电针促进局灶性脑缺血大鼠脑内血管新生并减轻神经元损伤的研究
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摘要
目的：脑卒中(Stroke)是一种突然起病的脑血液循环障碍性疾病,又叫脑血管意外,可分为缺血性和出血性。脑卒中患者中约85%为缺血性脑卒中,其发病率高,预后较差,已成为中老年人第一致残和前三位致死原因之一,严重危及人类的健康。中医学认为,缺血性脑卒中的病机概括为虚、火、风、痰、气、血六端,此六端在一定条件下,相互作用而致突然发病。而针刺作为中医有代表性的非药物治疗方法,具有操作简便、安全的特点,符合现代社会对健康的追求,且针刺在治疗缺血性脑血管疾病中的确切作用已为众多的临床实践所证实。根据临床实践及血管新生在脑缺血恢复中的重要作用,我们拟研究血管新生是否参与了电针改善脑缺血后神经功能缺损的治疗作用以及电针促进血管新生的可能机制。这将为研究电针促血管新生,发挥脑保护作用提供一定的实验依据。
方法：清洁级雄性SD大鼠随机分为电针组、模型组、假手术组,电针组与模型组大鼠采用线栓法栓塞大脑中动脉60min后恢复血流,电针组在再灌注2h后开始电针刺激(百会、水沟、足三里,疏密波,频率2Hz/15Hz,强度约1mA)30min,每隔12h重复刺激1次。再灌注24h后,采用实时荧光定量PCR法观察电针对缺血再灌注大鼠脑组织VEGF mRNA的影响；再灌注48h后,采用免疫印迹法分析电针对缺血区VEGF蛋白的影响,免疫组织化学法观察电针对缺血区促血管新生相关因子的影响；再灌注72h后,观察电针对局灶性脑缺血再灌注大鼠行为学障碍的影响,电针对缺血区微血管密度的影响,并用TTC法测量脑梗死体积,原位末端标记法观察缺血区细胞凋亡情况,并采用免疫印迹法观察电针对凋亡相关蛋白表达的影响。
结果：(1)脑缺血再灌注24h、48h、72h后,随再灌注时间的延长,模型组和电针组大鼠神经体征损伤评分逐渐降低；且各时间点电针组较模型组大鼠神经体征损伤评分明显降低,统计学处理有显著性差异(P<0.05,P<0.01)；病理形态学观察,可见假手术组大鼠细胞排列整齐,无水肿,未见炎性细胞浸润；模型组可见缺血坏死区结构疏松,间质水肿,大量细胞坏死,核仁消失,排列紊乱；电针治疗组缺血坏死区结构较假手术组疏松,但间质水肿不明显,坏死细胞数量较模型组明显减少,排列较模型组规则。
(2)脑梗死体积测定,假手术组大鼠脑组织染色呈鲜红色,未见白色缺血梗死区；模型组大鼠可见缺血侧大脑中动脉供血区脑组织大部分区域呈白色梗死区；电针治疗组大鼠缺血侧大脑中动脉供血区脑组织仅有较少区域呈白色,脑缺血梗死范围较模型组明显减少(P<0.01)；假手术组未见或少见CD34阳性表达；模型组大鼠可见脑缺血区CD34阳性表达,而电针组较模型组大鼠缺血区微血管密度显著增加,统计学处理有显著性差异(P<0.05)。
(3)数据分析表明假手术组大鼠几乎未见VEGF mRNA的表达,模型组可见一定量VEGF mRNA表达,而电针组VEGF mRNA的表达与模型组比较明显增强(P<0.01)；为进一步观察电针对缺血再灌注大鼠脑组织血管新生的影响,我们采用免疫印法检测了各组大鼠脑组织中VEGF蛋白的水平,结果显示,与模型组相比,脑缺血再灌注大鼠经电针治疗后,脑组织中VEGF蛋白水平明显增高(P<0.05)。
(4)假手术组未见或少见G-CSF表达；模型组大鼠可见脑缺血区G-CSF表达,而电针组较模型组大鼠缺血区G-CSF表达显著增加,统计学处理有显著性差异(P<0.05)；假手术组未见或少见Ang-1表达；模型组大鼠可见脑缺血区Ang-1表达,而电针组较模型组大鼠缺血区Ang-1表达显著增加,统计学处理有显著性差异(P<0.05)。
(5)假手术组未见或少见凋亡细胞,模型组缺血区可见较多凋亡细胞,主要见于梗死灶周围；电针组凋亡细胞数目明显减少,与模型组比较差异显著(P<0.01)；为进一步分析电针减轻缺血再灌注脑组织中神经元凋亡的机制,我们采用免疫印法检测了各组大鼠脑组织中抗凋亡蛋白Bcl-2的水平,结果显示,与模型组相比,脑缺血再灌注大鼠经电针治疗后,脑组织中抗凋亡蛋白Bcl-2水平明显增高(P<0.01)；我们也检测了各组大鼠脑组织中促凋亡蛋白Bax的水平,如所示,电针治疗组大鼠脑组织中Bax水平较模型组明显降低(P<0.05)。
结论：电针可能通过促进缺血区VEGF mRNA的表达,促使VEGF蛋白表达增加,并通过G-CSF、Ang-1等促血管新生因子的协同作用,增加缺血区微血管密度,发挥促血管新生效应；此外,电针可能通过调节Bax/Bcl-2等凋亡相关蛋白来减少缺血区细胞凋亡数,从而减轻缺血区病理形态学损伤,缩小脑梗死体积。多方面效应协同作用,有效减轻了脑缺血再灌注大鼠神经行为学障碍,发挥脑保护作用。
Objective:Stroke, also known as cerebrovascular accident, is an emergent cerebral blood circulation disorder. Stroke can be classified into two major categories:ischemic and hemorrhagic, about85%of strokes are caused by ischemia. Due to its the high incidence and poor prognosis, stroke has emerged as the leading cause of disability and one of the top three causes of mortality in the elderly, which is regarded as serious threat to human health. Chinese medicine believes that the pathogenesis of ischemic stroke might be attributed to virtual six factors, including weak, fire, wind, phlegm, qi and blood. The interaction of these six