丁苯酞预处理对急性脑缺血大鼠的脑保护作用及Smac、S100B蛋白表达的影响
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摘要
背景与目的
急性缺血性脑梗塞是最常见的脑血管病类型,占全部脑血管意外的60%-80%。其致死致残率很高,据相关资料统计约25%～75%的急性脑梗死在2-5年内有复发,已与心肌梗死、恶性肿瘤并列,称为致死率最高的三大疾病。其处理强调早期诊断、早期治疗、早期康复和早期预防再发。高复发率、高致残率以及昂贵的治疗费用决定了预防的重要性,预防性用药降低高危人群的发病率及复发率越来愈受到重视。
丁苯酞,(dl-n-butylphthalide, dl-NBP),可提高脑血管内皮NO及PGI2的水平,抑制谷氨酸释放,降低细胞内Ca2+浓度,抑制自由基生成并提高抗氧化酶活性等作用。早期用于急性缺血性卒中治疗,后逐渐试用于慢性脑卒中及其所致血管性痴呆,疗效确切。在基础研究中也有确切的分子生物学证据,鉴于其作用机理,拟将丁苯酞作为预防性用药,然目前研究甚少。
S100B蛋白是迄今最能反映脑损伤程度和预后的特异性蛋白。促凋亡蛋白Smac存在于线粒体,并调节半胱氨酸天冬氨酸蛋白水解酶(caspase)依赖路径的细胞凋亡。本研究通过建立wistar大鼠急性大脑中动脉脑缺血模型,观察丁苯酞预处理对急性脑缺血损伤的脑保护作用及对脑组织Smac、S100B蛋白表达的影响,探讨其可能的机制。
材料与方法
1、实验动物及分组健康雄性Wistar大鼠33只,体重200-250g,由郑州大学实验动物中心提供；随机分为C组(C组)、脑缺血模型组(M组)和丁苯酞预处理组(NBP组),每组11只。
2、脑缺血模型制作及药物预处理制模前14d起,给预处理组大鼠丁苯酞原液0.8g/kg灌胃,其他两组大鼠予以等体积花生油灌胃,每天1次。给大鼠10%水合氯醛(0.3ml/100g)腹腔注射麻醉。用改良Zea Longa线栓法阻塞NBP组和M组大鼠的左侧大脑中动脉,造成急性脑缺血；C组大鼠只分离、暴露左侧大脑中动脉,不予以结扎及插入线栓。脑缺血24小时后处死大鼠。
3、脑梗死体积检测每组取8只大鼠取脑,冠状切片5～6片,放置于2%的TTC磷酸盐缓冲液中,避光,37℃恒温水浴箱中染色。染色后将各脑片按顺序摆放,正反面拍照。计算各脑片梗死面积并以此计算梗死体积。
4、脑组织病理改变观察选取每组8只已行TTC染色的有典型梗死灶的脑组织切片并进行HE染色,观察半暗带区域,拍照。
5、脑组织Smac、S100B蛋白水平检测各组3只大鼠处死取脑,取左大脑中动脉供血区脑组织100mg提取蛋白,进行Western Blot法检测,化学发光显色并图像分析,计算灰度比值。
6、组织含水量检测用干湿重比值法。利用每组8只大鼠TTC染色后脑切片测干湿重。脑组织含水量(%)=(湿重—干重)/湿重×100%。
7、统计学方法用SPSS17.0软件进行数据分析、处理。计量资料以均数士标准差(x±s)表示,组间均数比较用单因素方差分析,两两比较采用SNK法。
结果
1、脑组织病理改变比较C组：细胞形态结构、密度正常,未见水肿。M组：脑组织结构疏松、排列紊乱、细胞间隙水肿严重,见不同程度的神经元变性、坏死,神经细胞数明显减少,有散在空腔形成。NBP组：以上观察指标轻微改变,水肿不明显,神经元坏死数少。
2、脑梗死体积比较C组大鼠脑部无梗死灶。M组与NBP组大鼠脑部均可见白色的梗死灶,界限清晰。NBP组大鼠的脑梗死体积较M组明显减小(P<0.05)。
3、脑组织Smac、S100B蛋白水平比较M组与NBP组脑组织Smac、S100B蛋白水平明显高于C组(P<0.05～0.01),而NBP组脑组织Smac、S100B蛋白水平明显低于M组(均P<0.05)。
4、脑组织含水量比较M组与NBP组脑组织含水量明显高于C组(P<0.05～0.01),而NBP组脑组织含水量明显低于M组(P<0.05)。
结论
1、在遭受急性缺血缺氧损害时,脑组织出现坏死灶；脑组织细胞损伤及神经元坏死严重；脑细胞通透性改变,明显水肿；促凋亡蛋白Smac和S100B蛋白表达增高；
2、促凋亡蛋白Smac和S100B蛋白参与了脑缺血损伤的病理途径；
3、丁苯酞预处理可明显减轻脑缺血性细胞损害,减小梗死面积,减少脑缺血后脑组织的渗出和脑水肿程度；
4、丁苯酞预处理可显著降低促凋亡蛋白Smac和S100B蛋白的表达。
Background and Objective
Acute ischemic cerebral vascular disease is the most common type of cerebral infarction, and makes up60%-80%per cent of total cerebral vascular accident. It has a higher death rate and high disability rates. According to the relevant statistics about25%-75%recur in2-5year. Those make it with myocardial infarctions and malignant referred to as the three diseases with the highest death rate. Its clinical treatment is emphasis on early diagnosis, early treatment, early rehabilitation and early prevention of recurrence. All above Characteristics as well as high costs of treatment determine the importance of prevention, prophylactic therapy reduces the incidence and recurrence rates among high-risk populations.
