脑缺血再灌注损伤神经保护策略研究
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摘要
目前，脑血管意外位居世界致死率排行榜的第二位。据我国卫生部统计数据，2009年脑血管病的城市死亡率为126.27/10万，占死亡人数的20.36%，农村为152.09/10万，占23.19%。意外幸存者的致残率也非常高。治疗的选择性小，风险高。对于缺血性脑血管意外，首要的是要恢复其血流供应，其后会发生脑缺血再灌注损伤。在脑缺血再灌注损伤进程的不同阶段起主导作用的可能有氧化损伤机制、免疫炎症机制、神经营养因子学说等，针对这些机制我们选用异丙酚、白介素1受体拮抗剂、PTD-BDNF，研究其对于脑缺血再灌注损伤后神经功能的保护作用，寻找合理的时间窗及神经保护因子组合。
异丙酚(2,6-Diisopropylphenol，propofol)是一种静脉麻醉药，具有抗氧化作用。在本研究中用于SH-SY5Y神经细胞缺糖缺氧再给氧模型（oxygen glucosedeprivation，OGD)后48h的流式细胞仪检测显示：异丙酚用药组与模型组比较SH-SY5Y神经细胞存活数量较多,晚期凋亡和死亡细胞减少。在海马细胞的OGD模型也有同样的结果。海马细胞钙成像试验显示异丙酚可以使钙内流延迟出现3-4min。在SD大鼠的大脑中动脉阻断模型（Middle Cerebral Artery Occlusion，MCAO)中，对于脑缺血大鼠的死亡率，体重恢复及神经症状改善情况最佳的为中异丙酚组，先异丙酚组次之，后异丙酚的体重恢复及神经症状改善情况与模型组没有统计学差异。中异丙酚组可提高SD大鼠MCAO后对Morris水迷宫的立体空间学习和记忆的能力，先、后异丙酚组不能提高。在随后的实验中，中异丙酚可减少脑梗死体积，HE染色显示异丙酚减少神经元凋亡和坏死，免疫印迹结果显示可增强脑中突触素（synaptophysin，syn）的表达。总之，先、后异丙酚应用对神经细胞保护也有一定程度的作用，但效果不及中异丙酚组明显。
白介素1受体拮抗剂（Interleukin-1receptor antagonist，IL-1RA)用于SH-SY5Y神经细胞OGD模型后48h的流式细胞仪检测显示：IL-1RA组与模型组比较SH-SY5Y神经细胞存活数量较多，晚期凋亡和死亡细胞减少，在海马细胞的OGD模型后也有同样结果。在不同时间点向细胞培养皿中加入IL-1RA均可以引起突触素的表达，增加GAP-43的表达。在MCAO模型，前IL-1RA组对MCAO大鼠死亡率改善不明显，中IL-1RA组可使死亡率较模型组明显降低，改善其体重恢复及神经症状，后IL-1RA组不仅不能降低死亡率，反而使其升高。。在对中IL-1RA组随后的实验中HE染色显示14天、21天后可以减少神经元凋亡和坏死，免疫组化和免疫印迹均显示可增强脑中突触素的表达。
脑源性神经营养因子(brain-derived neurotrophic factor，BDNF)与HIV-1反式激活蛋白(trans-activator transcription，TAT)中的蛋白转导区(protein transduc tiondomain， PTD)相连成重组的PTD-BDNF，用于SH-SY5Y神经细胞OGD模型后48h的流式细胞仪检测显示：PTD-BDNF组与模型组比较SH-SY5Y神经细胞存活数量较多，凋亡细胞减少，在海马细胞的OGD模型后也有同样结果。在海马细胞的OGD模型后，PTD-BDNF组与模型组比较细胞状态较好，CCK-8实验显示不同浓度PTD-BDNF可促进OGD后海马细胞的存活，在1-100ng/ml范围内呈浓度依赖性。PTD-BDNF可以使海马细胞突触素的表达增高。在MCAO模型，中、后PTD-BDNF组可使死亡率较模型组明显降低，改善其体重恢复及神经症状，先PTD-BDNF组没有降低死亡率，体重改善与神经症状评分也不及中、后PTD-BDNF组明显。中后PTD-BDNF组可提高SD大鼠MCAO后对Morris水迷宫的立体空间学习和记忆的能力，在随后的实验中，中PTD-BDNF组可以在7天、14天时增加脑中Brdu细胞的数量。免疫印迹显示PTD-BDNF可增强脑中突触素的表达。
联合应用不同因子组合实验中，在海马细胞免疫组化实验中，异丙酚联合IL-1RA组突触素表达不明显；异丙酚联合PTD-BDNF组、 PTD-BDNF联合IL-1RA组能明显增强突触素的表达。不同因子组合应用可增强GAP-43的表达。在MCAO大鼠模型中，不同因子组合死亡率、体重恢复及神经症状评分相对于单独应用有进一步的改善效果。
本研究表明异丙酚、白介素1受体拮抗剂、PTD-BDNF单独应用均可在细胞的OGD模型，SD大鼠的MCAO模型中显示神经保护作用，时间窗的选择以缺血后再灌注前1小时加入神经保护因子的神经细胞保护作用较好。不同因子组合在动物实验中显示，三种因子的各个组合联用相比单独应用有进一步的改善的作用。本研究为神经保护因子应用时合理的时间窗选择，应用因子组合后对于神经细胞的保护作用提供了实验依据。
At present, the disease of cerebral vascular which can upset millions of familieshas a high death and teratogenic rate with scant therapies. The treatment of acutephase is limited to reperfusion with tissue-type plasminogen activator or catheter. Aleading role in a different phase of cerebral ischemia and reperfusion injury processmay be the following mechanisms of oxidative damage, immune and inflammatorymechanisms, neurotrophic factor doctrine and so on. Focus on these mechanisms, wechose propofol, interleukin-1receptor antagonist and the PTD-BDNF as theprotective factor of each mechanism in cerebral ischemia and reperfusion injury. Weassume this study to work out which one is the best in the combinations among thedifferent factors and different inject time.
