参麦注射液对急性缺血性脑卒中大鼠脑可塑性影响的研究
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摘要
目的
探讨参麦注射液对局灶性脑缺血再灌注大鼠脑梗死灶周围大脑皮质可塑性的影响及其作用机制。
方法
取健康Sprague-Dawley大鼠264只,雌雄各半,随机抽取空白组、假手术组各6只大鼠,其余大鼠采用栓线法制作大鼠局灶性脑缺血再灌注模型,造模成功的大鼠随机分入模型组、三七皂苷对照组和参麦注射液低、中、高剂量治疗组,每组分3、7、14天三个时间段,每组每段6只大鼠,观察以下指标：①神经行为学观察：Bederson评分、肌力测定、平衡木实验评分；参麦注射液不同剂量与术后不同时间点Bederson评分的回归分析；②HE染色后光镜下观察病理形态学变化,电镜下观察神经元及突触超微结构,免疫组化染色观察GAP-43蛋白和SYP蛋白阳性表达情况,并分别作与Bederson评分的相关性分析；③RT-PCR方法检测BDNF mRNA和Nogo-A mRNA表达,并分别作与Bederson评分的相关性分析。
结果
①Bederson评分：造模各组在术后第1天,Bederson评分均高于假手术组,差异有极显著性(P<0.01)；术后3天,参麦注射液各剂量组评分低于模型组,但尚无统计学差异(P>0.05)；术后7天,参麦注射液中、高剂量组与模型组比较有显著差异(P<0.05)；术后14天,参麦注射液中剂量组大部分鼠已恢复到假手术组的功能状态,与模型组及三七组比较均有显著差异(P<0.05)。②肌力评定：术后第3天,各造模组大鼠肌力开始恢复,参麦注射液中剂量组评分已高于其余各组,差异有显著性(P<0.05),术后7天各用药组肌力较模型组有明显改善(P<0.05),尤其参麦注射液中剂量组改善最明显,与模型组比较差异有极显著性(P<0.01)；术后第14天,参麦中、高剂量组肌力已恢复正常,与模型组比较差异有极显著性(P<0.01)。③平衡木试验：术后7d,参麦注射液中、高剂量组得分明显低于其它实验组,差异有显著性(P<0.05);术后14d时,参麦注射液中、高剂量组得分均明显低于模型组(P<0.01),其中参麦注射液中剂量组改善最明显,得分低于三七组(P<0.05)。④多分类Logistic回归分析：经处理得到参麦注射液不同剂量和术后不同时间点Bederson评分的线性预测方程,剂量、恢复时间点回归系数均为正值,且其回归系数经假设检验均有统计学意义(p<0.05,p<0.01)。⑤电镜结果：造模后14天参麦注射液组脑梗死灶周围大脑皮质的突触数目大于模型组,差异有显著性(P<0.05),其突触后膜致密物厚度大于模型组(P<0.01)和三七组(p<0.05),与假手术组差异无显著性(p>0.05)。⑥GAP-43阳性表达：术后3天,参麦注射液各剂量组较模型组均升高,差异有显著性(p<0.05)；术后7天时,各组GAP-43表达均呈下降趋势,参麦注射液各组与三七组均高于模型组,差异均有极显著性(P<0.01)；术后14天,参麦注射液中、高剂量组GAP-43表达水平仍高于模型组(p<0.05),三七组已接近模型组水平(p>0.05)。⑦SYP阳性表达情况：术后7天,参麦注射液各剂量组SYP表达显著高于模型组(P<0.01)；术后14天,参麦各剂量组SYP表达仍显著高于模型组(P<0.01),其中参麦中剂量组高于三七组(P<0.05)。⑧BDNF mRNA表达：术后3天,参麦注射液组BDNF mRNA表达高于模型组,差异有极显著性(p<0.01)；术后7天时,各组BDNF mRNA表达均呈下降趋势,与模型组比较参麦注射液组与三七组均处于较高水平(P<0.01)；术后14天,参麦注射液组BDNF mRNA表达水平仍显著高于模型组(p<0.01),三七组已接近模型组水平(p>0.05)。⑨Nogo-A mRNA表达：术后3天参麦注射液组Nogo-A mRNA表达即低于模型组,差异有显著性(P<0.05)；术后7天,参麦注射液组Nogo-A mRNA表达仍低于模型组(P<0.05)；术后14天,参麦注射液组与三七组及模型组Nogo-A mRNA比较均无差异(P>0.05)。⑩等级相关分析：术后3天,神经功能恢复与GAP-43表达成正相关(p<0.01),与SYP表达不相关(p>0.05),与BDNF mRNA表达成正相关(p<0.01),与Nogo-A mRNA表达成负相关(p<0.01)；术后7天,神经功能恢复与GAP-43、SYP表达成正相关(p<0.01),与BDNF mRNA表达成正相关(p<0.01),与Nogo-A mRNA表达成负相关(p<0.01)；术后14天,神经功能恢复与GAP-43表达不相关(p>0.05),与SYP表达成正相关(p<0.01),与BDNF mRNA成较弱的正相关(p<0.05),与Nogo-A mRNA表达成正相关(p<0.01)。
