缺血后适应对树鼩血栓性脑缺血磁共振成像及脑保护的分子机制研究
|
摘要
目的：建立树鼩血栓性脑缺血及缺血后适应动物模型并进行磁共振(magnetic resonance imaging,MRI)成像研究,包括MRI平扫、弥散加权成像(diffusion weighted imaging,DWl)、二乙三胺五醋酸钆(gadolinium-diethylene-triaminepentaacetate, Gd-DTPA)增强等系列,观察缺血区72h不同时间点内演变规律,探讨树鼩血栓性脑缺血的MRI特点及其在脑缺血后适应过程中的监测价值,为临床提供实验依据和理论基础。方法：采用光化学反应诱导建立树鼩血栓性脑缺血模型,在造模成功4h后夹闭右侧颈总动脉5min,再灌注5min,共计交替进行3个循环实施缺血后适应。应用3.0T MRI在缺血后4h、24h、48h及72h对树鼩脑部行冠状扫描,观察树鼩脑缺血及缺血后适应后缺血灶改变特点。在工作站上测量并计算出以下数值：Tl加权图像(T1weighted image, T1WI). T2WI和表面扩散系数(apparent diffusion coefficient,ADC)图上感兴趣区(region of intrest,ROI)的T1WI相对信号强度(relative signal intensity,rSI)、T2WI rSI及相对表面扩散系数(relative apparent diffusion coefficient,rADC)值；异常信号中心区和边缘区rADC值；DWI和T2加权图像(T2weighted image,T2WI)上异常信号体积；增强后信号强度(signal intensity,SI)增加率。分别应用HE染色、2,3,5氯化三苯基四氮唑(2,3,5-triphenyltetrazolium chloride, TTC)染色技术显示脑缺血组及缺血后适应组缺血灶不同区域细胞改变和皮层梗死面积的变化。结果：假手术组各时间点MRI及TTC未见异常。缺血组4h MRI可见信号改变，T2WI rSI在缺血后可见增高,24h中心区T2WI rSI值最高(P<0.05),缺血后适应组各时间点中心区T2WI rSI值与缺血组比较,无统计学差异(P>0.05)。缺血组4h及24h缺血病灶中心区rADC均下降,48h及72h明显升高(P<0.05)；缺血后适应组各时间点中心区rADC与缺血组比较,无统计学差异(P>0.05)。缺血组病灶边缘区rADC值在4h也出现降低,24h时最低(P<0.05),降至66.16±4.98%,随后逐渐升高；缺血后适应组边缘区rADC随时间逐渐升高,与缺血组各时间点边缘区rADC值比较,在24h及48h两组之间具有统计学差异(P<0.05),4h及72h两组之间无统计学差异(P<0.05)；缺血组缺血病灶中心区rADC在4h低于边缘区(P<0.05),24h、48h、72h无统计学差异(P>0.05)。TTC染色所测梗死区的体积与DWI高信号区体积比较,4h时DWI所测体积大于TTC(P<0.05),24h、48h及72h DWI所测体积与TTC体积之间无统计学差异(P>0.05)。缺血组脑梗塞体积在4h时最小(P<0.05),随后增大；缺血后适应组脑梗塞体积从4h至24h未见明显增大,4h体积为64.9±6.8mm3,24h体积为69.1±5.7mm3,病灶体积随时间的变化无统计学差异(P>0.05)。缺血组及缺血后适应组所有动物不同时间点注入Gd-DTPA后均出现病变异常强化,缺血组24h时增强后SI增加率最高(P<0.05)；增强后所测强化体积小于T2WI所测体积(P<0.05)；缺血后适应组SI增加率与缺血组比较,在24h、48h及72h增强后SI增加率小于缺血组(P<0.05)。光镜示缺血后4h病灶中心区神经元可见皱缩,缺血组织与正常组织之间可见水肿带,缺血半暗带神经元肿胀、固缩,部分血管腔内见血小板积聚,血栓形成；缺血24h缺血中心区组织溶解,呈疏松网结构,神经元脱失,固缩明显；缺血后48h及72h,神经元脱失明显,出现嗜酸神经元,整个细胞均染为红色。结论：MRI能动态反应树鼩血栓性脑缺血动物模型缺血后不同时间点的病理演变过程；MRI可用于脑缺血后适应效果的评价,缺血后适应抑制缺血区的扩大,结合半定量化参数rADC值,可能与缺血后适应改善局部脑血流及挽救半暗带有关；增强后缺血后适应组SI增加率小于缺血组,可能系由于缺血后适应减轻血脑屏障的破坏。
目的：通过采用超顺磁性氧化铁颗粒(superparamagnetic iron oxide,SPIO)增强MRI对树鼩血栓性脑缺血及缺血后适应动物模型进行动态扫描,观察病灶的改变特点,并与普鲁士蓝染色及抗白介素-1β(Interleukin-1beta, IL-1β)与单核/巨噬细胞表面特异性标志抗原(Ectodermal dysplasia-1, ED-1)免疫荧光双标染色结果相对照,探讨SPIO增强MRI对缺血后适应所致脑缺血炎症反应改变的活体监测价值。方法：采用光化学反应诱导建立树鼩血栓性脑缺血模型,在造模成功4h后夹闭右侧颈总动脉5min,再灌注5min,共计交替进行3个循环实施缺血后适应。应用3.0T MRI,在缺血后4h、24h及48h注射SPIO,观察SPIO增强后MRI改变特点,测量不同时间点T2WI rSI值；通过普鲁士蓝染色显示缺血灶内铁粒子形态及部位；采用抗IL-1β与ED-1免疫荧光双标染色激光扫描共聚焦显微镜检查观察脑缺血组及缺血后适应组巨噬细胞浸润及IL-1β的表达情况。结果：假手术组各时间点MRI未见异常；缺血组于注射SPIO后24h及以后时间点扫描缺血灶内可见低信号,4h注射组24h、48h及72h低信号形态未见明显改变,T2WI rSI值未见变化(P>0.05),在24h、48h及72h时T2WI rSI低于缺血平扫组(P<0.05)；24h注射组48h及72h扫描可见低信号,低信号形态未见明显改变,T2WI rSI值未见变化(P>0.05),48h及72h T2WI rSI与缺血平扫组对比,无统计学差异(P>0.05)；48h注射组,72h时可见低信号,但T2WI rSI与缺血平扫组对比,无统计学差异(P>0.05)；缺血后适应组注射SPIO后24h及以后各时间点缺血灶内可见低信号,缺血后适应4h注射SPIO组24h、48h及72h时T2WI rSI高于缺血4h注射SPIO组(P<0.05),缺血后适应24h注射SPIO组48h及72h缺血灶T2WI rSI略低于缺血24h注射SPIO组,但经统计学分析,两组间T2WI rSl无统计学差异(P>0.05),缺血后适应48h注射SPIO组与缺血组72h T2WI rSI相比较,经统计学分析,无统计学差异(P>0.05)；普鲁士蓝染色显示缺血4h注射组24h时含铁粒子细胞主要位于血管腔内,随缺血时间延长,血管腔内含铁粒子细胞减少,于72h主要位于血管外组织内；24h及48h注射组含铁粒子细胞较4h注射组减少,缺血后适应组各时间点含铁粒子细胞均较缺血组减少；抗IL-1β与ED-1免疫荧光双标染色激光扫描共聚焦显微镜检查显示缺血后24h缺血灶可见大量ED-1阳性小胶质细胞/巨噬细胞浸润,IL-1β表达增强,随时间延长,48h及72h小胶质细胞/巨噬细胞数量减少,IL-1β表达减弱,但在72h病变周边出现了多个体积较大的巨噬细胞；IL-1β表达与ED-1共染。缺血组及缺血后适应组中24h时IL-1β与ED-1阳性表达细胞数均高于48h及72h(P<0.05),并且48h时IL-1β与ED-1阳性表达细胞数均高于72h(P<0.05),缺血组24h及48h时IL-1β与ED-1阳性表达细胞数均高于缺血后适应组同一时间点(P<0.05),缺血组72h时IL-1β与ED-1阳性表达细胞数与缺血后适应组无明显差别(P>0.05)。结论：小胶质/巨噬细胞参与了急性期血栓性脑梗塞动物模型的缺血性脑损伤的病理过程；应用SPIO增强MRI成像可用于活体监测脑缺血后急性期巨噬细胞的浸润情况：缺血后适应可以减轻脑缺血后小胶质/巨噬细胞的浸润及炎症介质的表达,SPIO增强MRI可以在活体内监测脑缺血后适应对脑缺血后急性期炎症反应的改变。
Objective: To establish the models of thrombotic cerebral ischemia and ischemic postconditioning in tree shrews,and to observe the the MRI characteristics,including plain, diffusion weighted imaging(DWI) and gadolinium-diethylenetriaminepenta-acetate (Gd-DTPA) enhanced scan,and to explore the value of MRI for monitoring thrombotic cerebral ischemia and ischemic postconditioning, which may provide a theoretical basis for clinical application and experimental evidence.
Methods:The thrombotic cerebral ischemia were induced by photochemical reaction in tree shrews to establish the ischemic models,and at4h after ischemia ischemic postconditioning were established by3repeated cycles of occlusion of the right carotid arteries5min,and reperfusion5min.3.0T MR imaging was performed after4h,24h,48h and72h after ischemia, to observe the change characteristics of thrombotic cerebral ischemia. The data were measured on the workstation including the volume of abnormal signal on the DWI and T2WI images, the values of relative signal intensity (rSI) on the T1WI and T2WI images, the relative apparent diffusion coefficient(rADC) on the ADC images and the signal intensity(SI) on the enhanced images of the lesion center and marginal area. The changes of the cells and cortical infarct size in the different regions were observed between cerebral ischemia group and ischemic postconditioning group through HE staining,2,3,5-triphenyltetrazolium chloride(TTC) staining, respectively.
Results:There were no abnormalities in MRI and TTC in the sham group at all time points. In the ischemia group,the signal changes were observed at4h and the signal relative value of the central area at24h was the largest, which had a significant difference in comparison with4h,48h and72h(P<0.05). Moreover, the signal relative values were no significant difference in different time points between the ischemia group and the ischemic postconditioning group(P>0.05). In the ischemia group, the rADC value decreased in the different parts of the lesions and decreased to about57.63%in the central area at4h, remained relative low level in24h. However, the rADC value in the central area significantly increased at48h and72h, which had significant difference at4h,24h,48h and72h(P<0.05). The rADC values were no significant difference at each time point in the central area between the ischemia group and the ischemic postconditioning group (P>0.05). In the ischemia group, the rADC value in the marginal area decreased from4h to24h and decreased to about66.16%in24h. However, the rADC value increased after24h, which were significant difference in comparison with at4h,48h and72h(P<0.05). In the ischemic postconditioning group, the rADC values in the marginal area gradually increased from4h to72h. Compared with ischemic group, at each time point, the rADC values of the ischemic postconditioning group was statistically different at24h,48h (P<0.05) and no significant difference at4h,72h (P>0.05). In the ischemic group, the rADC value at4h had statistically significant between the lesion center and marginal area (P <0.05), however, there were no significant difference at24h,48h,72h (P>0.05).Compare the volume of infarct area measured by TTC and high signal on DWI, there was statistically significant at4h (P<0.05), however, there were no significant difference at24h,48h and72h(P>0.05). In the ischemia group, the largest volume(83.5±9.2mm3)of cerebral ischemic lesion showed at24h. The largest volume at4h had significant difference in comparison with24h,48h and72h (P<0.05). In the ischemic postconditioning group, the volume of cerebral ischemic lesion showed no significant increase from4h(64.9±6.8mm3) to24h(69.1±5.7mm3). There had no significant difference at the different time (P>0.05). The lesions of all the animal between the ischemia group and ischemic postconditioning group showed abnormal enhancement after injection Gd-DTPA at different time points. SI increase rate at24h in the ischemia group was higher than the other time points, which was significant difference compared with that of4h,48h and72h (P＜0.05). The volume on enhanced images was lower than on T2WI images, which had significant difference (P<0.05). Compared SI increase rate in the ischemia group with the ischemic postconditioning group, there were significant difference at24h,48h and72h (P<0.05), which the latter was lower than the former. Light microscopy showed neurons shrinkage in the central area after4hour-ischemia and swelling between ischemic tissue and normal tissue edema, and ischemic penumbra neurons swelling and pyknosis, parts of the endovascular platelet accumulation and thrombosis. After24hour-ischemia, ischemic core tissue dissolved, showing the loose network structure and the demyelination of neurons, pyknosis were obviously observed by light microscopy. Moreover, after48and72hour-ischemia, eosinophilic neurons appeared, which made the whole cells be stained red.
Conclusion:MRI may be useful to reflect the pathological evolution process at different time points after ischemia of the thrombotic cerebral ischemia animal models and evaluate the effects of ischemic postconditioning. The infarcted volume of ischemic postconditioning group was smaller than ischemic group, combined with semi-quantitative parameter rADC value, through which the cause may be supposed to save the penumbra. In the ischemic postconditioning group, SI increase rate after enhance was lower than the ischemic group, which may be considered to decrease the damage to the blood-brain barrier.
Objective:To establish the models of thrombotic cerebral ischemia and ischemic postconditioning in tree shrews,and to observe the SPIO-enhanced MRI characteristics, compared with Prussian blue staining and anti-IL-1β and anti-ED-1by double immunofluorescence staining,and to explore the value of the SPIO-enhanced MRI for monitoring thrombotic cerebral ischemia and ischemic postconditioning, which may provide a theoretical basis for clinical application and experimental evidence.
Methods:The thrombotic cerebral ischemia were induced by photochemical reaction in tree shrews to establish the ischemic models,and at4h after ischemia ischemic postconditioning were established by3repeated cycles of occlusion of the right carotid arteries5min,and reperfusion5min. SPIO was injected at4h,24h and48h after ischemia and3.0T MR imaging was performed at24h after injection and to observe the characteristics of SPIO-enhanced MRI.The T2WI rSI were measured on the workstation on the T2WI images.By showed The morphology and location of iron particle in the lesion was detected by Prussian blue staining.The invasion of macrophages after cerebral ischemia in the lesion was observed with anti-IL-1β and anti-ED-1by double immunofluorescence staining laser scanning confocal microscopic examination.
