 27μl and 40μl before and after TCM treatment.There is significant difference (p<0.05) or no significant difference (p>0.05) when the bleeding amount is 53μl and 67μl.When the ROC curve analysis is made in serum NSE and S100 density level,serum NSE density level ranges from 19.95ng/ml to 21.65ng/ml,and the serum S100 density level ranges from 6.3ng/ml to 8.16ng/ml.
Conclusion:(1) It preliminarily deduced that 40μl in ICH rats (i.e.30ml in human ICH) is the critical point of specificity and sensitivity of NSE and S100 when the brain parenchyma has been damaged, which provides the valuable reference data for clinical diagnosis. (2) It preliminarily established that the optimum sensitive point of Detection of NSE and S100 is three days after ICH. which provides the best treatment for clinical diagnosis of opportunity. (3) It preliminarily deduced that less than 40μl in ICH rats (i.e.30ml in human ICH) is the best curative effect with TCM on ICH, which provides the basis for clinical choose reasonable and effective treatment methods. (4) It preliminarily deduced that when the serum NSE density level is between 19.95ng/ml-21.65ng/ml and the serum S100 density level is between 6.3ng/ml-8.16ng/ml, that is the safe and effective interval with TCM on ICH and which provides the objective diagnostic criteria for clinical treatments.
引文
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