结论
①大鼠脑缺血损伤后缺损神经功能随时间延长逐渐恢复,其机制与脑缺血后继发的脑可塑性有关。②参麦注射液治疗可加速神经运动功能恢复进程；参麦注射液中剂量更加有效。③急性缺血性脑卒中早期给予参麦注射液对于尽早促进神经康复有益；参麦注射液在脑缺血后可以长时间给药,对于促进脑缺血后期的神经康复也是有益的。④脑缺血后GAP-43、SYP蛋白表达增高,参麦注射液可提高GAP-43、SYP蛋白水平表达并促进缺血灶周围大脑皮质神经元轴突生长及突触重构。⑤脑缺血早期参麦注射液引起的神经功能恢复与GAP-43表达增高高度相关,而后期与SYP表达增高高度相关。⑥参麦注射液可上调BDNF mRNA表达并下调Nogo-A mRNA表达。⑦脑缺血后神经功能恢复与BDNF mRNA表达呈现从高到低的正相关性；而与Nogo-A mRNA表达早期呈负相关性,随后其负相关性下降,后期呈正相关性,体现了脑组织对于缺血性损伤和修复这一病理生理过程的复杂而精细的调节机制。
Objective:To study the effect of ShenMai injection on neuronal plasticity and mechanism of action after Focal Cerebral Ischemia Reperfusion Injury in rats.
Methods:132 male and 132 female SD rats were randomly divided into sham operation group, MCAO/R(middle cerebral artery occlusion/reperfusion) model group, Shenmai injection therapy group and the positive medicine control group (Panax pseudo-ginseng saponin). According to different drawing materials time there was 3 days,7 days, and 14 days time point after cerebral ischemia in each group, with 6 cases in each time point.Thread-induced occlusion of the middle cerebral artery was performed to establish the model of focal cerebral ischemia in model group, control group and Shenmai injection therapy group, but the middle cerebral arteries were exposed without occlusion in sham group. Panax pseudo-ginseng saponin or Shenmai injection was respectively applied to intraperitoneal injection six hours after surgery in corresponding group, while Sodium Chloride to the sham and model groups. The treatment was given once daily. Neurological deficit scores were observed in every group. then these rats were killed to be breaken out brain tissues as specimens after which were treated with medicine in 3,7,14 days. Synaptic number, the thickness of postsynaptic density (PSD) were observed by using transmission electronic microscope in the marginal zone of focal cerebral ischemia in rats. Immunhistochemistry was carried out to investigate the changes of neuronal plasticity markers GAP-43 and SYP protein, while RT-PCR was set up to detect the BDNF mRNA and Nogo-A mRNA variety of cerebrum cortex.