Results:There were no abnormalities in MRI in the sham group at all time points. In the ischemia group,the low signal changes in the ischemic lesions were observed at24h after injection and the patterns of the low signal were identical at24h,48h and72h after injected SPIO at4h.The T2WI rSI at24h,48h and72h after injected SPIO at4h had a significant difference in comparison with plain scan(P<0.05).The T2WI rSI had no significant difference among24h,48h and72h after injected SPIO at4h(P>0.05). The patterns of the low signal were identical at48h and72h after injected SPIO at24h.The T2WI rSI at48h and72h after injected SPIO at24h had no significant difference in comparison with plain scan(P>0.05).The T2WI rSI at72h after injected SPIO at48h had no significant difference in comparison with plain scan(P>0.05).In the ischemic postconditioning group,the T2WI rSI at24h,48h and72h after injected SPIO at4h were higher than in the ischemia group and there were a significant difference between the groups (P<0.05). The T2WI rSI at48h and72h in the ischemic postconditioning group after injected SPIO at24h had no significant difference in comparison with the ischemia group(P>0.05). The T2WI rSI at72h in the ischemic postconditioning group after injected SPIO at48h had no significant difference in comparison with the ischemia group(P>0.05). The iron particles were mainly located within the cells in the vascular lumens by Prussian blue staining at24h after ischemia. The iron particles were mainly located in the cells out of the vascular lumens at72h. The numbers of the iron particles at24h and48h after ischemia were lower than at4h.The numbers of the iron particles in the ischemic postconditioning group were lower than in the ischemia group.There were a large number of ED-1positive microglia/macrophages detected by double immuno-fluorescence staining laser scanning confocal microscopic examination in the surrounding area of the infarct at24h after ischemia. While the number of microglia/macrophages at48h and72h is less than at24h.But there were many large macrophages around the lesions at72h. The IL-1β expression can be seen at24h after ischemia which was stained with ED-1. The numbers of ED-1and IL-1B positive cells at24h after ischemia in the ischemic and postconditioning groups were more than at48h and72h (P<0.05). The numbers of ED-1and IL-1B positive cells at48h after ischemia in the ischemic and postconditioning groups were more than at72h (P<0.05). The numbers of ED-1and IL-1β positive cells at24h and48h after ischemia in the ischemic groups were more than and in the postconditioning group(P<0.05). The numbers of ED-1and IL-1β positive cells at72h after ischemia in the ischemic groups had no significant difference in comparison with the ischemic postconditioning group(P>0.05).
Conclusion: Microglia/macrophages involved in the pathological process of ischemic brain injury in the acute phase of thrombotic infarction animal models.In vivo SPIO-Enhanced MRI imaging can be used for monitoring of macrophage invasion situation of acute thrombotic cerebral ischemia induced by photochemical reaction in tree shrews.Ischemic postconditioning can reduce cerebral ischemia microglia/macrophage invasion and expression of inflammatory mediators. SPIO-enhanced MRI can monitor the changes in the acute phase inflammatory response after cerebral ischemia postconditioning in vivo.
目的：通过采用超顺磁性氧化铁颗粒(superparamagnetic iron oxide,SPIO)增强MRI对树鼩血栓性脑缺血及缺血后适应动物模型进行动态扫描,观察病灶的改变特点,并与普鲁士蓝染色及抗白介素-1β(Interleukin-1beta, IL-1β)与单核/巨噬细胞表面特异性标志抗原(Ectodermal dysplasia-1, ED-1)免疫荧光双标染色结果相对照,探讨SPIO增强MRI对缺血后适应所致脑缺血炎症反应改变的活体监测价值。方法：采用光化学反应诱导建立树鼩血栓性脑缺血模型,在造模成功4h后夹闭右侧颈总动脉5min,再灌注5min,共计交替进行3个循环实施缺血后适应。应用3.0T MRI,在缺血后4h、24h及48h注射SPIO,观察SPIO增强后MRI改变特点,测量不同时间点T2WI rSI值；通过普鲁士蓝染色显示缺血灶内铁粒子形态及部位；采用抗IL-1β与ED-1免疫荧光双标染色激光扫描共聚焦显微镜检查观察脑缺血组及缺血后适应组巨噬细胞浸润及IL-1β的表达情况。结果：假手术组各时间点MRI未见异常；缺血组于注射SPIO后24h及以后时间点扫描缺血灶内可见低信号,4h注射组24h、48h及72h低信号形态未见明显改变,T2WI rSI值未见变化(P>0.05),在24h、48h及72h时T2WI rSI低于缺血平扫组(P<0.05)；24h注射组48h及72h扫描可见低信号,低信号形态未见明显改变,T2WI rSI值未见变化(P>0.05),48h及72h T2WI rSI与缺血平扫组对比,无统计学差异(P>0.05)；48h注射组,72h时可见低信号,但T2WI rSI与缺血平扫组对比,无统计学差异(P>0.05)；缺血后适应组注射SPIO后24h及以后各时间点缺血灶内可见低信号,缺血后适应4h注射SPIO组24h、48h及72h时T2WI rSI高于缺血4h注射SPIO组(P<0.05),缺血后适应24h注射SPIO组48h及72h缺血灶T2WI rSI略低于缺血24h注射SPIO组,但经统计学分析,两组间T2WI rSl无统计学差异(P>0.05),缺血后适应48h注射SPIO组与缺血组72h T2WI rSI相比较,经统计学分析,无统计学差异(P>0.05)；普鲁士蓝染色显示缺血4h注射组24h时含铁粒子细胞主要位于血管腔内,随缺血时间延长,血管腔内含铁粒子细胞减少,于72h主要位于血管外组织内；24h及48h注射组含铁粒子细胞较4h注射组减少,缺血后适应组各时间点含铁粒子细胞均较缺血组减少；抗IL-1β与ED-1免疫荧光双标染色激光扫描共聚焦显微镜检查显示缺血后24h缺血灶可见大量ED-1阳性小胶质细胞/巨噬细胞浸润,IL-1β表达增强,随时间延长,48h及72h小胶质细胞/巨噬细胞数量减少,IL-1β表达减弱,但在72h病变周边出现了多个体积较大的巨噬细胞；IL-1β表达与ED-1共染。缺血组及缺血后适应组中24h时IL-1β与ED-1阳性表达细胞数均高于48h及72h(P<0.05),并且48h时IL-1β与ED-1阳性表达细胞数均高于72h(P<0.05),缺血组24h及48h时IL-1β与ED-1阳性表达细胞数均高于缺血后适应组同一时间点(P<0.05),缺血组72h时IL-1β与ED-1阳性表达细胞数与缺血后适应组无明显差别(P>0.05)。结论：小胶质/巨噬细胞参与了急性期血栓性脑梗塞动物模型的缺血性脑损伤的病理过程；应用SPIO增强MRI成像可用于活体监测脑缺血后急性期巨噬细胞的浸润情况：缺血后适应可以减轻脑缺血后小胶质/巨噬细胞的浸润及炎症介质的表达,SPIO增强MRI可以在活体内监测脑缺血后适应对脑缺血后急性期炎症反应的改变。
Objective: To establish the models of thrombotic cerebral ischemia and ischemic postconditioning in tree shrews,and to observe the the MRI characteristics,including plain, diffusion weighted imaging(DWI) and gadolinium-diethylenetriaminepenta-acetate (Gd-DTPA) enhanced scan,and to explore the value of MRI for monitoring thrombotic cerebral ischemia and ischemic postconditioning, which may provide a theoretical basis for clinical application and experimental evidence.
Methods:The thrombotic cerebral ischemia were induced by photochemical reaction in tree shrews to establish the ischemic models,and at4h after ischemia ischemic postconditioning were established by3repeated cycles of occlusion of the right carotid arteries5min,and reperfusion5min.3.0T MR imaging was performed after4h,24h,48h and72h after ischemia, to observe the change characteristics of thrombotic cerebral ischemia. The data were measured on the workstation including the volume of abnormal signal on the DWI and T2WI images, the values of relative signal intensity (rSI) on the T1WI and T2WI images, the relative apparent diffusion coefficient(rADC) on the ADC images and the signal intensity(SI) on the enhanced images of the lesion center and marginal area. The changes of the cells and cortical infarct size in the different regions were observed between cerebral ischemia group and ischemic postconditioning group through HE staining,2,3,5-triphenyltetrazolium chloride(TTC) staining, respectively.
Results:There were no abnormalities in MRI and TTC in the sham group at all time points. In the ischemia group,the signal changes were observed at4h and the signal relative value of the central area at24h was the largest, which had a significant difference in comparison with4h,48h and72h(P<0.05). Moreover, the signal relative values were no significant difference in different time points between the ischemia group and the ischemic postconditioning group(P>0.05). In the ischemia group, the rADC value decreased in the different parts of the lesions and decreased to about57.63%in the central area at4h, remained relative low level in24h. However, the rADC value in the central area significantly increased at48h and72h, which had significant difference at4h,24h,48h and72h(P<0.05). The rADC values were no significant difference at each time point in the central area between the ischemia group and the ischemic postconditioning group (P>0.05). In the ischemia group, the rADC value in the marginal area decreased from4h to24h and decreased to about66.16%in24h. However, the rADC value increased after24h, which were significant difference in comparison with at4h,48h and72h(P<0.05). In the ischemic postconditioning group, the rADC values in the marginal area gradually increased from4h to72h. Compared with ischemic group, at each time point, the rADC values of the ischemic postconditioning group was statistically different at24h,48h (P<0.05) and no significant difference at4h,72h (P>0.05). In the ischemic group, the rADC value at4h had statistically significant between the lesion center and marginal area (P <0.05), however, there were no significant difference at24h,48h,72h (P>0.05).Compare the volume of infarct area measured by TTC and high signal on DWI, there was statistically significant at4h (P<0.05), however, there were no significant difference at24h,48h and72h(P>0.05). In the ischemia group, the largest volume(83.5±9.2mm3)of cerebral ischemic lesion showed at24h. The largest volume at4h had significant difference in comparison with24h,48h and72h (P<0.05). In the ischemic postconditioning group, the volume of cerebral ischemic lesion showed no significant increase from4h(64.9±6.8mm3) to24h(69.1±5.7mm3). There had no significant difference at the different time (P>0.05). The lesions of all the animal between the ischemia group and ischemic postconditioning group showed abnormal enhancement after injection Gd-DTPA at different time points. SI increase rate at24h in the ischemia group was higher than the other time points, which was significant difference compared with that of4h,48h and72h (P＜0.05). The volume on enhanced images was lower than on T2WI images, which had significant difference (P<0.05). Compared SI increase rate in the ischemia group with the ischemic postconditioning group, there were significant difference at24h,48h and72h (P<0.05), which the latter was lower than the former. Light microscopy showed neurons shrinkage in the central area after4hour-ischemia and swelling between ischemic tissue and normal tissue edema, and ischemic penumbra neurons swelling and pyknosis, parts of the endovascular platelet accumulation and thrombosis. After24hour-ischemia, ischemic core tissue dissolved, showing the loose network structure and the demyelination of neurons, pyknosis were obviously observed by light microscopy. Moreover, after48and72hour-ischemia, eosinophilic neurons appeared, which made the whole cells be stained red.
Conclusion:MRI may be useful to reflect the pathological evolution process at different time points after ischemia of the thrombotic cerebral ischemia animal models and evaluate the effects of ischemic postconditioning. The infarcted volume of ischemic postconditioning group was smaller than ischemic group, combined with semi-quantitative parameter rADC value, through which the cause may be supposed to save the penumbra. In the ischemic postconditioning group, SI increase rate after enhance was lower than the ischemic group, which may be considered to decrease the damage to the blood-brain barrier.
Objective:To establish the models of thrombotic cerebral ischemia and ischemic postconditioning in tree shrews,and to observe the SPIO-enhanced MRI characteristics, compared with Prussian blue staining and anti-IL-1β and anti-ED-1by double immunofluorescence staining,and to explore the value of the SPIO-enhanced MRI for monitoring thrombotic cerebral ischemia and ischemic postconditioning, which may provide a theoretical basis for clinical application and experimental evidence.
Methods:The thrombotic cerebral ischemia were induced by photochemical reaction in tree shrews to establish the ischemic models,and at4h after ischemia ischemic postconditioning were established by3repeated cycles of occlusion of the right carotid arteries5min,and reperfusion5min. SPIO was injected at4h,24h and48h after ischemia and3.0T MR imaging was performed at24h after injection and to observe the characteristics of SPIO-enhanced MRI.The T2WI rSI were measured on the workstation on the T2WI images.By showed The morphology and location of iron particle in the lesion was detected by Prussian blue staining.The invasion of macrophages after cerebral ischemia in the lesion was observed with anti-IL-1β and anti-ED-1by double immunofluorescence staining laser scanning confocal microscopic examination.
Results:There were no abnormalities in MRI in the sham group at all time points. In the ischemia group,the low signal changes in the ischemic lesions were observed at24h after injection and the patterns of the low signal were identical at24h,48h and72h after injected SPIO at4h.The T2WI rSI at24h,48h and72h after injected SPIO at4h had a significant difference in comparison with plain scan(P<0.05).The T2WI rSI had no significant difference among24h,48h and72h after injected SPIO at4h(P>0.05). The patterns of the low signal were identical at48h and72h after injected SPIO at24h.The T2WI rSI at48h and72h after injected SPIO at24h had no significant difference in comparison with plain scan(P>0.05).The T2WI rSI at72h after injected SPIO at48h had no significant difference in comparison with plain scan(P>0.05).In the ischemic postconditioning group,the T2WI rSI at24h,48h and72h after injected SPIO at4h were higher than in the ischemia group and there were a significant difference between the groups (P<0.05). The T2WI rSI at48h and72h in the ischemic postconditioning group after injected SPIO at24h had no significant difference in comparison with the ischemia group(P>0.05). The T2WI rSI at72h in the ischemic postconditioning group after injected SPIO at48h had no significant difference in comparison with the ischemia group(P>0.05). The iron particles were mainly located within the cells in the vascular lumens by Prussian blue staining at24h after ischemia. The iron particles were mainly located in the cells out of the vascular lumens at72h. The numbers of the iron particles at24h and48h after ischemia were lower than at4h.The numbers of the iron particles in the ischemic postconditioning group were lower than in the ischemia group.There were a large number of ED-1positive microglia/macrophages detected by double immuno-fluorescence staining laser scanning confocal microscopic examination in the surrounding area of the infarct at24h after ischemia. While the number of microglia/macrophages at48h and72h is less than at24h.But there were many large macrophages around the lesions at72h. The IL-1β expression can be seen at24h after ischemia which was stained with ED-1. The numbers of ED-1and IL-1B positive cells at24h after ischemia in the ischemic and postconditioning groups were more than at48h and72h (P<0.05). The numbers of ED-1and IL-1B positive cells at48h after ischemia in the ischemic and postconditioning groups were more than at72h (P<0.05). The numbers of ED-1and IL-1β positive cells at24h and48h after ischemia in the ischemic groups were more than and in the postconditioning group(P<0.05). The numbers of ED-1and IL-1β positive cells at72h after ischemia in the ischemic groups had no significant difference in comparison with the ischemic postconditioning group(P>0.05).
Conclusion: Microglia/macrophages involved in the pathological process of ischemic brain injury in the acute phase of thrombotic infarction animal models.In vivo SPIO-Enhanced MRI imaging can be used for monitoring of macrophage invasion situation of acute thrombotic cerebral ischemia induced by photochemical reaction in tree shrews.Ischemic postconditioning can reduce cerebral ischemia microglia/macrophage invasion and expression of inflammatory mediators. SPIO-enhanced MRI can monitor the changes in the acute phase inflammatory response after cerebral ischemia postconditioning in vivo.
引文
1. 王伊龙,王拥军,吴敌等.中国卒中防治研究现状.中国卒中杂志.2001,,2(1)：20-37.
2. Adams H, Adams R, Del Zoppo G,,et al.Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke,2005;36:916-923.
3. 全国降纤酶临床再评价研究协作组.降纤酶治疗急性脑梗死临床再评价.中华神经科杂志,2005,38(1)：11-16.
4. 吴兆苏,姚崇华,赵东等.我国人群脑卒中发病率、死亡率的流行病学研究.中华流行病学杂志,2003,24(3)：236-239.
5. Zhao ZQ,Corvera JS,et al.Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning. Am J Physiol HeartCire Physiol,2003:285:579-588.