Butylphthalide,(dl-n-butylphthalide, dl-NBP), Can raise the level of cerebral vascular endothelial NO and PGI2, inhibit glutamate release, Can reduce the intracellular concentration of Ca2+, inhibition of free radicals and raise antioxidative enzyme activities and so on. Early treatment of acute ischemic stroke, gradually after the trial in chronic cerebral stroke and vascular dementia induced by, has good curative effect. In basic research have the exact molecular evidence, In view of its mechanism, intended to butylphthalide as prophylaxis, but similar studies currently rare.
By far, S100B is the best way to reflect the degree of brain damage and prognosis of specific protein. Smac in mitochondria, and adjust the cysteine-aspartic acid protease (Caspase) path-dependent apoptosis. This research through the establishment of Wistar Rat model of acute focal cerebral ischemia of middle cerebral artery, observe butyl phthalide pretreatment on acute cerebral ischemia injury in cerebral protection effect and influence on the expression of Smac, S100B protein in brain tissue, explore its possible mechanisms.
Materials and methods
1、Animals and groups:33healthy male Wistar rats, weighing200-250g, Provided by the laboratory animal Center of Zhengzhou University; Randomly assigned to c Group (Group C), cerebral ischemia model group (Group M) and butyl phthalide pretreatment groups (Group NBP), each group of11.
2、Cerebral ischemia model and pharmacological preconditioning:intragastric administration, Group NBP was treated by butyl phthalide liquid0.8g/kg of rat gavage, but the same volum of peanut oil for other two groups,Once a day for14days. And then, each one was treated by10%chloral hydrate (0.3ml/100g) intraperitoneal injection of anesthesia. for Group NBP and group M, Zea Longa improved intraluminal thread occlusion those Middle cerebral artery on the left side,but C not. After cerebral ischemia24hours, make them death.
3、Detection of cerebral infarction volume:Randomly take brains from8rats in each group, Coronal slice5-6,then placed them in2%TTC in phosphate buffer solution, keep in dark place and a37℃water bath box lasts for30min. After dyeing, place all the brain slices in order, And photograph them both positive and negative. Calculation of cerebral infarction area and to the calculation of infarct size.
4、Observation on pathological change in brain tissue:Select each group of8TTC staining typical infarct of brain tissue slice, dye them by HE staining, then observe on Penumbra area, finally take pictures.