Propofol (2,6-Diisopropylphenol) is an intravenous anesthetic with the propertyof antioxidant. We confirm that propofol can increase the survival rate and reduce theapoptosis and death rate of SH-SY5Y cell after the oxygen glucose deprivation model(OGD) by flow cytometry analysis. The same consequence can be observed inhippocampal cell. Calcium imaging testes showed that propofol may delay theemergence of calcium influx for3-4min in Hippocampal cell. The SD rat middlecerebral artery occlusion model (MCAO) is regarded as the representative of cerebralischemia and reperfusion injury. We found that injecting propofol in the surgery canachieve the best protective effect compared with injecting propofol before the surgeryand after the surgery. Propofol injected in the surgery and before the surgery havepositive effects on the recovery of weight, the score of neurological symptoms andthree-dimensional space learning and memory ability of the Morris water maze. Propofol injected after the surgery compared with the model group have nostatistically significant. Propofol groups can decrease the infarct volume by HTTstaining, reduce neuronal apoptosis and necrosis by HE staining and enhance theexpression of brain synaptophysin. In a word, propofol protect nerve cells sufferingcerebral ischemia and reperfusion injury and injecting before reperfusion achieve thebest effcacy.
Interleukin-1receptor antagonist (IL-1RA) can increase the survival rate andreduce the apoptosis and death rate of SH-SY5Y cell after the oxygen glucosedeprivation model (OGD) by flow cytometry analysis. The same consequence can beobserved in hippocampal cell. IL-1RA can cause an increase the expression ofsynaptophysin and GAP-43. We found that intravenous injecting IL-1RA havepositive effects on the significantly low of the mortality, the recovery of weight, thescore of neurological symptoms and three-dimensional space learning and memoryability of the Morris water maze. On the opposite, the other intravenous injectingways increase the death risk in MCAO even achieve75%and have no benefits oncerebral ischemia and reperfusion injury. IL-1RA increase three-dimensional space ofthe Morris water maze learning and memory capacity in the14days MCAO model; In14days and21days after MCAO surgery, IL-1RA shows a reduction of neuronsapoptosis and necrosis and the enhancement of healthy side brain synaptophysinexpression by HE staining.