6. Wang JY,Shen J,Gao Q,et al.lschemic postconditioning protects against global cerebral ischemia/reperfusion-induced injury in rats. Stroke,2008;39(3):983-90.
7. Xing B,Chen H,Zhang M,et al.Ischemic postconditioning inhibits apoptosis after focal cerebral ischemia/reperfusion injury in the rat. Stroke,2008;39(8):2362-9.
8. 彭燕章,叶智彰,邹如金等.树鼩生物学[M].云南：云南科技出版社,1991：358-360.
9. 李树清,赵文洁,杨琼英.光化学诱导的血栓形成局部脑缺血的动物模型.中国病理生理杂志,1992,8(3)：333.
10. Hagmann P,Jonasson L,Maeder P,et al. Understanding diffusion MR imaging techniques: from scalar diffusion-weighted imaging to diffusion tensor imaging and beyond. Radio-graphics,2006;26:S205-S223.
11. Schaefer PW.Romero JM,Grant PE,et al.Perfusion magnetic resonance imaging of acute ischemic stroke. Semin Roentgenol,2002,37:230-236.
12. Konig M. Brain perfusion CT in acute stroke:current status. EJR,2003,45:11-22.
13.程敬亮,冯敢生,孔祥泉等。兔急性期脑梗死核心和缺血半暗带磁共振表观扩散系数与病理对照观察.郑州大学学报(医学版),2005,40(2)：218-221.
14. Schaefer PW,Ozsunar Y,He J,et al.Assessing tissue viability with MR diffusion and perfusion imaging. AJNR,2003,24:436-443.
15. Robert TPL.Rowley HA.Diffusion weighted magnetic resonance imaging in stroke.EJR, 2003,45:185-194.
16. Li Shuqing.Meng Qiang,Zhang Lineng.Experimental therapy of palatelet-activating factor antagonist(ginkgolide B) on photochemically induced thrombotic cerebral ischemia in tree shrews. Clin Experiment Pharnacol Physiol,1999;26:824-826.
17. Yi-Wei Tsail,Yea-Ru Yang,Gun-Hao Chen,et al.The time window of intermittent hypoxia intervention after middle cerebral artery occlusion. Chinese Journal of Physiology,2008, 51(5):324-328.
18. Walberer M,Stolz E,Muller C,et al.Experimental stroke:ischemic lesion volume and edema formation differ among rat strains(a comparison between Wistar and Sprague-Dawley rats using MRI). Lab Anim,2006,40:1-8.
19. Gerriets T,Stolz E,Walberer M,et al.Noninvasive quantification of brain edema and the space-occupying effect in rat stroke models using magnetic resonance imaging.Stroke,2004, 35:566-571.
20.彭燕章,叶智彰,邹如金等.树鼩生物学.昆明：云南科技出版社：1991：14.
21.沈培清,郑红,刘汝文等.中国树鼩实验动物化研究进展和展望.动物学研究,2011；32(1)：109-114.
22.孙晓梅,叶尤松,罕圆圆等.树鼩的基本实验操作方法.中国比较医学杂志,2009,19(12)：76-78.
23.叶尤松,罕圆圆,黄璋琼等.野生成年树鼩主要脏器重量及脏器系数的测定分析.中国比较医学杂志,2011,21(4)：62-65.
24.叶峻.树鼩大脑皮层结构和功能分区的颅内定位.解剖学杂志,1996,19(6)：535-538.
25.李树清,张颖,杨丽君等.树鼩脑局部血栓性缺血的扩布性抑制机制探讨.微循环学杂志,2005,15(2)：4-7.
26. Zhang Z, Zhang RL, Jiang Q, et al. A new rat model of thrombotic focal cerebral ischemia. J Cereb Blood Flow Metab,1997;17(2):123-135.
27.赵瑾,苑琳,王驭龙等.线栓法复制昆明小鼠局灶性脑缺血再灌注模型的稳定性研究.中国病理生理杂志,2011,27(7)：1450-1452、1456.
28.何斌,张劲松,邵斌霞等.线栓法制大鼠脑缺血模型操作和评价的改良.中华急诊医学杂志,2009,18(12)：1248-1250.
29.郭巧生.药用植物栽培学.北京：高等教育出版社,2004,52.
30. Hatifield RH,Mendelow AD,Perry,et al.Triphenyltetrazolium chloride(TTC) as a marker for ischemic changes in rat brain following permanent middle cerebral artery occlusion. Neuro-pathol Appl Neurobiol,1991,17(1):61-67.
31. Robert A Knight,Kishor Karki,James R Ewing,et al.Estimating blood and brain concentrations and blood-to-brain influx by magnetic resonance imaging with step-down infusion of Gd-DTPA in focal transient cerebral ischemia and confirmation by quantitative autoradiography with Gd-[14C]DTPA.Journal of Cerebral Blood Flow & Metabolism,2009, 29 (3),1048-1058.
32. Gian Luca Breschi.Laura Librizzi.Chiara Pastori.et al.Functional and structural correlates of magnetic resonance patterns in a new in vitro model of cerebral ischemia by transient occlusion of the medial cerebral artery. Neurbiology of Disease,2010,39(4):181-191.
33. Teng-Nan Lin,Shu-Wei Sun,Wai-Mui Cheung,et al.Dynamic changes in cerebral blood flow and angiogenesis after transient focal cerebral ischemia in rats evaluation with serial magnetic resonance imaging.Stroke,2002,33(10):2985-2991.
34. Palmer GC.Peeling J,Corbett D,et al.T2WI MRI correlates with long-term histopathology, neurology scores,and skilled motor behavior in a rat stroke model.Ann N Y Acad Sci,2001, 939:283-296.
35. Bandera E,Botteri M,Minelli C,et al.Cerebral blood flow threshold of ischemic penumbra and infarct core in acute ischemic stroke: a systematic review. Stroke,2006;37:1334-1339.
36. Mullins ME,Schaefer PW,Sorensen AG,et al. CT and conventional and diffusion-weighted MR imaging in acute stroke:study in 691 patients at presentation to the emergency depart-ment. Radiology,2002;224:353-360.
37. Busza AL,Allen KL,King MD,et al.Diffusion-weighted imaging studies of cerebral ischemia in gerbils.Potential relevance to energy failure. Stroke,1992,23(11):1602-1612.
38. Mintorovitch H,Yang GY, Shimizu H,et al.Diffusion-weighted magnetic resonance imaging of acute focal cerebral ischemia: comparison of signal intensity with changes in brain water and Na+-K+-ATPase activity. J Cereb Blood Flow Metab,1994,14(2):332-336.
39. Kanemitsu H,Nakagomi T,Tamura A,et al.Differences in the extent of primary ischemic damage between middle cerebral artery coagulation and intraluminal occlusion models. J Cereb Blood Flow Metab,2002,22(10):1196-1204.
40. Hoehn-Berlage M,Norris DG.Kohno K.et al.Evolution of regional changes in apparent diffusion coefficient during focal ischemia of rat brain:the relationship of quantitative diffusion NMR imaging to reduction in cerebral blood flow and metabolic disturbances J Cereb Blood Flow MeTable.1995,15(6):1002-1011.
41. Minematsi K,Li L,Fisher M,et al.Diffusion weighted magnetic resonance imaging:rapid and quantitative detection of focal brain ischemia.Neurology.1992,42(1):235-240.
42. Li F,Silva MD,Sotak CH,et al.Temporal evolution of ischemia injury evaluated with diffusion perfusion and T2-weighted MRl.Neurology.2005,54(3):689-696.
43. Matsumoto K,Lo EH.Pierce AR.et al.Role of vasogenic edema and tissue evitation in ischemic evolution on diffusion-weighted imaging: comparison with multiparameter MR and immunohistochemistry.AJNR Am J Neuroradiol.1998,16(5):1107-1115.
44. Schaefer PW,Grant PE,Gonzalez RG.Diffusion-weighted MR imaging of the brain.Radiology 2000,217(2):331-345.
45. Stadnik T W,Demaerel P,Luypaet RR.et al.lmaging tutorial:diffusion diagnosis of bright lesions on diffusion-weighted M R images[J].Radiographics.2003.23:e7.
46. Rowley HA,Grant PE,Roberts TP.Diffusion MR Imaging:theory and application. Neuro-imaging Clin N Am.1999,9(2):343-361.
47. Rosso C,Drier A,Lacroix D,et al. Diffusion-weighted MRI in acute stroke within the first 6 hours:1.5 or 3.0 Tesla?[J].Neurology.2010,74(24):1946-53.
48. Wick M,Nagatomo Y,Prielmeier F.et al.Alteration of intracellular metabolite diffusion in rat brain in vivo during ischemia and reperfusion Stroke.1995,26(10):1930-1933.
49. Schlaug G,Siewert B,Beinfield A,et al.Time course of the apparent diffusion coefficient (ADC)abnormality in human stroke.Neurology.1997,49(1):113-119.
50. Astrup J,Siesjo BK,Symon L.Threshold in cerebral ischemia-the ischemic penumbra.Stroke. 1981,6:723-725.
51. Heiss WD,Graf R.The ischemic penumbra.Curr Opin Neurol.1994,7(1)11-19.
52. Heiss WD.The concept of the penumbra:can it be translated to stroke management?Int J Stroke.2010,5(4):290-295.
53.高晶,郭玉璞,谭静江,等.组织学方法界定脑梗死缺血半暗带的可行性探讨.中华神经科杂 志.2011,34(4)：99-102.
54. Feng Chen,Yi-Cheng Ni.Magnetic resonance diffusion-perfusion mismatch in acute ischemic stroke:an update. World J Radiol.2012,28;4(3):64-74.
55. Lee SK,Kim DI,Jeong EK,et al.Temporal changes in reversible cerebral ischemic on perfusion and diffusion-weighted magnetic resonance imaging:the value of relative cerebral blood volume maps.Neuroradiology,2002,44(2):103-108.
56. Lin TN.Sun SW.Cheung WM,et al.Dynamic changes in cerebral blood flow and angiogenesis after transient focal cerebral ischemic in rats.Evaluation with serial magnetic resonance imaging.Stroke,2002,33(12):2985-2991.
57. Kidwell CS,Alger JR,Saver JL.Beyond mismatch evolving paradigms in imaging the ischemic penumbra with multimodal magnetic resonance imaging.Stroke,2003,34:2729-2735.
58. Warach S.Moseley ME,Sorensen AG,et al.Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging.Ann neurol,1995,37:231-241.
59. Desmond PK,Lovell AC,Rawlinson AA,et al.The value of apparent diffusion coefficient maps in early cerebral ischemic.AJNR Am J Neuroradiol,2001:22(7):1260-1267.
60. Liu KF,Li F,Tatlisumak T,et al.Regional variations in the apparent diffusion coefficient and the intracellular distribution of water in rat brain during acute focal ischemia.Stroke 2001:32(8):1897-1905.
61.张川荛.后适应对树鼩血栓性脑缺血时神经保护效应的比较研究：硕士学位论文.昆明：昆明医学院,2011.
62. Harris NG,Gauden V,Fraser PA,et al. MRI measurement of blood-brain barrier permeability following spontaneous reperfusion in the microsphere model of ischemic[J].Magn Reson Imaging,2002,20(3):221-230.
63. Lo EH,Pan Y,Matsumoto K,et al.Blood-brain barrier disruption in experimental focal ischemia:comparison between in vivo MRI and immunocytochemistry.Magn Reson Imaging.1994; 12(3):403-11.
64. Felix R,Schorner W,Laniado M,et al.Brain tumors:MR imaging with Gd-DTPA.Radiology, 1985;156:681-688.
65.全冠民,张云亭.缺血后血脑屏障开放与血管源性水肿的MR研究.国外医学临床放射学 分册,2002：25(4)：221-224.
66. Virapongse C,Mancuse A,Quisling R.Human brain infarcts:Gd-DTPA-enhanced MR imaging. Radiology,1986; 161:785-794.
67.唐代彬.光化学诱导树鼩脑血栓形成后海马BBB通透性及缺血微环境动态变化的研究：[硕士学位论文].昆明：昆明医学院,2005
68. Barzo P,Marmarou A,Fatouros P,Corwin F,Dunbar J,Magnetic resonance imaging-monitored acute blood-brain barrier changes in experimental traumatic brain injury.J Neurosurg,1996; 85(6):1113-1121.
69. Wahlund LO,Bronge L.Contrast-enhanced MR1 of white matter lesions in patients with blood brain barrier dysfunction. Ann NY Acad Sci,2000,903(4):477-481.
70. Barzo P,Marmarou A,Fatouros P.Acute blood-brain barrier changes in experimental closed head injury as measured by MRI and Gd-DTPA.Acta Neurochir Suppl.1997.70:243-246.
71.徐凯,黄海东,沈天真.等.大鼠急性脑缺血再灌注后血脑屏障的变化.中国医学影像技术.2005,21(4)：519-522.
72.刘含秋,丁乙,陈学仁.增强MRI评价可逆性血脑屏障开发的可靠性及价值.中华放射学杂志.1998,32(5)：338-340.
73. Zhao H,Robert MS,Gary KS,et al.Interrupting reperfusion as a stroke therapy ischemic postconditioning reduces infarct size after focal ischemic in rats.Journal of Cerebral Blood Flow & Metabolism.2006,26:1114-1121.
74. Murry CE,Jennings RB,reamer KA.Preconditioning with ischemia:a delay of lethal cell injury in ischemic myocardium.Circulation.1986,74(5):1124-36.
75. Steiger H,Hanggi D.Ischemic Preconditioning of the brain,mechanisms and applications. Acta Neurochir(Wien).2007,149:1-10.
76. Perez-Pinzon M.Mechanisms of neuroprotection during ischemic preconditioning:lessons from anoxic tolerance.Comp Biochem Physiol A Mol Integrphysiol,207,147:291-299.
77. Perez-Pinzon M.Neuroprotective effects of ischemic preconditioning in brain mitochondria following cerebral ischemia.Bioenerg Biomembranes,2004,36:323-327.
78. Staat P,Rioufol G,Piot C,et al.Postconditioning the human heart.Circulation,2005,112: 2143-2148.
79. Gao XW,Ren CC,Zhao H.Protective effects of ischemic postconditioning compared with gradual reperfusion or preconditioning.Journal of Neuroscience Research,2008,86:2505-2511.
80. Kin H,Zatta AJ,Lofye MT,et al.Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine.Cardiovasc Res,2005,67(1):124-133.
81. Hausenloy DJ.Yellon DM.Survival kinases in ischemic preconditioning and postconditioning. CardiovascRes,2006,70:240-253.
82. Viera Danielisov'a,Miroslava Nemethovoa,Miroslav Gottlieb,et al.The changes in endogen-ous antioxidant enzyme activity after postconditioning.Cellular and Molecular Neurobiology, 2006,26:1181-1191.
83. Wang JY,shen J,Gao Q,et al.Ischemic postconditioning protects against global cerebral ischemia/reperfusion-induced injury in rats,Stroke,2008,39(3):983-990.
84. Xing B,Chen H,Zhang M,ct al.Ischemic post-conditioning protects brain and reduces inflammation in a rat model of focal cerebral ischemia/reperfusion.Neurochen,2008,54(12): 896.