5、Expression of Smac, S100B protein in brain tissue: take brains from3rats in each group, then take100mg brain tissue, which blood was supplied by the left middle cerebral artery, to test their expression with Western Blotting. at last, chemiluminescence image and analysis the image, calculate the ratio grayscale.
6、detect the moisture content of organization:by wet/dry weight ratio method. Brain tissue water content (%)=(wet-to-dry weight)/wet weight x100%.
7、Statistical Methods:All experimental data were expressed by mean±standard error,(x±s), the groups were compared using single-factor analysis of variance, among groups were using the S-N-K method, the statistical software SPASS17.0for windows was used to analysis data, a=0.05.
Result
1、Comparison of pathological changes of brain tissue'Group C:Cell morphology and density normally, no edema. Group M:Brain tissue structure loosely, intercellular edema severely, arrange disorderly, varying degrees of neuronal degeneration and necrosis can be seen, the number of nerve cells significantly reduced, in the formation of cavities. Group NBP:Outcome measures more than minor changes, edema is not obvious, and fewer neuronal necrosis.
2、 Comparison of cerebral infarction volume there is no brain infarcted area of rats in Group C; visible white brain infarcts can be seen in Group M and NBP, lines clearly.
3、 Smac, S100B protein levels in brain tissue Relative to Group C, Smac, S100B protein level obviously increased inGroup M and Group NBP (P<0.05), while the two indexes in Group NBP were significantly lower than Group M (P<0.05).
4、Comparison of water content in brain tissue Relative to Group C, water content obviously increased inGroup M and Group NBP (P<0.05), while it in Group NBP were significantly lower than Group M (P<0.05).
Conclusion
1、Suffering from acute hypoxic-ischemic damage, brain tissue necrosis occurs; Brain injuries and neuronal necrosis seriously, brain cell permeability change, apparent edema; the expression of Smac and S100B protein increase;
2、Smac and S100B protein take part in brain ischemic injury of the pathological pathway;
3、Butyl phthalide pretreatment can significantly reduce the ischemic brain cell damage, reduces infarct area and reduce brain edema in cerebral ischemic brain tissue;
4、Butyl phthalide pretreatment significantly reduces apoptosis protein expression of Smac and S100B protein.
急性缺血性脑梗塞是最常见的脑血管病类型,占全部脑血管意外的60%-80%。其致死致残率很高,据相关资料统计约25%～75%的急性脑梗死在2-5年内有复发,已与心肌梗死、恶性肿瘤并列,称为致死率最高的三大疾病。其处理强调早期诊断、早期治疗、早期康复和早期预防再发。高复发率、高致残率以及昂贵的治疗费用决定了预防的重要性,预防性用药降低高危人群的发病率及复发率越来愈受到重视。
丁苯酞,(dl-n-butylphthalide, dl-NBP),可提高脑血管内皮NO及PGI2的水平,抑制谷氨酸释放,降低细胞内Ca2+浓度,抑制自由基生成并提高抗氧化酶活性等作用。早期用于急性缺血性卒中治疗,后逐渐试用于慢性脑卒中及其所致血管性痴呆,疗效确切。在基础研究中也有确切的分子生物学证据,鉴于其作用机理,拟将丁苯酞作为预防性用药,然目前研究甚少。
S100B蛋白是迄今最能反映脑损伤程度和预后的特异性蛋白。促凋亡蛋白Smac存在于线粒体,并调节半胱氨酸天冬氨酸蛋白水解酶(caspase)依赖路径的细胞凋亡。本研究通过建立wistar大鼠急性大脑中动脉脑缺血模型,观察丁苯酞预处理对急性脑缺血损伤的脑保护作用及对脑组织Smac、S100B蛋白表达的影响,探讨其可能的机制。
材料与方法
1、实验动物及分组健康雄性Wistar大鼠33只,体重200-250g,由郑州大学实验动物中心提供；随机分为C组(C组)、脑缺血模型组(M组)和丁苯酞预处理组(NBP组),每组11只。
2、脑缺血模型制作及药物预处理制模前14d起,给预处理组大鼠丁苯酞原液0.8g/kg灌胃,其他两组大鼠予以等体积花生油灌胃,每天1次。给大鼠10%水合氯醛(0.3ml/100g)腹腔注射麻醉。用改良Zea Longa线栓法阻塞NBP组和M组大鼠的左侧大脑中动脉,造成急性脑缺血；C组大鼠只分离、暴露左侧大脑中动脉,不予以结扎及插入线栓。脑缺血24小时后处死大鼠。
3、脑梗死体积检测每组取8只大鼠取脑,冠状切片5～6片,放置于2%的TTC磷酸盐缓冲液中,避光,37℃恒温水浴箱中染色。染色后将各脑片按顺序摆放,正反面拍照。计算各脑片梗死面积并以此计算梗死体积。
4、脑组织病理改变观察选取每组8只已行TTC染色的有典型梗死灶的脑组织切片并进行HE染色,观察半暗带区域,拍照。
5、脑组织Smac、S100B蛋白水平检测各组3只大鼠处死取脑,取左大脑中动脉供血区脑组织100mg提取蛋白,进行Western Blot法检测,化学发光显色并图像分析,计算灰度比值。
6、组织含水量检测用干湿重比值法。利用每组8只大鼠TTC染色后脑切片测干湿重。脑组织含水量(%)=(湿重—干重)/湿重×100%。
7、统计学方法用SPSS17.0软件进行数据分析、处理。计量资料以均数士标准差(x±s)表示,组间均数比较用单因素方差分析,两两比较采用SNK法。
结果
1、脑组织病理改变比较C组：细胞形态结构、密度正常,未见水肿。M组：脑组织结构疏松、排列紊乱、细胞间隙水肿严重,见不同程度的神经元变性、坏死,神经细胞数明显减少,有散在空腔形成。NBP组：以上观察指标轻微改变,水肿不明显,神经元坏死数少。
2、脑梗死体积比较C组大鼠脑部无梗死灶。M组与NBP组大鼠脑部均可见白色的梗死灶,界限清晰。NBP组大鼠的脑梗死体积较M组明显减小(P<0.05)。
3、脑组织Smac、S100B蛋白水平比较M组与NBP组脑组织Smac、S100B蛋白水平明显高于C组(P<0.05～0.01),而NBP组脑组织Smac、S100B蛋白水平明显低于M组(均P<0.05)。
4、脑组织含水量比较M组与NBP组脑组织含水量明显高于C组(P<0.05～0.01),而NBP组脑组织含水量明显低于M组(P<0.05)。
结论
1、在遭受急性缺血缺氧损害时,脑组织出现坏死灶；脑组织细胞损伤及神经元坏死严重；脑细胞通透性改变,明显水肿；促凋亡蛋白Smac和S100B蛋白表达增高；
2、促凋亡蛋白Smac和S100B蛋白参与了脑缺血损伤的病理途径；
3、丁苯酞预处理可明显减轻脑缺血性细胞损害,减小梗死面积,减少脑缺血后脑组织的渗出和脑水肿程度；
4、丁苯酞预处理可显著降低促凋亡蛋白Smac和S100B蛋白的表达。
Background and Objective
Acute ischemic cerebral vascular disease is the most common type of cerebral infarction, and makes up60%-80%per cent of total cerebral vascular accident. It has a higher death rate and high disability rates. According to the relevant statistics about25%-75%recur in2-5year. Those make it with myocardial infarctions and malignant referred to as the three diseases with the highest death rate. Its clinical treatment is emphasis on early diagnosis, early treatment, early rehabilitation and early prevention of recurrence. All above Characteristics as well as high costs of treatment determine the importance of prevention, prophylactic therapy reduces the incidence and recurrence rates among high-risk populations.
Butylphthalide,(dl-n-butylphthalide, dl-NBP), Can raise the level of cerebral vascular endothelial NO and PGI2, inhibit glutamate release, Can reduce the intracellular concentration of Ca2+, inhibition of free radicals and raise antioxidative enzyme activities and so on. Early treatment of acute ischemic stroke, gradually after the trial in chronic cerebral stroke and vascular dementia induced by, has good curative effect. In basic research have the exact molecular evidence, In view of its mechanism, intended to butylphthalide as prophylaxis, but similar studies currently rare.
By far, S100B is the best way to reflect the degree of brain damage and prognosis of specific protein. Smac in mitochondria, and adjust the cysteine-aspartic acid protease (Caspase) path-dependent apoptosis. This research through the establishment of Wistar Rat model of acute focal cerebral ischemia of middle cerebral artery, observe butyl phthalide pretreatment on acute cerebral ischemia injury in cerebral protection effect and influence on the expression of Smac, S100B protein in brain tissue, explore its possible mechanisms.
Materials and methods
1、Animals and groups:33healthy male Wistar rats, weighing200-250g, Provided by the laboratory animal Center of Zhengzhou University; Randomly assigned to c Group (Group C), cerebral ischemia model group (Group M) and butyl phthalide pretreatment groups (Group NBP), each group of11.
2、Cerebral ischemia model and pharmacological preconditioning:intragastric administration, Group NBP was treated by butyl phthalide liquid0.8g/kg of rat gavage, but the same volum of peanut oil for other two groups,Once a day for14days. And then, each one was treated by10%chloral hydrate (0.3ml/100g) intraperitoneal injection of anesthesia. for Group NBP and group M, Zea Longa improved intraluminal thread occlusion those Middle cerebral artery on the left side,but C not. After cerebral ischemia24hours, make them death.
3、Detection of cerebral infarction volume:Randomly take brains from8rats in each group, Coronal slice5-6,then placed them in2%TTC in phosphate buffer solution, keep in dark place and a37℃water bath box lasts for30min. After dyeing, place all the brain slices in order, And photograph them both positive and negative. Calculation of cerebral infarction area and to the calculation of infarct size.
4、Observation on pathological change in brain tissue:Select each group of8TTC staining typical infarct of brain tissue slice, dye them by HE staining, then observe on Penumbra area, finally take pictures.
5、Expression of Smac, S100B protein in brain tissue: take brains from3rats in each group, then take100mg brain tissue, which blood was supplied by the left middle cerebral artery, to test their expression with Western Blotting. at last, chemiluminescence image and analysis the image, calculate the ratio grayscale.
6、detect the moisture content of organization:by wet/dry weight ratio method. Brain tissue water content (%)=(wet-to-dry weight)/wet weight x100%.
7、Statistical Methods:All experimental data were expressed by mean±standard error,(x±s), the groups were compared using single-factor analysis of variance, among groups were using the S-N-K method, the statistical software SPASS17.0for windows was used to analysis data, a=0.05.
Result
1、Comparison of pathological changes of brain tissue'Group C:Cell morphology and density normally, no edema. Group M:Brain tissue structure loosely, intercellular edema severely, arrange disorderly, varying degrees of neuronal degeneration and necrosis can be seen, the number of nerve cells significantly reduced, in the formation of cavities. Group NBP:Outcome measures more than minor changes, edema is not obvious, and fewer neuronal necrosis.
2、 Comparison of cerebral infarction volume there is no brain infarcted area of rats in Group C; visible white brain infarcts can be seen in Group M and NBP, lines clearly.
3、 Smac, S100B protein levels in brain tissue Relative to Group C, Smac, S100B protein level obviously increased inGroup M and Group NBP (P<0.05), while the two indexes in Group NBP were significantly lower than Group M (P<0.05).
4、Comparison of water content in brain tissue Relative to Group C, water content obviously increased inGroup M and Group NBP (P<0.05), while it in Group NBP were significantly lower than Group M (P<0.05).
Conclusion
1、Suffering from acute hypoxic-ischemic damage, brain tissue necrosis occurs; Brain injuries and neuronal necrosis seriously, brain cell permeability change, apparent edema; the expression of Smac and S100B protein increase;
2、Smac and S100B protein take part in brain ischemic injury of the pathological pathway;
3、Butyl phthalide pretreatment can significantly reduce the ischemic brain cell damage, reduces infarct area and reduce brain edema in cerebral ischemic brain tissue;
4、Butyl phthalide pretreatment significantly reduces apoptosis protein expression of Smac and S100B protein.
引文
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