PTD-BDNF is the combination of Brain-derived neurotrophic factor (BDNF),and the protein transduction District (PTD) in HIV-1trans-activator protein (TAT).PTD-BDNF can increase the survival rate and reduce the apoptosis and death rate ofSH-SY5Y cell after the oxygen glucose deprivation model (OGD) by flowcytometry analysis. Different concentrations of CCK-8experiments showed that thePTD-of BDNF can promote the added value of the OGD hippocampal cells,concentration-dependent manner1-100ng/ml range. The PTD-of BDNF groupcompared with model group increase the survival of live cells and early apoptoticcells in hippocampal cell. PTD-BDNF can cause synaptophysin significantlyincreased, but the expression of GAP-43have no obvious increased. Intravenousinjecting PTD-BDNF in the surgery and after the surgery groups can reduce themortality, the body weight recovery and neurological symptoms. Intravenousinjecting PTD-BDNF before surgery can’t reach the same goal. PTD-BDNFincrease three-dimensional space of the Morris water maze learning and memory capacity in the7days MCAO model; In7days and14days after MCAO surgery,PTD-BDNF shows an addition of Brdu expression and the enhancement of brainsynaptophysin expression by Immunohistochemical staining.
In the Combination of different factors experiments, propofol and thePTD-BDNF can significantly improve expression of synaptophysin the byimmunohistochemistry staining compared with the other combination. Only in thecombination of IL-1RA and PTD-BDNF in the surgery and after the surgery canobserve the increase the GAP-43expression. For body weight recovery andneurological symptom score, the combination of three factors in MCAO model canachieve the best results.
This study shows that propofol, IL-1RA and PTD-BDNF can showneuroprotective effects and before reperfusion is the best choice of injecting time inrat MCAO model. Propofol and PTD-of BDNF, IL-1RA and the PTD-BDNF havethe additive effect using before the irrigation in the cell experiments. In animalexperiments, various combinations of the three factors compared to a solo applicationto have a more visible effect. In this study, the application of drug combinationsprovides the experimental basis for the neuroprotective in cerebral ischemia andreperfusion injury.