85. Tsang A.Hausenloy DJ.Mocanu MM.et al.Postconditioning:a form of "modified reperfusion" protects the myocardium by activating the phosphatidyl inositol 3-kinase-Akt pathway.Circ Res.2004,95(3):230-232.
86.李树清,罗海芸.缺血后适应对树鼩海马CA1区脑血流及星形胶质细胞活化的影像及可能机制。中国病理生理杂志,2008,24(6)：1090-1095.
87.李树清,罗海芸,俞志成.后适应对树鼩不同脑缺血模型同一“时间窗”海马神经元保护的比较.中国病理生理杂志,2011,27(5)：890-894.
88. Takuma A,Takashi M,Mikhail N,et al.Serum and glucocorticoid-responsive kinase-1 regulates cardiomyocyte survival and hypertrophic response.Circulation,2005. 111(1):1652-1659.
89.陈诗鸿,倪一虹,庄向华.脂联素激活AKT抑制H202诱导的大鼠心肌细胞凋亡.中国病理生理杂志,2010,26(11)：2161-2164.
90. Majersik JJ,Smith MA, Zahuranec DB,et al.Population-based analysis of the impact of expanding the time window for acute stroke treatment.Stroke,2007,38(12):3213-3217.
91. Kin H,Zhao ZQ.Sun HY,et al.Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion.Cardiovasc Res,2004,62 (1):74-85.
92. Vinten-Johansen J,Zhao ZQ,Zatta AJ,et al.Postconditioning-A new link in nature's armor against myocardial ischemia-reperfusion injury.Basic Res Cardiol,2005,100(4):295-310.
93. Burda J, Danielisova V, Nem ethova M. Delayed postconditioning initiates additive mechanism necessary for survival of selectively vulnerable neurons after transient ischemia in rat brain.Cell Mol Neurobiol,2006,26(7-8):1141-1151.
94. Ren C,Gao X,Niu G,et al.Delayed postconditioning protects against focal ischemic brain injury in rats.Plos One,2008,3(12):3851.
95. Yang X M,Proctor J B,Cui L,et al.MuItiple brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. Am Coll Cardio,2004,44:1103-1110.
96. Wang JY,Shen J,Gao Q,et al.Ischemic postconditioning protects against global cerebral ischemia reperfusion-induced injury in rats.stroke,2008,399(3):983-990.
97. Zhao ZQ,Vinten-Johansen J.Postconditioning:reduction of reperfusion-induced injury. Cardiovasc Res,2006,70(2):200-211.
98. Ren C,Gao X,Niu G,et al.Delayed postconditioning protects against focal ischemic brain injury in rats.Plos One,2008,3(12):3851.
99. Lee JM,Grabb MC,Zipfel GJ,et al,Brain tissue responses to ischemia. Clin Invest.2000, 106:723-731.
100. Pignataro G,Meller R,Inoue K,et al.In vivo and in vitro characterization of a novel neuroprotective strategy for stroke:ischemic postconditioning. Cereb Blood Flow Metab,2008, 28(2):232-241.
101. Ashwal S,Tone B,Tian HR,et al.Core and penumbral nitric oxide synthase activity during cerebral ischemia and reperfusion. Stroke.1998; 29(5):1037-1046.
102. Mecoll BW,Rothwell NJ,Allan SM.Systemic inflammation alters the kinetics of cerebro-vascular tight junction disruption after experimental stroke in mice.Neurosei,2008, 28(38):9451-94612
103.崔相宁,尹岭,王玉来,等.创伤性脑损伤大鼠脑组织基金金属蛋白酶的表达：中华老年心脑血管病杂志,2008,10(1)：53-56.
104. Mun-Bryce S,Rosenberg GA.Gelatinase B modulates selective opening of the blood-brain barrier during inflammation.Am. Physiol,1998,274(5):R 1203-1211.
105.李淑婷,吉训明,朱榆红,等.脑缺血后适应对基质金属蛋白酶-9表达的影响.脑与神经疾病杂志,2008,16(6)：659-662.
106.朱榆红,吉训明,李春艳,等.缺血后适应对大鼠脑缺血/再灌注损伤的影响.中国病理学杂志,2008,24(11)：2151-2155.
107.罗海芸,李树清.树鼩脑缺血后适应升高海马区rCBF及VEGF的变化.基础医学与临床,2008,28(7)：676-680.
108。赵克森,黄巧冰.血管通透性增高的基本机制.中国病理生理杂志,2003,19(4)：549-553.
1. Mu S,Ouyang L,Liu B,et al.Relationship between inflammatory reaction and ischemic injury of caudate-putamen in rats: inflammatory reaction and brain ischemia.Anat Sci Int,2011, 86(2):86-97.
2. Becker KJ,Targeting the central nervous system inflammatory response in ischemic stroke.Curr Opin Neuro,2001,14(3):349-353.
3. Akopoy SE,Sitmomian NA,Grigorian GS,Dynamics of polymorphonuclear leukocyte accumulation in acute cerebral infraction and their correlation with brain tissue damage. Stroke,1996,27(10):1739.
4. Weissleder R,Mahmood U,Molecular imaging.Radiology,2001,219(2):316-333.
5. Weissleder R,Mahmood U,et al.In vivo magnetic resonance imaging of transgene expression. Nat Med,2000,6(3):351-355.
6. Kim J,Kim DI,Lee SK,et al.Imaging of the inflammatory response in reperfusion injury after transient cerebral ischemia in rats:orrelation of superparamagnetic iron oxide-enhanced magnetic resonance imaging with histopathology.Acta Radiol,2008,49(5):580-588.
7. Jander S,Schroeter M,Saleh A.Imaging inflammation in acute brain ischemia.Stroke,2007,38 (2 Suppl):642-64.
8. Rauch M,Sauter A,Frohlich J,et al.Dynamic patterns of USPIO enhancement can be observed in macrophages after ischemic brain damage.Magn Reson Med,2001,46(5):1018-1022.
9. Ausch M,Baumann D,Neubacher U,et al.In-vivo visualization of phagocytotic cells in rat brains after transient ischemia by USPIO.NMR Biomed,2002,15(4):278-283.
10. Kleinschnitz C,Bendszus M,Frank M,et al.In vivo monitoring of macrophage infiltration in experimental ischemic brain lesions by magnetic resonance imaging.J Cereb Blood Flow Metab.2003NOV,23(11):1356-61.
11. Kleinschnitz C,Schutz A,Nolte I,er al.In vivo detection of developing vessel occlusion in photothrombotic ischemic brain lesions in the rat by iron particle enhanced MRI.Cereb Blood Flow Merab,2005,25(11):1548-55.
12. G Weise TC,Basse-Lusebrink C,Kleinschntz,et al.In vivo imaging of stepwise vessel occlusion in cerebral photothrombosis of mice by 19F MRI.P1OS ONE,2011,(12):e18143.
13. Li Shuqing,Meng Qiang,Zhang Lineng.Experimental therapy of palatelet-activating factor antagonist(ginkgolide B)on photochemically induced thrombotic cerebxal ischemia in tree shrews.Clin Experiment Pharnacol Physiol,1999,26:824-826.
14. Christoph Kleinschnitz,Ansgar Schutz,Ingo Nolte,et al. In vivo detection of developing vessel occlusion in photothrombotic ischemic brain lesions in the rat by iron particle enhanced MRI.Journal of Cerebral Blood Flow & Metabolism,2005,25(11):1548-1555.
15. Schroeter M,Saleh A,Wiedermann D,et al.Histochemical detection of ultrasmall superpara-magnetic iron oxide (USPIO) contrast medium uptake in experimental brain ischemia.Magn Reson Med,2004,52(2):403-406.
16. Suzuke D,Yamaguchi M,Furuta T,er al.Cental high signal in inflammatory swollen lymph nodes on SPIO-enhanced interstitial MR lymphograms:a mimic of lymph node metastasis. Magn Reson Med Sci.2010,11(1):61-63.
17. Kotoura N,Sakamoto K,Fukuda Y,et al.Evaluation of magnetic resonance signal intensity in bone marrow after administration of super paramagnetic iron oxide(SPIO).Nihon Hoshasen Gijutsu Gakkai Zasshi,2011,67(3):212-20.
18. Stoll G,Bendszus M.New approaches to neuroimaging of central nervous system inflam-mation. Curr Opin Neurol.2010 Jun:23(3):282-6.
19. Matsuo M,Kanematsu M,Itoh K,et al.Detection of malignant hepatic tumors:comparison of gadolinium and ferumoxide-enhanced MR imaging.AJR AmJ Roentgenol,2001(3),177:637-643.
20. Sun R,Dittrich J,Le-Huu M,et al.Physical and biological characterization of superpara-magnetic iron oxide and ultrasmall superparamagnetic iron oxide-labeled cells.a comparison. Invest Radiol,2005,40(8):504-513.
21. Jung CW,Jacobs P.Physical and chemical properties of superparamagnetic iron oxide MR contrast agents:ferumoxides,ferumoxtran,ferumoxsil.Magn Reson Imaging,1995,13 (5):661-674.
22.李贵平,张辉,汪勇先.磁性纳米微粒在磁共振成像中的应用.放射免疫学杂志,2005,18(3)：216-217.
23. Peter F,Sanjay S.Liver-specific MR imaging contrast agents.Radiol Cli North Am.1998,36(2): 287-297.
24. Mcauley MA.Rodent models of focal ischemia.Cerebrovas Brain Metab Rev,1995,7(2): 153-180.
25. Neumann-Haefelin T,Kastrup A,Crespigny A,er al.Serial MRI after transient focal cerebral ischemia in rats:dynamics of tissue injury,blood-brain barrier damage,and edema formation.Stroke,2000,31(8):1965-1972
26. Weissleder R,Srark DD,Engelstad BL,er al.Superparamagnetic iron oxide:pharmacokinetics and toxicity.Am J Roentgenol,1989,152(1):167-173.
27. Stark DD,Weissleder R,Elizondo G,et al.Superparamagnetic iron oxide:clinical application as a contrast agent for MR imaging of the liver.Radiology,1988,168(2):297-301.
28. Vogl TJ,Hammerstinl R,Schwarz W,et al.Superparamagnetic iron oxide-enhanced versus gadolinium-enhanced MR imaging for differential diagnosis of focal liver lesions.Radiology, 1996,198(3):881-887.
29. Reimer P,Rummery EJ,Daldrup HE,et al.Clinical results with Resovist:a phase 2 clinical trial.Radiology,1995,195(2):489-496.
30. Bellin MR,Zaim S,Auberton E,er al.Liver metastases:safety and efficacy of detection with superparamagnetic iron oxide MR imaging.Radiology,1994,193(3):657-663.
31. L.H.Shen.Y Li.J Chen,et al.Intracarotid transplantation of bone marrow stromal cells increases axon-myelin remodeling after stroke.Neuroscince,2006,137(2):393-399.
32.袁琼兰,李瑞祥,羊惠君,等.大鼠局部缺血再灌注时小胶质细胞或巨噬细胞的活化与增值.中国神经免疫学和神经病学杂志,2003,10(1)：54-59.
33. Rausch M,Baumann D,Neubacher U,et al.In-vivo visualization of phagocytotic cells in rat brains after transient ischemia by USPIO.NMR Biomed,2002,15(4):278-283.
34. Weissleder R,Elizondo G,Wittenberg J,et al.Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging.Radiology,1990,175(2): 489-493.
35. Birdsall HH,Green DM,Trail J,et al.Complement C5a,TGT-Pl,and MCP-l,insequence,induce migration of monocytes into ischemic canine myocardium with in the first on to five hours after reperfusion.Circulation,1997,95(3):684-700.
36. Graeber MB.Streit WJ.Kreutzberg GW.Identity of ED2-positive perivascular cells in rat brain.Neurosci Res,1989,22(1):103-106.
37. Garcia JH,Kamijyo Y.Cerebral infarction evolution of histopathological changes after occlusion of a middle cerebral artery in primates.Neuropathol Exp Neurol,1974,33(3):408.
38. Kochanek PM,Hallenbeck JM.Polymorphonuclear leukocytes and monocytes in the pathogenesis of cerebral ischemia and strok.Stroke,1992,23(9):1367.
39. Matsuo Y,Onodera H,Shiga Y,et al.Correlation between myeloperoxidate quantified neutrophil accumulation and ischemic brain injury in the rat. Effect of neutrophil depletion.Stroke,1994,25(7):1469.
40. Giulian,Roberson C.Inhibition of Mononuclear phagocytes reduces ischemic injury in the spinal cord.Ann Neurol.1990,27(1):33.
41.殷伟.脑梗塞与免疫应答.国外医学脑血管疾病分册.1996；4(6)：332.
42. Morioka T, Audreg NK, Wolfgang J,et al. Characterization of microglial reaction after cerebral artery occlusion in rat brain. J Comp Neurol,1993; 327(1):123-132.
43. Benjelloun N, Renolleau S, Represa A, et al.Inflammatory responses in the cerebral cortex after ischemia in the P7 neonatal rat.Stroke,1999;30(9):1916-1924.
44. Kato H, Kogure K, Liu XH, et al. Progressive expression of immunomolecules on activated microglia and invading leukocytes following focal cerebral ischemia in the rat. Brain Res,1996,734(9):203-212.
45. Yamagami S, Tamura M, Hayashi M, et al. Differential production of MCP-1 and cytokine-induced neutrophil chemoattractant in the ischemic brain after transient focal ischemia in rats. J Leukoc Biol,1999,65(6):744-749.
46. Yamasaki Y, Matsuura N, Shozuhara H, et al. Interleukin-1β as a pathogenetic mediator of ischemic brain damage in rat. Stroke.1995;26:676-681.
47. Fabry Z, Waldschmidt MM, Hendrickson D, et al. Adhesion molecules on murine brain microvascular endothelial cell:expression and regulation of ICAM-1 and Ldp55. J Neuroimmunol.1992,36(1):1-11.
48. Sairanen,T.R, Lindsberg. P. J,Brenner, M, et al. Global forebrain ischemia results in differential cellular expression of interleukin-1β(IL-1β) and its receptor at mRNA and protein level.J Cere Blood Flow Metab.1997,17(10):1107-1120.
49. Liu T,Mc Donnell P.C,Young P.R,et al.Interleukin-1 β mRNA expression in ischemic rat cortex.Stroke,1993,24(11):1746-1751.
50. Hillhouse E. W, Kida S, Lannotti F. Middle cerebral artery occlusion in the rat causes a iphasic production of immunoreactive interleukin-1βin the cerebral cortex. Neuroscience Letters 1998;249(6):177-179.
51. Zhang ZG, Chopp M, Goussev A, et al. Cerebral vessels express interleukin-1β after focal cerebral ischemia. Brain Research,1998;784:210-217.
52. Yang G.Y, Zhao Y.J, Davidson B. L,et al. Over expression of interleukin-1 receptor antagonist in the mouse reduces ischemic brain injury.Brain Research,1997;751(2):181-188.
53. Loddick,S.A, Rothwell, N.J.Neuroprotective effects of human recombinant interleukin-1 receptor antagonist in focal cerebral ischemia in the rat. J Cereb Blood Flow Metab. 1996;16(5):932-940.
54. Garcia-JH,Liu-KF,Relton-JK,et al. Interleukin-1 receptor antagonist decreases the number of necrotic neurons in rats with middle cerebral artery occlusion. Am J Pathol,1995; 147(5): 1477-1486.