Results:There were no obvious differences in neuroethology among these surgery groups at 1 day. Neurological deficit symptoms were aggravated in model group at 3 day,, and compared with that in model group, neurological deficit scores of Shenmai injection middle dose treatment groups significantly increased in muscle power tests (P<0.05). At 7days and 14 days, neurological deficit scores in all of Shenmai injection treated groups obviously better than those in model group (P<0.05). Logistic regression analysis showed that the Shenmai injection middle dose treatment group winned the best therapeutic effect in improving some nervous deficit symptoms after cerebral ischemia in rats. The level of GAP-43 expression was increased rapidly 3 days after MCAO/R injury and then decreased gradually, while the SYP was decreased at first and then increased obviously at about 7 days after MCAO/R injury. the level of BDNF mRNA expression was increased immediately after MCAO/R injury and then decreased gradually, while the Nogo-A mRNA was decreased at first and then increased obviously at about 14 days after MCAO/R injury. Compared with the model group and the positive control group, Shenmai injection treated groups could obviously increase GAP-43 and SYP protein amount, up-regulate the expression of BDNF mRNA and down-regulate Nogo-A mRNA that in the cerebrum cortex at different period after rats MCAO/R injury(P<0.05). Rank correlation analysis revealed that there was a closely correlation between the changes of Bederson neurological deficit scores and GAP-43 protein, SYP protein, BDNF mRNA and Nogo-A mRNA respectively at 3 days,7 days and 14 days after cerebral ischemia.
Conclusion:Neurologic impairment and pathomorphology changes of rats have the trend of self-repair after ischemic brain damage. The development and outcome of brain damage is affected by synaptic plasticity, reactive changes of GAP-43 protein, SYP protein, BDNF mRNA andogo-A mRNA, which indicates that brain plasticity is taken place after brain damage. ShenMai injection can improve brain plasticity and can be used as a therapy method after cerebral ischemia injury.
探讨参麦注射液对局灶性脑缺血再灌注大鼠脑梗死灶周围大脑皮质可塑性的影响及其作用机制。
方法
取健康Sprague-Dawley大鼠264只,雌雄各半,随机抽取空白组、假手术组各6只大鼠,其余大鼠采用栓线法制作大鼠局灶性脑缺血再灌注模型,造模成功的大鼠随机分入模型组、三七皂苷对照组和参麦注射液低、中、高剂量治疗组,每组分3、7、14天三个时间段,每组每段6只大鼠,观察以下指标：①神经行为学观察：Bederson评分、肌力测定、平衡木实验评分；参麦注射液不同剂量与术后不同时间点Bederson评分的回归分析；②HE染色后光镜下观察病理形态学变化,电镜下观察神经元及突触超微结构,免疫组化染色观察GAP-43蛋白和SYP蛋白阳性表达情况,并分别作与Bederson评分的相关性分析；③RT-PCR方法检测BDNF mRNA和Nogo-A mRNA表达,并分别作与Bederson评分的相关性分析。
结果
①Bederson评分：造模各组在术后第1天,Bederson评分均高于假手术组,差异有极显著性(P<0.01)；术后3天,参麦注射液各剂量组评分低于模型组,但尚无统计学差异(P>0.05)；术后7天,参麦注射液中、高剂量组与模型组比较有显著差异(P<0.05)；术后14天,参麦注射液中剂量组大部分鼠已恢复到假手术组的功能状态,与模型组及三七组比较均有显著差异(P<0.05)。②肌力评定：术后第3天,各造模组大鼠肌力开始恢复,参麦注射液中剂量组评分已高于其余各组,差异有显著性(P<0.05),术后7天各用药组肌力较模型组有明显改善(P<0.05),尤其参麦注射液中剂量组改善最明显,与模型组比较差异有极显著性(P<0.01)；术后第14天,参麦中、高剂量组肌力已恢复正常,与模型组比较差异有极显著性(P<0.01)。③平衡木试验：术后7d,参麦注射液中、高剂量组得分明显低于其它实验组,差异有显著性(P<0.05);术后14d时,参麦注射液中、高剂量组得分均明显低于模型组(P<0.01),其中参麦注射液中剂量组改善最明显,得分低于三七组(P<0.05)。④多分类Logistic回归分析：经处理得到参麦注射液不同剂量和术后不同时间点Bederson评分的线性预测方程,剂量、恢复时间点回归系数均为正值,且其回归系数经假设检验均有统计学意义(p<0.05,p<0.01)。⑤电镜结果：造模后14天参麦注射液组脑梗死灶周围大脑皮质的突触数目大于模型组,差异有显著性(P<0.05),其突触后膜致密物厚度大于模型组(P<0.01)和三七组(p<0.05),与假手术组差异无显著性(p>0.05)。⑥GAP-43阳性表达：术后3天,参麦注射液各剂量组较模型组均升高,差异有显著性(p<0.05)；术后7天时,各组GAP-43表达均呈下降趋势,参麦注射液各组与三七组均高于模型组,差异均有极显著性(P<0.01)；术后14天,参麦注射液中、高剂量组GAP-43表达水平仍高于模型组(p<0.05),三七组已接近模型组水平(p>0.05)。⑦SYP阳性表达情况：术后7天,参麦注射液各剂量组SYP表达显著高于模型组(P<0.01)；术后14天,参麦各剂量组SYP表达仍显著高于模型组(P<0.01),其中参麦中剂量组高于三七组(P<0.05)。⑧BDNF mRNA表达：术后3天,参麦注射液组BDNF mRNA表达高于模型组,差异有极显著性(p<0.01)；术后7天时,各组BDNF mRNA表达均呈下降趋势,与模型组比较参麦注射液组与三七组均处于较高水平(P<0.01)；术后14天,参麦注射液组BDNF mRNA表达水平仍显著高于模型组(p<0.01),三七组已接近模型组水平(p>0.05)。⑨Nogo-A mRNA表达：术后3天参麦注射液组Nogo-A mRNA表达即低于模型组,差异有显著性(P<0.05)；术后7天,参麦注射液组Nogo-A mRNA表达仍低于模型组(P<0.05)；术后14天,参麦注射液组与三七组及模型组Nogo-A mRNA比较均无差异(P>0.05)。⑩等级相关分析：术后3天,神经功能恢复与GAP-43表达成正相关(p<0.01),与SYP表达不相关(p>0.05),与BDNF mRNA表达成正相关(p<0.01),与Nogo-A mRNA表达成负相关(p<0.01)；术后7天,神经功能恢复与GAP-43、SYP表达成正相关(p<0.01),与BDNF mRNA表达成正相关(p<0.01),与Nogo-A mRNA表达成负相关(p<0.01)；术后14天,神经功能恢复与GAP-43表达不相关(p>0.05),与SYP表达成正相关(p<0.01),与BDNF mRNA成较弱的正相关(p<0.05),与Nogo-A mRNA表达成正相关(p<0.01)。
结论
①大鼠脑缺血损伤后缺损神经功能随时间延长逐渐恢复,其机制与脑缺血后继发的脑可塑性有关。②参麦注射液治疗可加速神经运动功能恢复进程；参麦注射液中剂量更加有效。③急性缺血性脑卒中早期给予参麦注射液对于尽早促进神经康复有益；参麦注射液在脑缺血后可以长时间给药,对于促进脑缺血后期的神经康复也是有益的。④脑缺血后GAP-43、SYP蛋白表达增高,参麦注射液可提高GAP-43、SYP蛋白水平表达并促进缺血灶周围大脑皮质神经元轴突生长及突触重构。⑤脑缺血早期参麦注射液引起的神经功能恢复与GAP-43表达增高高度相关,而后期与SYP表达增高高度相关。⑥参麦注射液可上调BDNF mRNA表达并下调Nogo-A mRNA表达。⑦脑缺血后神经功能恢复与BDNF mRNA表达呈现从高到低的正相关性；而与Nogo-A mRNA表达早期呈负相关性,随后其负相关性下降,后期呈正相关性,体现了脑组织对于缺血性损伤和修复这一病理生理过程的复杂而精细的调节机制。
Objective:To study the effect of ShenMai injection on neuronal plasticity and mechanism of action after Focal Cerebral Ischemia Reperfusion Injury in rats.
Methods:132 male and 132 female SD rats were randomly divided into sham operation group, MCAO/R(middle cerebral artery occlusion/reperfusion) model group, Shenmai injection therapy group and the positive medicine control group (Panax pseudo-ginseng saponin). According to different drawing materials time there was 3 days,7 days, and 14 days time point after cerebral ischemia in each group, with 6 cases in each time point.Thread-induced occlusion of the middle cerebral artery was performed to establish the model of focal cerebral ischemia in model group, control group and Shenmai injection therapy group, but the middle cerebral arteries were exposed without occlusion in sham group. Panax pseudo-ginseng saponin or Shenmai injection was respectively applied to intraperitoneal injection six hours after surgery in corresponding group, while Sodium Chloride to the sham and model groups. The treatment was given once daily. Neurological deficit scores were observed in every group. then these rats were killed to be breaken out brain tissues as specimens after which were treated with medicine in 3,7,14 days. Synaptic number, the thickness of postsynaptic density (PSD) were observed by using transmission electronic microscope in the marginal zone of focal cerebral ischemia in rats. Immunhistochemistry was carried out to investigate the changes of neuronal plasticity markers GAP-43 and SYP protein, while RT-PCR was set up to detect the BDNF mRNA and Nogo-A mRNA variety of cerebrum cortex.
Results:There were no obvious differences in neuroethology among these surgery groups at 1 day. Neurological deficit symptoms were aggravated in model group at 3 day,, and compared with that in model group, neurological deficit scores of Shenmai injection middle dose treatment groups significantly increased in muscle power tests (P<0.05). At 7days and 14 days, neurological deficit scores in all of Shenmai injection treated groups obviously better than those in model group (P<0.05). Logistic regression analysis showed that the Shenmai injection middle dose treatment group winned the best therapeutic effect in improving some nervous deficit symptoms after cerebral ischemia in rats. The level of GAP-43 expression was increased rapidly 3 days after MCAO/R injury and then decreased gradually, while the SYP was decreased at first and then increased obviously at about 7 days after MCAO/R injury. the level of BDNF mRNA expression was increased immediately after MCAO/R injury and then decreased gradually, while the Nogo-A mRNA was decreased at first and then increased obviously at about 14 days after MCAO/R injury. Compared with the model group and the positive control group, Shenmai injection treated groups could obviously increase GAP-43 and SYP protein amount, up-regulate the expression of BDNF mRNA and down-regulate Nogo-A mRNA that in the cerebrum cortex at different period after rats MCAO/R injury(P<0.05). Rank correlation analysis revealed that there was a closely correlation between the changes of Bederson neurological deficit scores and GAP-43 protein, SYP protein, BDNF mRNA and Nogo-A mRNA respectively at 3 days,7 days and 14 days after cerebral ischemia.
Conclusion:Neurologic impairment and pathomorphology changes of rats have the trend of self-repair after ischemic brain damage. The development and outcome of brain damage is affected by synaptic plasticity, reactive changes of GAP-43 protein, SYP protein, BDNF mRNA andogo-A mRNA, which indicates that brain plasticity is taken place after brain damage. ShenMai injection can improve brain plasticity and can be used as a therapy method after cerebral ischemia injury.
引文
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