异丙酚(2,6-Diisopropylphenol，propofol)是一种静脉麻醉药，具有抗氧化作用。在本研究中用于SH-SY5Y神经细胞缺糖缺氧再给氧模型（oxygen glucosedeprivation，OGD)后48h的流式细胞仪检测显示：异丙酚用药组与模型组比较SH-SY5Y神经细胞存活数量较多,晚期凋亡和死亡细胞减少。在海马细胞的OGD模型也有同样的结果。海马细胞钙成像试验显示异丙酚可以使钙内流延迟出现3-4min。在SD大鼠的大脑中动脉阻断模型（Middle Cerebral Artery Occlusion，MCAO)中，对于脑缺血大鼠的死亡率，体重恢复及神经症状改善情况最佳的为中异丙酚组，先异丙酚组次之，后异丙酚的体重恢复及神经症状改善情况与模型组没有统计学差异。中异丙酚组可提高SD大鼠MCAO后对Morris水迷宫的立体空间学习和记忆的能力，先、后异丙酚组不能提高。在随后的实验中，中异丙酚可减少脑梗死体积，HE染色显示异丙酚减少神经元凋亡和坏死，免疫印迹结果显示可增强脑中突触素（synaptophysin，syn）的表达。总之，先、后异丙酚应用对神经细胞保护也有一定程度的作用，但效果不及中异丙酚组明显。
白介素1受体拮抗剂（Interleukin-1receptor antagonist，IL-1RA)用于SH-SY5Y神经细胞OGD模型后48h的流式细胞仪检测显示：IL-1RA组与模型组比较SH-SY5Y神经细胞存活数量较多，晚期凋亡和死亡细胞减少，在海马细胞的OGD模型后也有同样结果。在不同时间点向细胞培养皿中加入IL-1RA均可以引起突触素的表达，增加GAP-43的表达。在MCAO模型，前IL-1RA组对MCAO大鼠死亡率改善不明显，中IL-1RA组可使死亡率较模型组明显降低，改善其体重恢复及神经症状，后IL-1RA组不仅不能降低死亡率，反而使其升高。。在对中IL-1RA组随后的实验中HE染色显示14天、21天后可以减少神经元凋亡和坏死，免疫组化和免疫印迹均显示可增强脑中突触素的表达。
脑源性神经营养因子(brain-derived neurotrophic factor，BDNF)与HIV-1反式激活蛋白(trans-activator transcription，TAT)中的蛋白转导区(protein transduc tiondomain， PTD)相连成重组的PTD-BDNF，用于SH-SY5Y神经细胞OGD模型后48h的流式细胞仪检测显示：PTD-BDNF组与模型组比较SH-SY5Y神经细胞存活数量较多，凋亡细胞减少，在海马细胞的OGD模型后也有同样结果。在海马细胞的OGD模型后，PTD-BDNF组与模型组比较细胞状态较好，CCK-8实验显示不同浓度PTD-BDNF可促进OGD后海马细胞的存活，在1-100ng/ml范围内呈浓度依赖性。PTD-BDNF可以使海马细胞突触素的表达增高。在MCAO模型，中、后PTD-BDNF组可使死亡率较模型组明显降低，改善其体重恢复及神经症状，先PTD-BDNF组没有降低死亡率，体重改善与神经症状评分也不及中、后PTD-BDNF组明显。中后PTD-BDNF组可提高SD大鼠MCAO后对Morris水迷宫的立体空间学习和记忆的能力，在随后的实验中，中PTD-BDNF组可以在7天、14天时增加脑中Brdu细胞的数量。免疫印迹显示PTD-BDNF可增强脑中突触素的表达。
联合应用不同因子组合实验中，在海马细胞免疫组化实验中，异丙酚联合IL-1RA组突触素表达不明显；异丙酚联合PTD-BDNF组、 PTD-BDNF联合IL-1RA组能明显增强突触素的表达。不同因子组合应用可增强GAP-43的表达。在MCAO大鼠模型中，不同因子组合死亡率、体重恢复及神经症状评分相对于单独应用有进一步的改善效果。
本研究表明异丙酚、白介素1受体拮抗剂、PTD-BDNF单独应用均可在细胞的OGD模型，SD大鼠的MCAO模型中显示神经保护作用，时间窗的选择以缺血后再灌注前1小时加入神经保护因子的神经细胞保护作用较好。不同因子组合在动物实验中显示，三种因子的各个组合联用相比单独应用有进一步的改善的作用。本研究为神经保护因子应用时合理的时间窗选择，应用因子组合后对于神经细胞的保护作用提供了实验依据。
At present, the disease of cerebral vascular which can upset millions of familieshas a high death and teratogenic rate with scant therapies. The treatment of acutephase is limited to reperfusion with tissue-type plasminogen activator or catheter. Aleading role in a different phase of cerebral ischemia and reperfusion injury processmay be the following mechanisms of oxidative damage, immune and inflammatorymechanisms, neurotrophic factor doctrine and so on. Focus on these mechanisms, wechose propofol, interleukin-1receptor antagonist and the PTD-BDNF as theprotective factor of each mechanism in cerebral ischemia and reperfusion injury. Weassume this study to work out which one is the best in the combinations among thedifferent factors and different inject time.