55. Yamasaki Y, Suzuki T, Yamaya H, et al. Possible involvement of interleukin-1 in ischemic brain edema formation. NeuroscienceLetters,1992;142(1):45-47.
56. Gibson RM,Rothwell NJ,Le Feuvre RA,et al.CNS injury:the role of the cytokine IL-1.Vet J, 2004,168(3):230-237.
57. Davies C. A, Loddick S. A, Toulmond S, et al. The procession and topographic distribution of interelukin-1βexpression after permanent middle cerebral artery occlusion in the rat. J Cere Blood Flow Metab,1999;19:87-98.
58. Ren C,Gao X,Niu G,et al.Delayed postconditioning protects against focal ischemic brain injury in rats.PLos oNE,2008,3(12):e385.
59. Becker KJ.Targeting the central nervous system inflammatory response in ischemic stroke. Curr Opin Neurol,2001,14(3):349-353.
60. Xing B,Chen H,Zhang M,et al.Ischemia postconditioning protects brain and reduces inflammation in a rat model of focal cerebral ischemia/reperfusion.J Neurochem,2008,105: 17371745.
61.姚树桐,刘秀华,汤旭明等.缺血后处理改善脑缺血再灌注大鼠软脑膜微循环.中国病理生理杂志,2009,25(3)：451-455.
1. Hossmann K.Experimental models for the investigation of brain ischemia,Cardio Res, 1998,39(2):106-120.
2. Macrae IM.New models of focal cerebral ischemic.Br J Clin Pharmacol,1992,34(3):302-308.
3. Aysan Durukan,Turgut Tatlisumak.Acute ischemic stroke:Overview of major experimental rodent models,pathophysiology,and therapy of focal cerebral ischemia.Pharmacology, Biochemistry and Behavior,2007,87(1):179-197.
4. Takizawa S,Hogan M,Hakin AM.The effects of a competitive NMDA receptor antagonist (CGS-19755)on cerebral blood flow and pH in focal ischemia.J Cereb Blood Flow Metab, 1991,11(5):786-793.
5. Brinker G,Franke C,Hoehn M,et al,Thrombolysis of cerebral clot embolism in rat:effect of treatment delay.Neuroreport,1999,10:3269-3272.
6. Fujimura M,Morita-Fujimura Y,Kawase M,et al.Manganese superoxide dismutase mediates the early release of mitochondrial cyoshrome C and subsequent DNA fragmentation after permentation after permanent focal cerebral ischemia in mice.J Neurosci,1999,19:3414-3422.
7. Chen J,Zacharek A,Zhang C,et al.Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice.J Neurosci,2005,25: 2366-2375.
8. STAIR.Reconnendations for standards regarding preclinical neuroprotective and restorative drug development,Stroke,1999,30:2751-2758.
9. Shuaib A. Neuroprotection-STAIR-way to the future? Cerebrovasc Dis,2006;22(Supp11):10-7.
10.刘恩岐,尹海林,顾为望.医学实验动物学[M].北京：科学出版社,2008,5：68.
11. Duverger D,MarKrenzie E T.The quantification of cerebral infarction following focal ischemia in the rat:influence of strain,arterial pressure,blood glucose concentration,and age.J cereb blood Flow Metab,1988,8(3):449.
12. Markgraf CG,Kraydieh S,Pmdo R,et al.Comparative histopathologic consequences of photothrombotic occlusion of the distal middle cerebral artery in Sprague-Dawley and Wistary rats.Stroke,1993,24:(2)286-293.
13. Olsson T,Wieloch T,Smith Mf.Brain damage in a mouse model of global cerebral ischemia effect of NMIDA receptor blockade[J].Brain Res.2003,982:260.
14. Fang Hua, Jing Ma, Yan Li, et al. The development of a novel mouse model of transient global cerebral ischemia.Neuroscience Letters,2006,400:49-74.
15. Ito D.Tanaka K,Suzuki S,et al.Enhanced expression of Ibal,ionized cacium-binding adapter molecule 1,after transient focal cerebral ischemia in rat brain.Stroke,2001,32(5):1208-1215.
16. Alonso de LM,Diez TE,Carceller F,et al.Cerebral ischemia:from animal studies to clinical practice.Cerebrovasc Dis,2001,11(Supp11):20.
17. Alonso de LM,Diez TE.Carceller F,et al.Cerebral ischemia:from animal studies to clinical practice[J].Cerebrovasc Dis,2001,11(supp11):20.
18.刘恩岐,尹海林,顾为望.医学实验动物学[M].北京：科学出版社,2008,5：78.
19.张绍东,张淑珍,罗芳等.猫脑缺血时脑不同部位脑血流与氨基酸的变化.中华实验外科杂志,2005,22(8)：971-972.
20. Heiss WD,Graf R,Ohta K,et al.Repeat positron emission tomographic studies in transient middle cerebral artery occlusion in cats:residual perfusion anf efficacy of postischemic reperfusion.J Cereb Blood Flow Metab,1997,17(4):388-400.
21. Yonas H, Gur D, Claassen D, et al. Stable xenon enhanced computed tomography in the study of clinical and pathologic correlates of focal ischemic in baboons [J]. Stroke,1988, 19(2):228-238.
22. Purdy PD,Devous Sr MD,Hunt Batjer PH.Microfibrillar collagen model of canine cerebral infarction.Stroke,1989,20(10):1361-1367.
23. Gene Brenowitz MD.Howard Yonas MD.Selective occlusion of blood supply to the anterior perforated substance of the dog:a highly reproducible stroke model.Surg Neurol,1990,33(4): 47-252.
24. St-Jacques R,Gorczyca W,Mohr G. Microvascular anatomy of striate vessels in dogs:contribution to an experimental model of forebrain ischemia. Neurol Res.1996,18(2): 157-62.
25. Bederson JB,Pitts LH,Germano SM et al.Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats.Stroke,1986, 7(6):1304-1308.
26. Scremin OU,sonnenschein RR,Rubinstein EH,Cerebrovascular anatomy and blood flow measurements in the rabbit.J Cereb Blood Flow Metab,1982,2(1):55-56.
27.杨冀萍,刘怀军,张聪敏.适合MRI评价的兔脑缺血再灌注模型.放射学实践.2007,22(4)：348-349.
28. Lee JS,Hamilton MG,Zabramski JM,Variations in the anatomy of the rabbit cervical carotid artery.Stroke,1994,25(2):502.
29.顾正中主编.脑循环与临床.上海：上海科学技术出版社,1983.1.
30. Marshall JW, Ridley RM. Assessment of cognitive and motor deficits in a marmoset model of stroke[J]. ILAR J,2003,44(2):153-160.
31.韦日明,冯飞玲,黄志宏等.局部脑缺血食蟹猴动物模型的建立.广西医科大学学报,2006；23(3)：456-458.
32.詹美云,刘崇柏,李成明,等.甲型肝炎病毒感染树鼩的初步研究[J].中国医学科学院学报,1981,3(3)：148-152.
33. Barth H,Cerino R,A rcuriM,et al.Scavenger receptor class B type I and hepatitis C virus infection of primary Tupaia hepatocytes[J].J Virol,2005,79 (9):5774-5785.
34. Cao X M,Ben K L,Wang Y Q,et al.Effects of aminobutyric acid,progesterone and ionophore A23187 on acrosome reaction of tree shrew sperm in vitro:examination of acrosome reaction with an improved fluorescence microscopy [J]. Animal Reprod,1997,49:225-234
35. Fuchs E,Flugge G.Social stress in tree shrews:effects on physiology.brain function,and behavior of subordinate individuals[J].Pharmacol Biochem Behavior,2002,73:247-258.
36.彭燕章.树鼩生物学[M].云南：云南科技出版社,1991,358-360.
37.角建林,何保丽,郑红,等.树晌、恒河猴和大鼠脑发育的比较研究.昆明医学院学报,2010,31(5)：39-41.
38.刘能保,张敏海,刘少纯,等.中国树鼩下丘脑视上核和视旁核内加压素能和催产素能神经元的形态计量学分析.中国组织学与细胞化学杂志,1995,4(1)：64-70.
39.李树清,赵文洁,杨琼英.光化学诱导的血栓形成局部脑缺血的动物模型.中国病理生理杂志,1992,8(3)：33.
40. Toshiko Yusa.Effects of nitric oxide synthase inhibition on extracellular glutathione and cerebral blood flow during forebrain ischemia-reperfusion in rat in vivo[J].Journal of Anesthsia.2000; 14(1):24-29.
41. Hoff EI,Egbrink MG.Heijnen VV,et al.In vivo visualization of vascular leakage in photoche-mically induced cortical infarction.J Neurosci Methods,2005,141(1):135-141.
42. Levine S,Sohn D.Cerebral ischemia in infant and adult gerhils:relation to incomplete circle of millis. Arch Pathol,1969,87(3):315-317.
43.马志健,罗刚,易西南.脑缺血再灌注动物模型的制备及评价.海南医学院学报,2009,15(6)：556-559.
44.张庆丰,董斌,徐英辉,等.梯度灌注对沙土鼠全脑缺血神经元凋亡的保护作用[J].中华实验外科杂志,2005,22(1)：93-94.
45. Eklof B,Siedjo BK.The effect of bilateral carotid ligation upon the blood flow and the energy state of the rat brain.Acta Physiol Scand,1972,86:155-165.
46. Nordstrom CH,Siesjo BK.Effects of Phenobarbital in cerebral ischemia.Part I:cerebral energy metabolism during pronounced ischemia.Stroke,1978,9:327-335.
47. Kameyama M,Suzuki J,Shirane R,et al.A new model of bilateral hemispheric ischemia in the rat-three vessel occlusion model.Stroke,1985,16(3):489-493.
48. Pulsinelli WA,Brierley JB.A new model of bilateral hemispheric ischemia in the unanesthetized rat.Stroke,1979,10(2):267-272.
49.李兵,章翔,蒋晓帆,等.全脑缺血后海马区单胺类神经递质的变化.中华神经外科疾病研究杂志,2006,5：244-247.
50. Nita DA,Nita V,Spulber S,et al.Oxidative damage following cerebral ischemia depends on reperfusion-a biochemical study in rat.Cell Mol Med,2001,5(2):163-170.
51.张华,任朝胜.大鼠四血管脑缺血模型建立方法的改进.郑州大学学报(医学版),2005,40(1)：115.
52.吴俊芳,刘志.现代神经科学研究方法[M].北京：中国协和医科大学出版社,2005.810-818.
53. Reid KH,Young C,Schurr A.Audiogenic seizures following global ischemia induced by chest compression in Long-Ewan rats.Epilepst Res,1996,23:195.
54. Bethal-A,et al.Intravenous basic fibroblast growth decrease brain injury resulting from focal ischemia in rats.Stroke,1997,28:609.
55. Truong DD,Matsumoto RR,Schwarta PH.Cardiac arrest model of posthypoxic myoclonus. Mov Disord,1994,9:201.
56. P Blomqvist,T Wieloch.Ischemic brain damage in rats following cardiac arrest using a long-term recovery model. J Cereb Blood Flow Metab.1985,5 (3):420-431.
57. Douglas T,Ross,Ann-Christine.Degeneration of neurons in the thalamic reticular nucleus following transient ischemia due to raised intracranial pressure: excitotoxic degeneration mediated via non-NMDA receptors?Brain Res,1989,501(1):129-143.
58. Siemkowicz E,Hansen AJ:Clinical restitution following cerebral ischemia in hypo-,normo-and hyperglycemic rats.Ada Neurol Scand,1978,58:1-8.
59. Li F,Fisher M.Animal modeling for developing stroke theraphy. In: Fisher M,editor. Stroke therapy. Woburn, MA: Butterworth-Heinemann; 2001. p.83-96.
60. Tamum AA,Graham DI,Mcculloch,et al.Focal cerebral ischemia in the rat:description of technique and early neuropathological consequences following middle cerebral artery occlusion.J Cereb Blood Flow Metab,1981,1(1):53-60.
61. Bederson JB.Pitis LH,Pavis DL,et al.Rat middle cerebral artery occlusion:Evaluation of the model and development of a neurologic examination.Stroke,1986,17(3):472-476
62. Abumiya T,Fitridge R,Mazur C,et al.Integrin aIIbP3 inhibitor preserves microvascular patency in experiment acute focal cerebral ischemia. Stroke,2000,31:1402-1409.
63. Fukuda S,del Zoppo GJ.Models of focal cerebral ischemia in the nonhuman primate.ILAR J,2003,44:96-104.
64. Wang LC,Futrell N,Wang DZ,et al.A reproducible model of middle of cerebral infarcts, compatible with long-term survival in aged rats.Stroke,1995:26(11):2087-2090.
65. Reid JL,Dawson D,Macrae IM.Endothelin,cerebral ischemia and infarction.Ciin Exp Hypertens, 995,17:399-407.
66. Maerae IM,Robinson MJ.Graham DI,et al.Endothlin-1-induced reductions in cerebral blood flow:dose dependency,time course,and neuropathological consequences.J Cereb Blood Flow Metab,1993,13:276-284.
67. Koizumi J,Yoshida Y,Nakazawa T,et al.Experimental studies of ischemic brain edema.A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area,Jpn J Stoke,1986,8:1-8..
68. Longa EZ,Weinstein PR,Carlson S,et al.Reversible middle cerebral artery occlusion without craniectomy in the rats.Stroke,1989,20(1):84-91.
69.章军建,阮旭中,张苏明.大鼠局灶性脑缺血模型半暗带的定位研究.中国临床神经科 学,2000,8(3)：159-161.
70. Lee JS,Hamilton MG,Zabramski JM. Variations in the anatomy of the rabbit cervical carotid artery.Stroke,1994,25:501-503.
71. Burbridge B,Matte G,Remedies A.Complex intracranial arterial anatomy in swine is unsuit-able for cerebral infarction projects.Can Assoc Rsdiol J,2004,55:326-329.
72. Palmer GC,Peeling J.Corbett D,et al.T2-weighted MRI correlate with long-term histopathology.neurology scores and skilled motor behavior in a rat stroke model[J].Ann N Y Acad Sci,2006:283-296.
73. Dittmer MS,Fehm NP,Vatankhah B,et al.Adverse effects of the intraluminal filment model of middle cerebral artery occlusion.Stroke,2005,36(3):530-532.
74. Robert S,Stefen Z,Edwin H,et al.A critical reevaluation of the lintraluminal thread model of focal cerebral ischemia.Stroke,1998,29:2162-2170.
75. Yang Y,Yang T,Li Q,et al.A new reproducible focal cerebral ischemia model by introduction of polyvinylsiloxane into the middle cerebral artery.a comparison study.J Neurosci Methods, 2002,118(2):199-206.
76. Watson BD,Dietrich WD,Busto R,et al.Induction of reproducible brain infarction by photochemically initiated thrombosis.Ann Neurol,1985,17:497-504.
77. Yao H,Sugimori,Fukda K,et al.Photothrombotic middle cerebral artery occlusion and reperfusion laser system in spontaneously hypertensive rats.Stroke,2003,34(11):2716-2721.
2. Adams H, Adams R, Del Zoppo G,,et al.Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke,2005;36:916-923.
3. 全国降纤酶临床再评价研究协作组.降纤酶治疗急性脑梗死临床再评价.中华神经科杂志,2005,38(1)：11-16.