factors under certain conditions might lead to the sudden onset of stroke. Acupuncture, the representative non-drug treatments of traditional Chinese medicine, is easy to be operated with high safety, meeting the healthy demands of modern society. The therapeutic benefits of acupuncture in the treatment of ischemic cerebrovascular disease have been extensively confirmed in clinical practice. Given the clinical benefits of acupuncture and the important roles of angiogenesis in the recovery of cerebral ischemia, we planed to investigate whether angiogenesis is involved in the therapeutic effects of electroacupuncture (EA) in cerebral ischemia and the possible mechanism. The present researches would provide experimental basis for the modulatory effects on angiogensis and the protective effects on ischemic brain injury of EA.
Methods:Male SD rats with clean grade were randomly divided into EA group, model group, sham operation group (n=10). Middle cerebral artery occlusion was induced by intraluminal filament in EA group and model group for60min, and then the blood flow was restored. After reperfusion for2h, rats in EA group received EA at Baihui, Zusanl i and Baihui with density wave (frequency:2Hz/15Hz, intensity:1mA) for30min and this treatment was repeated every12h. Tweenty-four hours later, brain tissue was harvested and the level of VEGF mRNA was determined by real time PCR. Immunoblot was performed to detect the expression of VEGF and immunohistochemistry was used to examine the expression of angiogenesis-related factors in the ischemic area after24hours'reperfusion. At72h after reperfusion, the behavior impairment of the experimental animals and the microvessel density of the ischemic area were evaluated. In addition, the infarct volume was determined by TTC stain method, the apoptosis was detected with Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and the expression of apoptosis-related protein was determined by immunoblot.
Results:(1) The neurological injury score gradually decreased with the prolongation of reperfusion time for24h,48h and72h in model group and EA group, and at each time point EA group compared with model rats the neurological injury score of EA group was significantly lower than that of model group(P<0.05). Histomorphological examination showed normal tissue structure without edema or infiltration of inflammatory cells in sham-operated rats. In model group, the abnormal histomorphology manifested as loose tissue structure, interstitial edema, a large number of cell necrosis with nucleoli disappear and disorganized structure. The histological alterations were obviously alleivated in EA group.