Propofol (2,6-Diisopropylphenol) is an intravenous anesthetic with the propertyof antioxidant. We confirm that propofol can increase the survival rate and reduce theapoptosis and death rate of SH-SY5Y cell after the oxygen glucose deprivation model(OGD) by flow cytometry analysis. The same consequence can be observed inhippocampal cell. Calcium imaging testes showed that propofol may delay theemergence of calcium influx for3-4min in Hippocampal cell. The SD rat middlecerebral artery occlusion model (MCAO) is regarded as the representative of cerebralischemia and reperfusion injury. We found that injecting propofol in the surgery canachieve the best protective effect compared with injecting propofol before the surgeryand after the surgery. Propofol injected in the surgery and before the surgery havepositive effects on the recovery of weight, the score of neurological symptoms andthree-dimensional space learning and memory ability of the Morris water maze. Propofol injected after the surgery compared with the model group have nostatistically significant. Propofol groups can decrease the infarct volume by HTTstaining, reduce neuronal apoptosis and necrosis by HE staining and enhance theexpression of brain synaptophysin. In a word, propofol protect nerve cells sufferingcerebral ischemia and reperfusion injury and injecting before reperfusion achieve thebest effcacy.
Interleukin-1receptor antagonist (IL-1RA) can increase the survival rate andreduce the apoptosis and death rate of SH-SY5Y cell after the oxygen glucosedeprivation model (OGD) by flow cytometry analysis. The same consequence can beobserved in hippocampal cell. IL-1RA can cause an increase the expression ofsynaptophysin and GAP-43. We found that intravenous injecting IL-1RA havepositive effects on the significantly low of the mortality, the recovery of weight, thescore of neurological symptoms and three-dimensional space learning and memoryability of the Morris water maze. On the opposite, the other intravenous injectingways increase the death risk in MCAO even achieve75%and have no benefits oncerebral ischemia and reperfusion injury. IL-1RA increase three-dimensional space ofthe Morris water maze learning and memory capacity in the14days MCAO model; In14days and21days after MCAO surgery, IL-1RA shows a reduction of neuronsapoptosis and necrosis and the enhancement of healthy side brain synaptophysinexpression by HE staining.
PTD-BDNF is the combination of Brain-derived neurotrophic factor (BDNF),and the protein transduction District (PTD) in HIV-1trans-activator protein (TAT).PTD-BDNF can increase the survival rate and reduce the apoptosis and death rate ofSH-SY5Y cell after the oxygen glucose deprivation model (OGD) by flowcytometry analysis. Different concentrations of CCK-8experiments showed that thePTD-of BDNF can promote the added value of the OGD hippocampal cells,concentration-dependent manner1-100ng/ml range. The PTD-of BDNF groupcompared with model group increase the survival of live cells and early apoptoticcells in hippocampal cell. PTD-BDNF can cause synaptophysin significantlyincreased, but the expression of GAP-43have no obvious increased. Intravenousinjecting PTD-BDNF in the surgery and after the surgery groups can reduce themortality, the body weight recovery and neurological symptoms. Intravenousinjecting PTD-BDNF before surgery can’t reach the same goal. PTD-BDNFincrease three-dimensional space of the Morris water maze learning and memory capacity in the7days MCAO model; In7days and14days after MCAO surgery,PTD-BDNF shows an addition of Brdu expression and the enhancement of brainsynaptophysin expression by Immunohistochemical staining.
In the Combination of different factors experiments, propofol and thePTD-BDNF can significantly improve expression of synaptophysin the byimmunohistochemistry staining compared with the other combination. Only in thecombination of IL-1RA and PTD-BDNF in the surgery and after the surgery canobserve the increase the GAP-43expression. For body weight recovery andneurological symptom score, the combination of three factors in MCAO model canachieve the best results.
This study shows that propofol, IL-1RA and PTD-BDNF can showneuroprotective effects and before reperfusion is the best choice of injecting time inrat MCAO model. Propofol and PTD-of BDNF, IL-1RA and the PTD-BDNF havethe additive effect using before the irrigation in the cell experiments. In animalexperiments, various combinations of the three factors compared to a solo applicationto have a more visible effect. In this study, the application of drug combinationsprovides the experimental basis for the neuroprotective in cerebral ischemia andreperfusion injury.
引文
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