4. 吴兆苏,姚崇华,赵东等.我国人群脑卒中发病率、死亡率的流行病学研究.中华流行病学杂志,2003,24(3)：236-239.
5. Zhao ZQ,Corvera JS,et al.Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning. Am J Physiol HeartCire Physiol,2003:285:579-588.
6. Wang JY,Shen J,Gao Q,et al.lschemic postconditioning protects against global cerebral ischemia/reperfusion-induced injury in rats. Stroke,2008;39(3):983-90.
7. Xing B,Chen H,Zhang M,et al.Ischemic postconditioning inhibits apoptosis after focal cerebral ischemia/reperfusion injury in the rat. Stroke,2008;39(8):2362-9.
8. 彭燕章,叶智彰,邹如金等.树鼩生物学[M].云南：云南科技出版社,1991：358-360.
9. 李树清,赵文洁,杨琼英.光化学诱导的血栓形成局部脑缺血的动物模型.中国病理生理杂志,1992,8(3)：333.
10. Hagmann P,Jonasson L,Maeder P,et al. Understanding diffusion MR imaging techniques: from scalar diffusion-weighted imaging to diffusion tensor imaging and beyond. Radio-graphics,2006;26:S205-S223.
11. Schaefer PW.Romero JM,Grant PE,et al.Perfusion magnetic resonance imaging of acute ischemic stroke. Semin Roentgenol,2002,37:230-236.
12. Konig M. Brain perfusion CT in acute stroke:current status. EJR,2003,45:11-22.
13.程敬亮,冯敢生,孔祥泉等。兔急性期脑梗死核心和缺血半暗带磁共振表观扩散系数与病理对照观察.郑州大学学报(医学版),2005,40(2)：218-221.
14. Schaefer PW,Ozsunar Y,He J,et al.Assessing tissue viability with MR diffusion and perfusion imaging. AJNR,2003,24:436-443.
15. Robert TPL.Rowley HA.Diffusion weighted magnetic resonance imaging in stroke.EJR, 2003,45:185-194.
16. Li Shuqing.Meng Qiang,Zhang Lineng.Experimental therapy of palatelet-activating factor antagonist(ginkgolide B) on photochemically induced thrombotic cerebral ischemia in tree shrews. Clin Experiment Pharnacol Physiol,1999;26:824-826.
17. Yi-Wei Tsail,Yea-Ru Yang,Gun-Hao Chen,et al.The time window of intermittent hypoxia intervention after middle cerebral artery occlusion. Chinese Journal of Physiology,2008, 51(5):324-328.
18. Walberer M,Stolz E,Muller C,et al.Experimental stroke:ischemic lesion volume and edema formation differ among rat strains(a comparison between Wistar and Sprague-Dawley rats using MRI). Lab Anim,2006,40:1-8.
19. Gerriets T,Stolz E,Walberer M,et al.Noninvasive quantification of brain edema and the space-occupying effect in rat stroke models using magnetic resonance imaging.Stroke,2004, 35:566-571.
20.彭燕章,叶智彰,邹如金等.树鼩生物学.昆明：云南科技出版社：1991：14.
21.沈培清,郑红,刘汝文等.中国树鼩实验动物化研究进展和展望.动物学研究,2011；32(1)：109-114.
22.孙晓梅,叶尤松,罕圆圆等.树鼩的基本实验操作方法.中国比较医学杂志,2009,19(12)：76-78.
23.叶尤松,罕圆圆,黄璋琼等.野生成年树鼩主要脏器重量及脏器系数的测定分析.中国比较医学杂志,2011,21(4)：62-65.
24.叶峻.树鼩大脑皮层结构和功能分区的颅内定位.解剖学杂志,1996,19(6)：535-538.
25.李树清,张颖,杨丽君等.树鼩脑局部血栓性缺血的扩布性抑制机制探讨.微循环学杂志,2005,15(2)：4-7.
26. Zhang Z, Zhang RL, Jiang Q, et al. A new rat model of thrombotic focal cerebral ischemia. J Cereb Blood Flow Metab,1997;17(2):123-135.
27.赵瑾,苑琳,王驭龙等.线栓法复制昆明小鼠局灶性脑缺血再灌注模型的稳定性研究.中国病理生理杂志,2011,27(7)：1450-1452、1456.
28.何斌,张劲松,邵斌霞等.线栓法制大鼠脑缺血模型操作和评价的改良.中华急诊医学杂志,2009,18(12)：1248-1250.
29.郭巧生.药用植物栽培学.北京：高等教育出版社,2004,52.
30. Hatifield RH,Mendelow AD,Perry,et al.Triphenyltetrazolium chloride(TTC) as a marker for ischemic changes in rat brain following permanent middle cerebral artery occlusion. Neuro-pathol Appl Neurobiol,1991,17(1):61-67.
31. Robert A Knight,Kishor Karki,James R Ewing,et al.Estimating blood and brain concentrations and blood-to-brain influx by magnetic resonance imaging with step-down infusion of Gd-DTPA in focal transient cerebral ischemia and confirmation by quantitative autoradiography with Gd-[14C]DTPA.Journal of Cerebral Blood Flow & Metabolism,2009, 29 (3),1048-1058.
32. Gian Luca Breschi.Laura Librizzi.Chiara Pastori.et al.Functional and structural correlates of magnetic resonance patterns in a new in vitro model of cerebral ischemia by transient occlusion of the medial cerebral artery. Neurbiology of Disease,2010,39(4):181-191.
33. Teng-Nan Lin,Shu-Wei Sun,Wai-Mui Cheung,et al.Dynamic changes in cerebral blood flow and angiogenesis after transient focal cerebral ischemia in rats evaluation with serial magnetic resonance imaging.Stroke,2002,33(10):2985-2991.
34. Palmer GC.Peeling J,Corbett D,et al.T2WI MRI correlates with long-term histopathology, neurology scores,and skilled motor behavior in a rat stroke model.Ann N Y Acad Sci,2001, 939:283-296.
35. Bandera E,Botteri M,Minelli C,et al.Cerebral blood flow threshold of ischemic penumbra and infarct core in acute ischemic stroke: a systematic review. Stroke,2006;37:1334-1339.
36. Mullins ME,Schaefer PW,Sorensen AG,et al. CT and conventional and diffusion-weighted MR imaging in acute stroke:study in 691 patients at presentation to the emergency depart-ment. Radiology,2002;224:353-360.
37. Busza AL,Allen KL,King MD,et al.Diffusion-weighted imaging studies of cerebral ischemia in gerbils.Potential relevance to energy failure. Stroke,1992,23(11):1602-1612.
38. Mintorovitch H,Yang GY, Shimizu H,et al.Diffusion-weighted magnetic resonance imaging of acute focal cerebral ischemia: comparison of signal intensity with changes in brain water and Na+-K+-ATPase activity. J Cereb Blood Flow Metab,1994,14(2):332-336.
39. Kanemitsu H,Nakagomi T,Tamura A,et al.Differences in the extent of primary ischemic damage between middle cerebral artery coagulation and intraluminal occlusion models. J Cereb Blood Flow Metab,2002,22(10):1196-1204.
40. Hoehn-Berlage M,Norris DG.Kohno K.et al.Evolution of regional changes in apparent diffusion coefficient during focal ischemia of rat brain:the relationship of quantitative diffusion NMR imaging to reduction in cerebral blood flow and metabolic disturbances J Cereb Blood Flow MeTable.1995,15(6):1002-1011.
41. Minematsi K,Li L,Fisher M,et al.Diffusion weighted magnetic resonance imaging:rapid and quantitative detection of focal brain ischemia.Neurology.1992,42(1):235-240.
42. Li F,Silva MD,Sotak CH,et al.Temporal evolution of ischemia injury evaluated with diffusion perfusion and T2-weighted MRl.Neurology.2005,54(3):689-696.
43. Matsumoto K,Lo EH.Pierce AR.et al.Role of vasogenic edema and tissue evitation in ischemic evolution on diffusion-weighted imaging: comparison with multiparameter MR and immunohistochemistry.AJNR Am J Neuroradiol.1998,16(5):1107-1115.
44. Schaefer PW,Grant PE,Gonzalez RG.Diffusion-weighted MR imaging of the brain.Radiology 2000,217(2):331-345.
45. Stadnik T W,Demaerel P,Luypaet RR.et al.lmaging tutorial:diffusion diagnosis of bright lesions on diffusion-weighted M R images[J].Radiographics.2003.23:e7.
46. Rowley HA,Grant PE,Roberts TP.Diffusion MR Imaging:theory and application. Neuro-imaging Clin N Am.1999,9(2):343-361.
47. Rosso C,Drier A,Lacroix D,et al. Diffusion-weighted MRI in acute stroke within the first 6 hours:1.5 or 3.0 Tesla?[J].Neurology.2010,74(24):1946-53.
48. Wick M,Nagatomo Y,Prielmeier F.et al.Alteration of intracellular metabolite diffusion in rat brain in vivo during ischemia and reperfusion Stroke.1995,26(10):1930-1933.
49. Schlaug G,Siewert B,Beinfield A,et al.Time course of the apparent diffusion coefficient (ADC)abnormality in human stroke.Neurology.1997,49(1):113-119.
50. Astrup J,Siesjo BK,Symon L.Threshold in cerebral ischemia-the ischemic penumbra.Stroke. 1981,6:723-725.
51. Heiss WD,Graf R.The ischemic penumbra.Curr Opin Neurol.1994,7(1)11-19.
52. Heiss WD.The concept of the penumbra:can it be translated to stroke management?Int J Stroke.2010,5(4):290-295.
53.高晶,郭玉璞,谭静江,等.组织学方法界定脑梗死缺血半暗带的可行性探讨.中华神经科杂 志.2011,34(4)：99-102.
54. Feng Chen,Yi-Cheng Ni.Magnetic resonance diffusion-perfusion mismatch in acute ischemic stroke:an update. World J Radiol.2012,28;4(3):64-74.
55. Lee SK,Kim DI,Jeong EK,et al.Temporal changes in reversible cerebral ischemic on perfusion and diffusion-weighted magnetic resonance imaging:the value of relative cerebral blood volume maps.Neuroradiology,2002,44(2):103-108.
56. Lin TN.Sun SW.Cheung WM,et al.Dynamic changes in cerebral blood flow and angiogenesis after transient focal cerebral ischemic in rats.Evaluation with serial magnetic resonance imaging.Stroke,2002,33(12):2985-2991.
57. Kidwell CS,Alger JR,Saver JL.Beyond mismatch evolving paradigms in imaging the ischemic penumbra with multimodal magnetic resonance imaging.Stroke,2003,34:2729-2735.
58. Warach S.Moseley ME,Sorensen AG,et al.Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging.Ann neurol,1995,37:231-241.
59. Desmond PK,Lovell AC,Rawlinson AA,et al.The value of apparent diffusion coefficient maps in early cerebral ischemic.AJNR Am J Neuroradiol,2001:22(7):1260-1267.
60. Liu KF,Li F,Tatlisumak T,et al.Regional variations in the apparent diffusion coefficient and the intracellular distribution of water in rat brain during acute focal ischemia.Stroke 2001:32(8):1897-1905.
61.张川荛.后适应对树鼩血栓性脑缺血时神经保护效应的比较研究：硕士学位论文.昆明：昆明医学院,2011.
62. Harris NG,Gauden V,Fraser PA,et al. MRI measurement of blood-brain barrier permeability following spontaneous reperfusion in the microsphere model of ischemic[J].Magn Reson Imaging,2002,20(3):221-230.
63. Lo EH,Pan Y,Matsumoto K,et al.Blood-brain barrier disruption in experimental focal ischemia:comparison between in vivo MRI and immunocytochemistry.Magn Reson Imaging.1994; 12(3):403-11.
64. Felix R,Schorner W,Laniado M,et al.Brain tumors:MR imaging with Gd-DTPA.Radiology, 1985;156:681-688.
65.全冠民,张云亭.缺血后血脑屏障开放与血管源性水肿的MR研究.国外医学临床放射学 分册,2002：25(4)：221-224.
66. Virapongse C,Mancuse A,Quisling R.Human brain infarcts:Gd-DTPA-enhanced MR imaging. Radiology,1986; 161:785-794.
67.唐代彬.光化学诱导树鼩脑血栓形成后海马BBB通透性及缺血微环境动态变化的研究：[硕士学位论文].昆明：昆明医学院,2005
68. Barzo P,Marmarou A,Fatouros P,Corwin F,Dunbar J,Magnetic resonance imaging-monitored acute blood-brain barrier changes in experimental traumatic brain injury.J Neurosurg,1996; 85(6):1113-1121.
69. Wahlund LO,Bronge L.Contrast-enhanced MR1 of white matter lesions in patients with blood brain barrier dysfunction. Ann NY Acad Sci,2000,903(4):477-481.
70. Barzo P,Marmarou A,Fatouros P.Acute blood-brain barrier changes in experimental closed head injury as measured by MRI and Gd-DTPA.Acta Neurochir Suppl.1997.70:243-246.
71.徐凯,黄海东,沈天真.等.大鼠急性脑缺血再灌注后血脑屏障的变化.中国医学影像技术.2005,21(4)：519-522.
72.刘含秋,丁乙,陈学仁.增强MRI评价可逆性血脑屏障开发的可靠性及价值.中华放射学杂志.1998,32(5)：338-340.
73. Zhao H,Robert MS,Gary KS,et al.Interrupting reperfusion as a stroke therapy ischemic postconditioning reduces infarct size after focal ischemic in rats.Journal of Cerebral Blood Flow & Metabolism.2006,26:1114-1121.
74. Murry CE,Jennings RB,reamer KA.Preconditioning with ischemia:a delay of lethal cell injury in ischemic myocardium.Circulation.1986,74(5):1124-36.
75. Steiger H,Hanggi D.Ischemic Preconditioning of the brain,mechanisms and applications. Acta Neurochir(Wien).2007,149:1-10.
76. Perez-Pinzon M.Mechanisms of neuroprotection during ischemic preconditioning:lessons from anoxic tolerance.Comp Biochem Physiol A Mol Integrphysiol,207,147:291-299.
77. Perez-Pinzon M.Neuroprotective effects of ischemic preconditioning in brain mitochondria following cerebral ischemia.Bioenerg Biomembranes,2004,36:323-327.
78. Staat P,Rioufol G,Piot C,et al.Postconditioning the human heart.Circulation,2005,112: 2143-2148.
79. Gao XW,Ren CC,Zhao H.Protective effects of ischemic postconditioning compared with gradual reperfusion or preconditioning.Journal of Neuroscience Research,2008,86:2505-2511.
80. Kin H,Zatta AJ,Lofye MT,et al.Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine.Cardiovasc Res,2005,67(1):124-133.
81. Hausenloy DJ.Yellon DM.Survival kinases in ischemic preconditioning and postconditioning. CardiovascRes,2006,70:240-253.
82. Viera Danielisov'a,Miroslava Nemethovoa,Miroslav Gottlieb,et al.The changes in endogen-ous antioxidant enzyme activity after postconditioning.Cellular and Molecular Neurobiology, 2006,26:1181-1191.
83. Wang JY,shen J,Gao Q,et al.Ischemic postconditioning protects against global cerebral ischemia/reperfusion-induced injury in rats,Stroke,2008,39(3):983-990.