(2) The TTC stain showed that the rat brain tissue were stained bright red without white ischemic infarction in the sham operated group. In model group, most regions of the middle cerebral artery-distributed area was stained white, whereas there was only a smaller region of the brain tissue was white in EA-treated rats (P <0.01). In addition, there are few CD34-positive cells in the brain tissue of sham operation group. The brain tissue from model group showed visible CD34expression. There was significantly increased microvessel density in ischemic areas in the EA group when compared with that of model group (P<0.05).
(3) Data analysis showed that there was very low level of VEGF mRNA in the sham operation group while the expression of VEGF mRNA obviously increased in the model group. The expression of VEGF mRNA further increased in the EA group(P<0.01). To further investigate the effects of EA on for angiogenesis in rat brain tissue with ischemia-reperfusion, immunoblot was performed to detect VEGF protein levels in brain tissue. The results showed that EA treatment significantly increased brain VEGF protein levels as compared with model group (P<0.05).
(4) In sham operation group, there was no obvious G-CSF expression in brain tissue. There was visible G-CSF expression in cerebral tissue of model group, while the EA treatmen significantly increased G-CSF expression in ischemic areas as compared with model group (P<0.05). The expression of Ang-1was also very low in sham operation group. There was visible Ang-1expression in ischemic areas of model group. The expression of Ang-1was further increased after EA treatment (P<0.05).
(5) In sham operation group, there were few apoptotic cells, whereas there were massive apoptotic cells in ischemic areas of the model group. The number of apoptotic cells decreased significantly in the EA group, as compared with model group (P<0.01). To further analyze the anti-apoptotic mechanisms of EA, the anti-apoptotic protein Bcl-2level was determined using immunoblot method. The results showed that the expression of Bcl-2was significantly higher than that of model group (P<0.01). We also examined the pro-apoptotic protein Bax levels in brain tissue, and we found that the level of Bax in the EA group was significantly lower than that in model group (P<0.05).
Conclusion:EA may upregulate VEGF mRNA level and increase VEGF protein level in the ischemic area, which might promote angiogenessi and increase microvessel density of the ischemic area. Other angiogenic factors such as G-CSF and Ang-1also play important roles in the angiogenesis processes stimulated by EA. In addition, EA treatment might reduce the number of apoptotic cells of the ischemic area through regulating Bax/Bcl-2, thereby attenuating the pathological morphological damage of the ischemic area and reducing the infarct volume. These effects of EA might corporately reduce neurobehavioral disorders in rats with cerebral ischemia and reperfusion, providing effective cerebral protective effect.
方法：清洁级雄性SD大鼠随机分为电针组、模型组、假手术组,电针组与模型组大鼠采用线栓法栓塞大脑中动脉60min后恢复血流,电针组在再灌注2h后开始电针刺激(百会、水沟、足三里,疏密波,频率2Hz/15Hz,强度约1mA)30min,每隔12h重复刺激1次。再灌注24h后,采用实时荧光定量PCR法观察电针对缺血再灌注大鼠脑组织VEGF mRNA的影响；再灌注48h后,采用免疫印迹法分析电针对缺血区VEGF蛋白的影响,免疫组织化学法观察电针对缺血区促血管新生相关因子的影响；再灌注72h后,观察电针对局灶性脑缺血再灌注大鼠行为学障碍的影响,电针对缺血区微血管密度的影响,并用TTC法测量脑梗死体积,原位末端标记法观察缺血区细胞凋亡情况,并采用免疫印迹法观察电针对凋亡相关蛋白表达的影响。
结果：(1)脑缺血再灌注24h、48h、72h后,随再灌注时间的延长,模型组和电针组大鼠神经体征损伤评分逐渐降低；且各时间点电针组较模型组大鼠神经体征损伤评分明显降低,统计学处理有显著性差异(P<0.05,P<0.01)；病理形态学观察,可见假手术组大鼠细胞排列整齐,无水肿,未见炎性细胞浸润；模型组可见缺血坏死区结构疏松,间质水肿,大量细胞坏死,核仁消失,排列紊乱；电针治疗组缺血坏死区结构较假手术组疏松,但间质水肿不明显,坏死细胞数量较模型组明显减少,排列较模型组规则。
(2)脑梗死体积测定,假手术组大鼠脑组织染色呈鲜红色,未见白色缺血梗死区；模型组大鼠可见缺血侧大脑中动脉供血区脑组织大部分区域呈白色梗死区；电针治疗组大鼠缺血侧大脑中动脉供血区脑组织仅有较少区域呈白色,脑缺血梗死范围较模型组明显减少(P<0.01)；假手术组未见或少见CD34阳性表达；模型组大鼠可见脑缺血区CD34阳性表达,而电针组较模型组大鼠缺血区微血管密度显著增加,统计学处理有显著性差异(P<0.05)。
(3)数据分析表明假手术组大鼠几乎未见VEGF mRNA的表达,模型组可见一定量VEGF mRNA表达,而电针组VEGF mRNA的表达与模型组比较明显增强(P<0.01)；为进一步观察电针对缺血再灌注大鼠脑组织血管新生的影响,我们采用免疫印法检测了各组大鼠脑组织中VEGF蛋白的水平,结果显示,与模型组相比,脑缺血再灌注大鼠经电针治疗后,脑组织中VEGF蛋白水平明显增高(P<0.05)。
(4)假手术组未见或少见G-CSF表达；模型组大鼠可见脑缺血区G-CSF表达,而电针组较模型组大鼠缺血区G-CSF表达显著增加,统计学处理有显著性差异(P<0.05)；假手术组未见或少见Ang-1表达；模型组大鼠可见脑缺血区Ang-1表达,而电针组较模型组大鼠缺血区Ang-1表达显著增加,统计学处理有显著性差异(P<0.05)。
(5)假手术组未见或少见凋亡细胞,模型组缺血区可见较多凋亡细胞,主要见于梗死灶周围；电针组凋亡细胞数目明显减少,与模型组比较差异显著(P<0.01)；为进一步分析电针减轻缺血再灌注脑组织中神经元凋亡的机制,我们采用免疫印法检测了各组大鼠脑组织中抗凋亡蛋白Bcl-2的水平,结果显示,与模型组相比,脑缺血再灌注大鼠经电针治疗后,脑组织中抗凋亡蛋白Bcl-2水平明显增高(P<0.01)；我们也检测了各组大鼠脑组织中促凋亡蛋白Bax的水平,如所示,电针治疗组大鼠脑组织中Bax水平较模型组明显降低(P<0.05)。
结论：电针可能通过促进缺血区VEGF mRNA的表达,促使VEGF蛋白表达增加,并通过G-CSF、Ang-1等促血管新生因子的协同作用,增加缺血区微血管密度,发挥促血管新生效应；此外,电针可能通过调节Bax/Bcl-2等凋亡相关蛋白来减少缺血区细胞凋亡数,从而减轻缺血区病理形态学损伤,缩小脑梗死体积。多方面效应协同作用,有效减轻了脑缺血再灌注大鼠神经行为学障碍,发挥脑保护作用。
Objective:Stroke, also known as cerebrovascular accident, is an emergent cerebral blood circulation disorder. Stroke can be classified into two major categories:ischemic and hemorrhagic, about85%of strokes are caused by ischemia. Due to its the high incidence and poor prognosis, stroke has emerged as the leading cause of disability and one of the top three causes of mortality in the elderly, which is regarded as serious threat to human health. Chinese medicine believes that the pathogenesis of ischemic stroke might be attributed to virtual six factors, including weak, fire, wind, phlegm, qi and blood. The interaction of these six factors under certain conditions might lead to the sudden onset of stroke. Acupuncture, the representative non-drug treatments of traditional Chinese medicine, is easy to be operated with high safety, meeting the healthy demands of modern society. The therapeutic benefits of acupuncture in the treatment of ischemic cerebrovascular disease have been extensively confirmed in clinical practice. Given the clinical benefits of acupuncture and the important roles of angiogenesis in the recovery of cerebral ischemia, we planed to investigate whether angiogenesis is involved in the therapeutic effects of electroacupuncture (EA) in cerebral ischemia and the possible mechanism. The present researches would provide experimental basis for the modulatory effects on angiogensis and the protective effects on ischemic brain injury of EA.
Methods:Male SD rats with clean grade were randomly divided into EA group, model group, sham operation group (n=10). Middle cerebral artery occlusion was induced by intraluminal filament in EA group and model group for60min, and then the blood flow was restored. After reperfusion for2h, rats in EA group received EA at Baihui, Zusanl i and Baihui with density wave (frequency:2Hz/15Hz, intensity:1mA) for30min and this treatment was repeated every12h. Tweenty-four hours later, brain tissue was harvested and the level of VEGF mRNA was determined by real time PCR. Immunoblot was performed to detect the expression of VEGF and immunohistochemistry was used to examine the expression of angiogenesis-related factors in the ischemic area after24hours'reperfusion. At72h after reperfusion, the behavior impairment of the experimental animals and the microvessel density of the ischemic area were evaluated. In addition, the infarct volume was determined by TTC stain method, the apoptosis was detected with Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and the expression of apoptosis-related protein was determined by immunoblot.
Results:(1) The neurological injury score gradually decreased with the prolongation of reperfusion time for24h,48h and72h in model group and EA group, and at each time point EA group compared with model rats the neurological injury score of EA group was significantly lower than that of model group(P<0.05). Histomorphological examination showed normal tissue structure without edema or infiltration of inflammatory cells in sham-operated rats. In model group, the abnormal histomorphology manifested as loose tissue structure, interstitial edema, a large number of cell necrosis with nucleoli disappear and disorganized structure. The histological alterations were obviously alleivated in EA group.
(2) The TTC stain showed that the rat brain tissue were stained bright red without white ischemic infarction in the sham operated group. In model group, most regions of the middle cerebral artery-distributed area was stained white, whereas there was only a smaller region of the brain tissue was white in EA-treated rats (P <0.01). In addition, there are few CD34-positive cells in the brain tissue of sham operation group. The brain tissue from model group showed visible CD34expression. There was significantly increased microvessel density in ischemic areas in the EA group when compared with that of model group (P<0.05).
(3) Data analysis showed that there was very low level of VEGF mRNA in the sham operation group while the expression of VEGF mRNA obviously increased in the model group. The expression of VEGF mRNA further increased in the EA group(P<0.01). To further investigate the effects of EA on for angiogenesis in rat brain tissue with ischemia-reperfusion, immunoblot was performed to detect VEGF protein levels in brain tissue. The results showed that EA treatment significantly increased brain VEGF protein levels as compared with model group (P<0.05).
(4) In sham operation group, there was no obvious G-CSF expression in brain tissue. There was visible G-CSF expression in cerebral tissue of model group, while the EA treatmen significantly increased G-CSF expression in ischemic areas as compared with model group (P<0.05). The expression of Ang-1was also very low in sham operation group. There was visible Ang-1expression in ischemic areas of model group. The expression of Ang-1was further increased after EA treatment (P<0.05).
(5) In sham operation group, there were few apoptotic cells, whereas there were massive apoptotic cells in ischemic areas of the model group. The number of apoptotic cells decreased significantly in the EA group, as compared with model group (P<0.01). To further analyze the anti-apoptotic mechanisms of EA, the anti-apoptotic protein Bcl-2level was determined using immunoblot method. The results showed that the expression of Bcl-2was significantly higher than that of model group (P<0.01). We also examined the pro-apoptotic protein Bax levels in brain tissue, and we found that the level of Bax in the EA group was significantly lower than that in model group (P<0.05).
Conclusion:EA may upregulate VEGF mRNA level and increase VEGF protein level in the ischemic area, which might promote angiogenessi and increase microvessel density of the ischemic area. Other angiogenic factors such as G-CSF and Ang-1also play important roles in the angiogenesis processes stimulated by EA. In addition, EA treatment might reduce the number of apoptotic cells of the ischemic area through regulating Bax/Bcl-2, thereby attenuating the pathological morphological damage of the ischemic area and reducing the infarct volume. These effects of EA might corporately reduce neurobehavioral disorders in rats with cerebral ischemia and reperfusion, providing effective cerebral protective effect.
引文
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