84. Xing B,Chen H,Zhang M,ct al.Ischemic post-conditioning protects brain and reduces inflammation in a rat model of focal cerebral ischemia/reperfusion.Neurochen,2008,54(12): 896.
85. Tsang A.Hausenloy DJ.Mocanu MM.et al.Postconditioning:a form of "modified reperfusion" protects the myocardium by activating the phosphatidyl inositol 3-kinase-Akt pathway.Circ Res.2004,95(3):230-232.
86.李树清,罗海芸.缺血后适应对树鼩海马CA1区脑血流及星形胶质细胞活化的影像及可能机制。中国病理生理杂志,2008,24(6)：1090-1095.
87.李树清,罗海芸,俞志成.后适应对树鼩不同脑缺血模型同一“时间窗”海马神经元保护的比较.中国病理生理杂志,2011,27(5)：890-894.
88. Takuma A,Takashi M,Mikhail N,et al.Serum and glucocorticoid-responsive kinase-1 regulates cardiomyocyte survival and hypertrophic response.Circulation,2005. 111(1):1652-1659.
89.陈诗鸿,倪一虹,庄向华.脂联素激活AKT抑制H202诱导的大鼠心肌细胞凋亡.中国病理生理杂志,2010,26(11)：2161-2164.
90. Majersik JJ,Smith MA, Zahuranec DB,et al.Population-based analysis of the impact of expanding the time window for acute stroke treatment.Stroke,2007,38(12):3213-3217.
91. Kin H,Zhao ZQ.Sun HY,et al.Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion.Cardiovasc Res,2004,62 (1):74-85.
92. Vinten-Johansen J,Zhao ZQ,Zatta AJ,et al.Postconditioning-A new link in nature's armor against myocardial ischemia-reperfusion injury.Basic Res Cardiol,2005,100(4):295-310.
93. Burda J, Danielisova V, Nem ethova M. Delayed postconditioning initiates additive mechanism necessary for survival of selectively vulnerable neurons after transient ischemia in rat brain.Cell Mol Neurobiol,2006,26(7-8):1141-1151.
94. Ren C,Gao X,Niu G,et al.Delayed postconditioning protects against focal ischemic brain injury in rats.Plos One,2008,3(12):3851.
95. Yang X M,Proctor J B,Cui L,et al.MuItiple brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. Am Coll Cardio,2004,44:1103-1110.
96. Wang JY,Shen J,Gao Q,et al.Ischemic postconditioning protects against global cerebral ischemia reperfusion-induced injury in rats.stroke,2008,399(3):983-990.
97. Zhao ZQ,Vinten-Johansen J.Postconditioning:reduction of reperfusion-induced injury. Cardiovasc Res,2006,70(2):200-211.
98. Ren C,Gao X,Niu G,et al.Delayed postconditioning protects against focal ischemic brain injury in rats.Plos One,2008,3(12):3851.
99. Lee JM,Grabb MC,Zipfel GJ,et al,Brain tissue responses to ischemia. Clin Invest.2000, 106:723-731.
100. Pignataro G,Meller R,Inoue K,et al.In vivo and in vitro characterization of a novel neuroprotective strategy for stroke:ischemic postconditioning. Cereb Blood Flow Metab,2008, 28(2):232-241.
101. Ashwal S,Tone B,Tian HR,et al.Core and penumbral nitric oxide synthase activity during cerebral ischemia and reperfusion. Stroke.1998; 29(5):1037-1046.
102. Mecoll BW,Rothwell NJ,Allan SM.Systemic inflammation alters the kinetics of cerebro-vascular tight junction disruption after experimental stroke in mice.Neurosei,2008, 28(38):9451-94612
103.崔相宁,尹岭,王玉来,等.创伤性脑损伤大鼠脑组织基金金属蛋白酶的表达：中华老年心脑血管病杂志,2008,10(1)：53-56.
104. Mun-Bryce S,Rosenberg GA.Gelatinase B modulates selective opening of the blood-brain barrier during inflammation.Am. Physiol,1998,274(5):R 1203-1211.
105.李淑婷,吉训明,朱榆红,等.脑缺血后适应对基质金属蛋白酶-9表达的影响.脑与神经疾病杂志,2008,16(6)：659-662.
106.朱榆红,吉训明,李春艳,等.缺血后适应对大鼠脑缺血/再灌注损伤的影响.中国病理学杂志,2008,24(11)：2151-2155.
107.罗海芸,李树清.树鼩脑缺血后适应升高海马区rCBF及VEGF的变化.基础医学与临床,2008,28(7)：676-680.
108。赵克森,黄巧冰.血管通透性增高的基本机制.中国病理生理杂志,2003,19(4)：549-553.
1. Mu S,Ouyang L,Liu B,et al.Relationship between inflammatory reaction and ischemic injury of caudate-putamen in rats: inflammatory reaction and brain ischemia.Anat Sci Int,2011, 86(2):86-97.
2. Becker KJ,Targeting the central nervous system inflammatory response in ischemic stroke.Curr Opin Neuro,2001,14(3):349-353.
3. Akopoy SE,Sitmomian NA,Grigorian GS,Dynamics of polymorphonuclear leukocyte accumulation in acute cerebral infraction and their correlation with brain tissue damage. Stroke,1996,27(10):1739.
4. Weissleder R,Mahmood U,Molecular imaging.Radiology,2001,219(2):316-333.
5. Weissleder R,Mahmood U,et al.In vivo magnetic resonance imaging of transgene expression. Nat Med,2000,6(3):351-355.
6. Kim J,Kim DI,Lee SK,et al.Imaging of the inflammatory response in reperfusion injury after transient cerebral ischemia in rats:orrelation of superparamagnetic iron oxide-enhanced magnetic resonance imaging with histopathology.Acta Radiol,2008,49(5):580-588.
7. Jander S,Schroeter M,Saleh A.Imaging inflammation in acute brain ischemia.Stroke,2007,38 (2 Suppl):642-64.
8. Rauch M,Sauter A,Frohlich J,et al.Dynamic patterns of USPIO enhancement can be observed in macrophages after ischemic brain damage.Magn Reson Med,2001,46(5):1018-1022.
9. Ausch M,Baumann D,Neubacher U,et al.In-vivo visualization of phagocytotic cells in rat brains after transient ischemia by USPIO.NMR Biomed,2002,15(4):278-283.
10. Kleinschnitz C,Bendszus M,Frank M,et al.In vivo monitoring of macrophage infiltration in experimental ischemic brain lesions by magnetic resonance imaging.J Cereb Blood Flow Metab.2003NOV,23(11):1356-61.
11. Kleinschnitz C,Schutz A,Nolte I,er al.In vivo detection of developing vessel occlusion in photothrombotic ischemic brain lesions in the rat by iron particle enhanced MRI.Cereb Blood Flow Merab,2005,25(11):1548-55.
12. G Weise TC,Basse-Lusebrink C,Kleinschntz,et al.In vivo imaging of stepwise vessel occlusion in cerebral photothrombosis of mice by 19F MRI.P1OS ONE,2011,(12):e18143.
13. Li Shuqing,Meng Qiang,Zhang Lineng.Experimental therapy of palatelet-activating factor antagonist(ginkgolide B)on photochemically induced thrombotic cerebxal ischemia in tree shrews.Clin Experiment Pharnacol Physiol,1999,26:824-826.
14. Christoph Kleinschnitz,Ansgar Schutz,Ingo Nolte,et al. In vivo detection of developing vessel occlusion in photothrombotic ischemic brain lesions in the rat by iron particle enhanced MRI.Journal of Cerebral Blood Flow & Metabolism,2005,25(11):1548-1555.
15. Schroeter M,Saleh A,Wiedermann D,et al.Histochemical detection of ultrasmall superpara-magnetic iron oxide (USPIO) contrast medium uptake in experimental brain ischemia.Magn Reson Med,2004,52(2):403-406.
16. Suzuke D,Yamaguchi M,Furuta T,er al.Cental high signal in inflammatory swollen lymph nodes on SPIO-enhanced interstitial MR lymphograms:a mimic of lymph node metastasis. Magn Reson Med Sci.2010,11(1):61-63.
17. Kotoura N,Sakamoto K,Fukuda Y,et al.Evaluation of magnetic resonance signal intensity in bone marrow after administration of super paramagnetic iron oxide(SPIO).Nihon Hoshasen Gijutsu Gakkai Zasshi,2011,67(3):212-20.
18. Stoll G,Bendszus M.New approaches to neuroimaging of central nervous system inflam-mation. Curr Opin Neurol.2010 Jun:23(3):282-6.
19. Matsuo M,Kanematsu M,Itoh K,et al.Detection of malignant hepatic tumors:comparison of gadolinium and ferumoxide-enhanced MR imaging.AJR AmJ Roentgenol,2001(3),177:637-643.
20. Sun R,Dittrich J,Le-Huu M,et al.Physical and biological characterization of superpara-magnetic iron oxide and ultrasmall superparamagnetic iron oxide-labeled cells.a comparison. Invest Radiol,2005,40(8):504-513.
21. Jung CW,Jacobs P.Physical and chemical properties of superparamagnetic iron oxide MR contrast agents:ferumoxides,ferumoxtran,ferumoxsil.Magn Reson Imaging,1995,13 (5):661-674.
22.李贵平,张辉,汪勇先.磁性纳米微粒在磁共振成像中的应用.放射免疫学杂志,2005,18(3)：216-217.
23. Peter F,Sanjay S.Liver-specific MR imaging contrast agents.Radiol Cli North Am.1998,36(2): 287-297.
24. Mcauley MA.Rodent models of focal ischemia.Cerebrovas Brain Metab Rev,1995,7(2): 153-180.
25. Neumann-Haefelin T,Kastrup A,Crespigny A,er al.Serial MRI after transient focal cerebral ischemia in rats:dynamics of tissue injury,blood-brain barrier damage,and edema formation.Stroke,2000,31(8):1965-1972
26. Weissleder R,Srark DD,Engelstad BL,er al.Superparamagnetic iron oxide:pharmacokinetics and toxicity.Am J Roentgenol,1989,152(1):167-173.
27. Stark DD,Weissleder R,Elizondo G,et al.Superparamagnetic iron oxide:clinical application as a contrast agent for MR imaging of the liver.Radiology,1988,168(2):297-301.
28. Vogl TJ,Hammerstinl R,Schwarz W,et al.Superparamagnetic iron oxide-enhanced versus gadolinium-enhanced MR imaging for differential diagnosis of focal liver lesions.Radiology, 1996,198(3):881-887.
29. Reimer P,Rummery EJ,Daldrup HE,et al.Clinical results with Resovist:a phase 2 clinical trial.Radiology,1995,195(2):489-496.
30. Bellin MR,Zaim S,Auberton E,er al.Liver metastases:safety and efficacy of detection with superparamagnetic iron oxide MR imaging.Radiology,1994,193(3):657-663.
31. L.H.Shen.Y Li.J Chen,et al.Intracarotid transplantation of bone marrow stromal cells increases axon-myelin remodeling after stroke.Neuroscince,2006,137(2):393-399.
32.袁琼兰,李瑞祥,羊惠君,等.大鼠局部缺血再灌注时小胶质细胞或巨噬细胞的活化与增值.中国神经免疫学和神经病学杂志,2003,10(1)：54-59.
33. Rausch M,Baumann D,Neubacher U,et al.In-vivo visualization of phagocytotic cells in rat brains after transient ischemia by USPIO.NMR Biomed,2002,15(4):278-283.
34. Weissleder R,Elizondo G,Wittenberg J,et al.Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging.Radiology,1990,175(2): 489-493.
35. Birdsall HH,Green DM,Trail J,et al.Complement C5a,TGT-Pl,and MCP-l,insequence,induce migration of monocytes into ischemic canine myocardium with in the first on to five hours after reperfusion.Circulation,1997,95(3):684-700.
36. Graeber MB.Streit WJ.Kreutzberg GW.Identity of ED2-positive perivascular cells in rat brain.Neurosci Res,1989,22(1):103-106.
37. Garcia JH,Kamijyo Y.Cerebral infarction evolution of histopathological changes after occlusion of a middle cerebral artery in primates.Neuropathol Exp Neurol,1974,33(3):408.
38. Kochanek PM,Hallenbeck JM.Polymorphonuclear leukocytes and monocytes in the pathogenesis of cerebral ischemia and strok.Stroke,1992,23(9):1367.
39. Matsuo Y,Onodera H,Shiga Y,et al.Correlation between myeloperoxidate quantified neutrophil accumulation and ischemic brain injury in the rat. Effect of neutrophil depletion.Stroke,1994,25(7):1469.
40. Giulian,Roberson C.Inhibition of Mononuclear phagocytes reduces ischemic injury in the spinal cord.Ann Neurol.1990,27(1):33.
41.殷伟.脑梗塞与免疫应答.国外医学脑血管疾病分册.1996；4(6)：332.
42. Morioka T, Audreg NK, Wolfgang J,et al. Characterization of microglial reaction after cerebral artery occlusion in rat brain. J Comp Neurol,1993; 327(1):123-132.
43. Benjelloun N, Renolleau S, Represa A, et al.Inflammatory responses in the cerebral cortex after ischemia in the P7 neonatal rat.Stroke,1999;30(9):1916-1924.
44. Kato H, Kogure K, Liu XH, et al. Progressive expression of immunomolecules on activated microglia and invading leukocytes following focal cerebral ischemia in the rat. Brain Res,1996,734(9):203-212.
45. Yamagami S, Tamura M, Hayashi M, et al. Differential production of MCP-1 and cytokine-induced neutrophil chemoattractant in the ischemic brain after transient focal ischemia in rats. J Leukoc Biol,1999,65(6):744-749.
46. Yamasaki Y, Matsuura N, Shozuhara H, et al. Interleukin-1β as a pathogenetic mediator of ischemic brain damage in rat. Stroke.1995;26:676-681.
47. Fabry Z, Waldschmidt MM, Hendrickson D, et al. Adhesion molecules on murine brain microvascular endothelial cell:expression and regulation of ICAM-1 and Ldp55. J Neuroimmunol.1992,36(1):1-11.
48. Sairanen,T.R, Lindsberg. P. J,Brenner, M, et al. Global forebrain ischemia results in differential cellular expression of interleukin-1β(IL-1β) and its receptor at mRNA and protein level.J Cere Blood Flow Metab.1997,17(10):1107-1120.
49. Liu T,Mc Donnell P.C,Young P.R,et al.Interleukin-1 β mRNA expression in ischemic rat cortex.Stroke,1993,24(11):1746-1751.
50. Hillhouse E. W, Kida S, Lannotti F. Middle cerebral artery occlusion in the rat causes a iphasic production of immunoreactive interleukin-1βin the cerebral cortex. Neuroscience Letters 1998;249(6):177-179.
51. Zhang ZG, Chopp M, Goussev A, et al. Cerebral vessels express interleukin-1β after focal cerebral ischemia. Brain Research,1998;784:210-217.
52. Yang G.Y, Zhao Y.J, Davidson B. L,et al. Over expression of interleukin-1 receptor antagonist in the mouse reduces ischemic brain injury.Brain Research,1997;751(2):181-188.
53. Loddick,S.A, Rothwell, N.J.Neuroprotective effects of human recombinant interleukin-1 receptor antagonist in focal cerebral ischemia in the rat. J Cereb Blood Flow Metab. 1996;16(5):932-940.
54. Garcia-JH,Liu-KF,Relton-JK,et al. Interleukin-1 receptor antagonist decreases the number of necrotic neurons in rats with middle cerebral artery occlusion. Am J Pathol,1995; 147(5): 1477-1486.
55. Yamasaki Y, Suzuki T, Yamaya H, et al. Possible involvement of interleukin-1 in ischemic brain edema formation. NeuroscienceLetters,1992;142(1):45-47.
56. Gibson RM,Rothwell NJ,Le Feuvre RA,et al.CNS injury:the role of the cytokine IL-1.Vet J, 2004,168(3):230-237.
57. Davies C. A, Loddick S. A, Toulmond S, et al. The procession and topographic distribution of interelukin-1βexpression after permanent middle cerebral artery occlusion in the rat. J Cere Blood Flow Metab,1999;19:87-98.
58. Ren C,Gao X,Niu G,et al.Delayed postconditioning protects against focal ischemic brain injury in rats.PLos oNE,2008,3(12):e385.
59. Becker KJ.Targeting the central nervous system inflammatory response in ischemic stroke. Curr Opin Neurol,2001,14(3):349-353.
60. Xing B,Chen H,Zhang M,et al.Ischemia postconditioning protects brain and reduces inflammation in a rat model of focal cerebral ischemia/reperfusion.J Neurochem,2008,105: 17371745.
61.姚树桐,刘秀华,汤旭明等.缺血后处理改善脑缺血再灌注大鼠软脑膜微循环.中国病理生理杂志,2009,25(3)：451-455.
1. Hossmann K.Experimental models for the investigation of brain ischemia,Cardio Res, 1998,39(2):106-120.
2. Macrae IM.New models of focal cerebral ischemic.Br J Clin Pharmacol,1992,34(3):302-308.
3. Aysan Durukan,Turgut Tatlisumak.Acute ischemic stroke:Overview of major experimental rodent models,pathophysiology,and therapy of focal cerebral ischemia.Pharmacology, Biochemistry and Behavior,2007,87(1):179-197.
4. Takizawa S,Hogan M,Hakin AM.The effects of a competitive NMDA receptor antagonist (CGS-19755)on cerebral blood flow and pH in focal ischemia.J Cereb Blood Flow Metab, 1991,11(5):786-793.
5. Brinker G,Franke C,Hoehn M,et al,Thrombolysis of cerebral clot embolism in rat:effect of treatment delay.Neuroreport,1999,10:3269-3272.
6. Fujimura M,Morita-Fujimura Y,Kawase M,et al.Manganese superoxide dismutase mediates the early release of mitochondrial cyoshrome C and subsequent DNA fragmentation after permentation after permanent focal cerebral ischemia in mice.J Neurosci,1999,19:3414-3422.
7. Chen J,Zacharek A,Zhang C,et al.Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice.J Neurosci,2005,25: 2366-2375.
8. STAIR.Reconnendations for standards regarding preclinical neuroprotective and restorative drug development,Stroke,1999,30:2751-2758.
9. Shuaib A. Neuroprotection-STAIR-way to the future? Cerebrovasc Dis,2006;22(Supp11):10-7.
10.刘恩岐,尹海林,顾为望.医学实验动物学[M].北京：科学出版社,2008,5：68.
11. Duverger D,MarKrenzie E T.The quantification of cerebral infarction following focal ischemia in the rat:influence of strain,arterial pressure,blood glucose concentration,and age.J cereb blood Flow Metab,1988,8(3):449.
12. Markgraf CG,Kraydieh S,Pmdo R,et al.Comparative histopathologic consequences of photothrombotic occlusion of the distal middle cerebral artery in Sprague-Dawley and Wistary rats.Stroke,1993,24:(2)286-293.
13. Olsson T,Wieloch T,Smith Mf.Brain damage in a mouse model of global cerebral ischemia effect of NMIDA receptor blockade[J].Brain Res.2003,982:260.
14. Fang Hua, Jing Ma, Yan Li, et al. The development of a novel mouse model of transient global cerebral ischemia.Neuroscience Letters,2006,400:49-74.
15. Ito D.Tanaka K,Suzuki S,et al.Enhanced expression of Ibal,ionized cacium-binding adapter molecule 1,after transient focal cerebral ischemia in rat brain.Stroke,2001,32(5):1208-1215.
16. Alonso de LM,Diez TE,Carceller F,et al.Cerebral ischemia:from animal studies to clinical practice.Cerebrovasc Dis,2001,11(Supp11):20.
17. Alonso de LM,Diez TE.Carceller F,et al.Cerebral ischemia:from animal studies to clinical practice[J].Cerebrovasc Dis,2001,11(supp11):20.
18.刘恩岐,尹海林,顾为望.医学实验动物学[M].北京：科学出版社,2008,5：78.
19.张绍东,张淑珍,罗芳等.猫脑缺血时脑不同部位脑血流与氨基酸的变化.中华实验外科杂志,2005,22(8)：971-972.
20. Heiss WD,Graf R,Ohta K,et al.Repeat positron emission tomographic studies in transient middle cerebral artery occlusion in cats:residual perfusion anf efficacy of postischemic reperfusion.J Cereb Blood Flow Metab,1997,17(4):388-400.
21. Yonas H, Gur D, Claassen D, et al. Stable xenon enhanced computed tomography in the study of clinical and pathologic correlates of focal ischemic in baboons [J]. Stroke,1988, 19(2):228-238.
22. Purdy PD,Devous Sr MD,Hunt Batjer PH.Microfibrillar collagen model of canine cerebral infarction.Stroke,1989,20(10):1361-1367.
23. Gene Brenowitz MD.Howard Yonas MD.Selective occlusion of blood supply to the anterior perforated substance of the dog:a highly reproducible stroke model.Surg Neurol,1990,33(4): 47-252.
24. St-Jacques R,Gorczyca W,Mohr G. Microvascular anatomy of striate vessels in dogs:contribution to an experimental model of forebrain ischemia. Neurol Res.1996,18(2): 157-62.
25. Bederson JB,Pitts LH,Germano SM et al.Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats.Stroke,1986, 7(6):1304-1308.
26. Scremin OU,sonnenschein RR,Rubinstein EH,Cerebrovascular anatomy and blood flow measurements in the rabbit.J Cereb Blood Flow Metab,1982,2(1):55-56.
27.杨冀萍,刘怀军,张聪敏.适合MRI评价的兔脑缺血再灌注模型.放射学实践.2007,22(4)：348-349.
28. Lee JS,Hamilton MG,Zabramski JM,Variations in the anatomy of the rabbit cervical carotid artery.Stroke,1994,25(2):502.
29.顾正中主编.脑循环与临床.上海：上海科学技术出版社,1983.1.
30. Marshall JW, Ridley RM. Assessment of cognitive and motor deficits in a marmoset model of stroke[J]. ILAR J,2003,44(2):153-160.
31.韦日明,冯飞玲,黄志宏等.局部脑缺血食蟹猴动物模型的建立.广西医科大学学报,2006；23(3)：456-458.
32.詹美云,刘崇柏,李成明,等.甲型肝炎病毒感染树鼩的初步研究[J].中国医学科学院学报,1981,3(3)：148-152.
33. Barth H,Cerino R,A rcuriM,et al.Scavenger receptor class B type I and hepatitis C virus infection of primary Tupaia hepatocytes[J].J Virol,2005,79 (9):5774-5785.
34. Cao X M,Ben K L,Wang Y Q,et al.Effects of aminobutyric acid,progesterone and ionophore A23187 on acrosome reaction of tree shrew sperm in vitro:examination of acrosome reaction with an improved fluorescence microscopy [J]. Animal Reprod,1997,49:225-234
35. Fuchs E,Flugge G.Social stress in tree shrews:effects on physiology.brain function,and behavior of subordinate individuals[J].Pharmacol Biochem Behavior,2002,73:247-258.
36.彭燕章.树鼩生物学[M].云南：云南科技出版社,1991,358-360.
37.角建林,何保丽,郑红,等.树晌、恒河猴和大鼠脑发育的比较研究.昆明医学院学报,2010,31(5)：39-41.
38.刘能保,张敏海,刘少纯,等.中国树鼩下丘脑视上核和视旁核内加压素能和催产素能神经元的形态计量学分析.中国组织学与细胞化学杂志,1995,4(1)：64-70.
39.李树清,赵文洁,杨琼英.光化学诱导的血栓形成局部脑缺血的动物模型.中国病理生理杂志,1992,8(3)：33.
40. Toshiko Yusa.Effects of nitric oxide synthase inhibition on extracellular glutathione and cerebral blood flow during forebrain ischemia-reperfusion in rat in vivo[J].Journal of Anesthsia.2000; 14(1):24-29.
41. Hoff EI,Egbrink MG.Heijnen VV,et al.In vivo visualization of vascular leakage in photoche-mically induced cortical infarction.J Neurosci Methods,2005,141(1):135-141.
42. Levine S,Sohn D.Cerebral ischemia in infant and adult gerhils:relation to incomplete circle of millis. Arch Pathol,1969,87(3):315-317.
43.马志健,罗刚,易西南.脑缺血再灌注动物模型的制备及评价.海南医学院学报,2009,15(6)：556-559.
44.张庆丰,董斌,徐英辉,等.梯度灌注对沙土鼠全脑缺血神经元凋亡的保护作用[J].中华实验外科杂志,2005,22(1)：93-94.
45. Eklof B,Siedjo BK.The effect of bilateral carotid ligation upon the blood flow and the energy state of the rat brain.Acta Physiol Scand,1972,86:155-165.
46. Nordstrom CH,Siesjo BK.Effects of Phenobarbital in cerebral ischemia.Part I:cerebral energy metabolism during pronounced ischemia.Stroke,1978,9:327-335.
47. Kameyama M,Suzuki J,Shirane R,et al.A new model of bilateral hemispheric ischemia in the rat-three vessel occlusion model.Stroke,1985,16(3):489-493.
48. Pulsinelli WA,Brierley JB.A new model of bilateral hemispheric ischemia in the unanesthetized rat.Stroke,1979,10(2):267-272.
49.李兵,章翔,蒋晓帆,等.全脑缺血后海马区单胺类神经递质的变化.中华神经外科疾病研究杂志,2006,5：244-247.
50. Nita DA,Nita V,Spulber S,et al.Oxidative damage following cerebral ischemia depends on reperfusion-a biochemical study in rat.Cell Mol Med,2001,5(2):163-170.
51.张华,任朝胜.大鼠四血管脑缺血模型建立方法的改进.郑州大学学报(医学版),2005,40(1)：115.
52.吴俊芳,刘志.现代神经科学研究方法[M].北京：中国协和医科大学出版社,2005.810-818.
53. Reid KH,Young C,Schurr A.Audiogenic seizures following global ischemia induced by chest compression in Long-Ewan rats.Epilepst Res,1996,23:195.
54. Bethal-A,et al.Intravenous basic fibroblast growth decrease brain injury resulting from focal ischemia in rats.Stroke,1997,28:609.
55. Truong DD,Matsumoto RR,Schwarta PH.Cardiac arrest model of posthypoxic myoclonus. Mov Disord,1994,9:201.
56. P Blomqvist,T Wieloch.Ischemic brain damage in rats following cardiac arrest using a long-term recovery model. J Cereb Blood Flow Metab.1985,5 (3):420-431.
57. Douglas T,Ross,Ann-Christine.Degeneration of neurons in the thalamic reticular nucleus following transient ischemia due to raised intracranial pressure: excitotoxic degeneration mediated via non-NMDA receptors?Brain Res,1989,501(1):129-143.
58. Siemkowicz E,Hansen AJ:Clinical restitution following cerebral ischemia in hypo-,normo-and hyperglycemic rats.Ada Neurol Scand,1978,58:1-8.
59. Li F,Fisher M.Animal modeling for developing stroke theraphy. In: Fisher M,editor. Stroke therapy. Woburn, MA: Butterworth-Heinemann; 2001. p.83-96.
60. Tamum AA,Graham DI,Mcculloch,et al.Focal cerebral ischemia in the rat:description of technique and early neuropathological consequences following middle cerebral artery occlusion.J Cereb Blood Flow Metab,1981,1(1):53-60.
61. Bederson JB.Pitis LH,Pavis DL,et al.Rat middle cerebral artery occlusion:Evaluation of the model and development of a neurologic examination.Stroke,1986,17(3):472-476
62. Abumiya T,Fitridge R,Mazur C,et al.Integrin aIIbP3 inhibitor preserves microvascular patency in experiment acute focal cerebral ischemia. Stroke,2000,31:1402-1409.
63. Fukuda S,del Zoppo GJ.Models of focal cerebral ischemia in the nonhuman primate.ILAR J,2003,44:96-104.
64. Wang LC,Futrell N,Wang DZ,et al.A reproducible model of middle of cerebral infarcts, compatible with long-term survival in aged rats.Stroke,1995:26(11):2087-2090.
65. Reid JL,Dawson D,Macrae IM.Endothelin,cerebral ischemia and infarction.Ciin Exp Hypertens, 995,17:399-407.
66. Maerae IM,Robinson MJ.Graham DI,et al.Endothlin-1-induced reductions in cerebral blood flow:dose dependency,time course,and neuropathological consequences.J Cereb Blood Flow Metab,1993,13:276-284.
67. Koizumi J,Yoshida Y,Nakazawa T,et al.Experimental studies of ischemic brain edema.A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area,Jpn J Stoke,1986,8:1-8..
68. Longa EZ,Weinstein PR,Carlson S,et al.Reversible middle cerebral artery occlusion without craniectomy in the rats.Stroke,1989,20(1):84-91.
69.章军建,阮旭中,张苏明.大鼠局灶性脑缺血模型半暗带的定位研究.中国临床神经科 学,2000,8(3)：159-161.
70. Lee JS,Hamilton MG,Zabramski JM. Variations in the anatomy of the rabbit cervical carotid artery.Stroke,1994,25:501-503.
71. Burbridge B,Matte G,Remedies A.Complex intracranial arterial anatomy in swine is unsuit-able for cerebral infarction projects.Can Assoc Rsdiol J,2004,55:326-329.
72. Palmer GC,Peeling J.Corbett D,et al.T2-weighted MRI correlate with long-term histopathology.neurology scores and skilled motor behavior in a rat stroke model[J].Ann N Y Acad Sci,2006:283-296.
73. Dittmer MS,Fehm NP,Vatankhah B,et al.Adverse effects of the intraluminal filment model of middle cerebral artery occlusion.Stroke,2005,36(3):530-532.
74. Robert S,Stefen Z,Edwin H,et al.A critical reevaluation of the lintraluminal thread model of focal cerebral ischemia.Stroke,1998,29:2162-2170.
75. Yang Y,Yang T,Li Q,et al.A new reproducible focal cerebral ischemia model by introduction of polyvinylsiloxane into the middle cerebral artery.a comparison study.J Neurosci Methods, 2002,118(2):199-206.
76. Watson BD,Dietrich WD,Busto R,et al.Induction of reproducible brain infarction by photochemically initiated thrombosis.Ann Neurol,1985,17:497-504.
77. Yao H,Sugimori,Fukda K,et al.Photothrombotic middle cerebral artery occlusion and reperfusion laser system in spontaneously hypertensive rats.Stroke,2003,34(11):2716-2721.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |