脑缺血病理过程中ADAM17-TNF-α通路的变化及通络救脑方药的干预机制
摘要
随着现代医学的发展,传统中医络病学说被赋予了新的含义。许多中枢神经系统疾病如缺血性脑卒中、阿尔茨海默病等均属于传统中医络病的范畴,“毒损脑络”是其关键病机,并且在络病学说的指导下,取得了行之有效的治疗效果。传统中医络病学说与微循环关系极为密切,特别是神经血管单元概念的提出为传统中医络病学说提供了现代医学基础。
众所周知,TNF-α作为一种炎症因子在许多疾病,如缺血性脑卒中、中枢神经变性疾病等的发病过程中发挥关键作用。ADAM17是一种在TNF-α分泌成熟过程中起关键作用的脱落酶。在中枢神经系统中,脑微血管内皮细胞、神经元及胶质细胞均可分泌ADAM17和TNF-α。ADAM17-TNF-a通路在中枢神经系统疾病尤其是缺血性脑卒中的发病过程中发挥极其关键的作用。因此,在传统中医络病学说的指导下,我们观察拟缺血状态(脑缺血及细胞氧糖剥夺)下脑内ADAM17-TNF-a通路的变化特点,并且用通络救脑注射液(TLJN)干预来探讨TLJN抗神经损伤机制,进而为“病从络治”提供了现代生物学基础。
目的：
观察ADAM17、TNF-a在MCAO脑缺血大鼠模型脑组织及血清中的时序性表达特征,探索其与缺血性脑损伤的相关性；并且采用TLJN干预,探索该药抗缺血性脑损伤的途径,进而研究TLJN的抗神经损伤机制是否与ADAM17-TNF-a通路有关。此外,通过体外实验来观察ADAM17、TNF-a在正常、缺氧及通络救脑注射液干预下脑微血管内皮细胞条件培养液中表达的时序特征,进一步为传统中医络病学说提供现代医学依据。
方法：
1.对MCAO大鼠模型进行神经功能评分后,采用TTC染色观察MCAO大鼠模型脑损伤的程度、脑组织切片HE染色观察脑组织形态结构的变化,探讨通络救脑注射液在不同时间点的抗神经损伤作用。
2.采用ELISA和免疫组织化学的方法观察MCAO大鼠模型脑组织及血清中ADAM17、TNF-α在不同时间点的变化特征,探讨ADAM17-TNF-a通路在缺血性脑疾病的发病过程中的作用,以及通络救脑注射液是否通过该通路发挥其神经保护作用。
3.观察脑微血管内皮细胞条件培养液(CMEC-CM)中ADAM17、TNF-a的表达情况及通络救脑注射液对CMEC-CM中ADAM17、TNF-a表达的影响。在成功培养并鉴别脑微血管内皮细胞(CMEC)的基础上,制备OGD CMEC模型,采用TLJN干预OGD CMEC后,采用ELISA方法分析CMEC-CM中ADAM17、TNF-a时序变化情况。
结果：
1.通过对MCAO大鼠模型进行神经功能评分以及观察MCAO大鼠模型脑组织脑损伤水平和形态结构状况,我们发现随着脑缺血的进展,脑梗死体积增加,脑组织形态结构损伤恶化。光镜显示,脑梗死灶及梗死灶周围的神经元数量明显减少、细胞水肿、细胞核碎裂、溶解及间质疏松呈水肿样,血管间隙增宽,内皮细胞和胶质细胞水肿,炎性细胞浸润及继发性出血。通络救脑注射液能显著缩减脑梗死面积、减轻脑水肿和上述病理学变化,并能显著恢复神经功能。阳性对照药依达拉奉注射液具有相似的药效但其疗效不如通络救脑注射液。
2. MCAO大鼠模型血清及脑组织中ADAM17、TNF-a在脑缺血早期均显著升高,并具有时序性特征,通络救脑注射液对MCAO大鼠模型各时间点血清及脑组织中均能ADAM17、TNF-a的表达均有显著的降低作用。
3.通过观察脑微血管内皮细胞条件培养液(CMEC-CM)中AD AM17、TNF-a表达时序特征及通络救脑注射液对CMEC-CM中ADAM17、TNF-a含量的影响,我们发现OGD可促进CMEC在不同时间点分泌更多的ADAM17、TNF-α; TLJN能够减少不同时间点OGD脑微血管内皮细胞分泌ADAM17、TNF-α。
结论：
1. TLJN能够改善神经功能、显著缩小脑梗死体积、减轻脑组织病理损害,表明TLJN具有显著的抗脑缺血损伤作用。阳性对照药依达拉奉注射液也具有相似的作用但作用弱于TLJN.
2.脑缺血后,受损脑组织中ADAM 17、TNF-a表达显著增高且呈现同步性ADAM17-TNF-a通路在脑缺血病理过程中起关键作用,TLJN的抗脑缺血损伤机制与抑制缺血后脑组织中ADAM17-TNF-a通路有关。
3. TLJN抑制缺血后脑组织中ADAM17-TNF-a通路抗缺血性脑损伤作用的实现途径,与影响脑微血管内皮细胞分泌ADAM17和TNF-α密切相关。
With the development of modern medicine, Collateral disease in traditional Chinese medicine boasts a new meaning.A great many central nervous system(CNS) disease such as ischemic stroke, AD belong to the category of Collateral disease in trditional Chinese medicine,'toxin attacks brain collaterals'is the key point in its progressive pathogenesis, and in the guide of collateral, effective clinical curative outcome has been acquired. The relationship between Collateral in trditional Chinese medicine and microcirculation is extremely close, especially, the concept of neurovascular unit (NVU) coming up provides Collateral in trditional Chinese medicine with morden medical basis.
It is well known that TNF-αas a imflemation factor plays a important role in the pathgenesis of a great many disease such as ischemic stroke and so on. ADAM17/TACE is a key shadase that play a key role in release of TNF-α. ADAM17 and TNF-αcan be secreted by cerebral microvascular endothelial cells(CMEC), neuron and glial in CNS. ADAM17-TNF-αpathway is extremely immportant for the pathgenesis of CNS disease especially ischemic stroke.As a result, under guide of'collateral theory'in traditional Chinese medicine, we observe change characters of the ADAM17-TNF-αpathway in brain after hypoxia(cerebral ischemia and OGD) and intervention by injection of Tongluojiunao (TLJN) to explore the mechanism of neuroprotection by TLJN, and provide the modern biological basis for'cure from collateral disease'.
Objective:
Observe characteristic changes in time series of ADAM17, TNF-αin serum and brain tissue of middle cerebral artery occlusion (MCAO) rat model to explore the relationship between ADAM17, TNF-αand brain injury,in addition, through intervention by TLJN observe the neuroprotection of TLJN after cerebral ischemia, furthermore, to explore weather there is the relationship between the mechanism neuroprotection of TLJN and the pathway of ADAM17-TNF-αIn addition, in vitro observe characteristic changes in time series of ADAM17,TNF-αin normal, oxygen and gclucose deprivation (OGD) and TLJN intervention CMEC condition medium (CMEC-CM). The researchs above furthermore provide Collateral disease in traditional Chinese medicine with modern medical basis.
Method:
1. Appraise the neurofunction rate of MCAO rat model,and observe morphological stractural changes and information about brain injury of MCAO rat brain tissue to study neuroprotection of TLJN in different time, using brain tissue slice with HE staining and TTC staining
2. Observe characteristic changes in different time of ADAM17, TNF-a of MCAO rat serum and brain tissue using ELISA and immunohistochemistry to explore the role of ADAM17-TNF-a pathway played in pathgenesis of ischemic stroke in vivo and weather TLJN plays its neuroprotective role through ADAM17-TNF-a pathway in ischamic stroke in vivo.
3. Observe expression of ADAM17,TNF-a in CMEC-CM and influence on expression of ADAM 17,TNF-a in CMEC-CM intervented by TLJN.First, successfully cultivate and identify CMEC. Second,make OGD CMEC model. Third, add TLJN to intervene OGD CMEC. Finally, using ELISA to detect changes in time series of ADAM17, TNF-a in CMEC-CM.
Result:
1. Through appraising the neurofunction rate of MCAO rat model,and observing morphological stractural changes and information about brain injury of MCAO rat brain tissue, we found that with cerebral ischemia span extending, neuro function morphological stracture of cerebral tissue and cerebral infarct size become deteriorated. Through light microscope (LM), we found that neuron obviously decrease, cellular swell, karyorrhexis, and matrix swell in ischemic infarct focus. It also can be observed that interspace of blood vessel become large; endothelial cells obviously decrease, cell deflate and karyorrhexis; glia become swell and dropsy and inflaming cell infiltrating around ischemic infarct focus. Hemorrhagic focus also can be observed. TLJN can significantly extenuate cerebral infarct size, brain edema and obviously restore neuro function. Through light microscope, we found that TLJN can significantly extenuate pathological changes. Positive control drug injection of Edaravone has the similar effect but its effect is less than TLJN's.
2. ADAM17 and TNF-a in serum and brain tissue of MCAO rat model significantly elevate in the earlier stage after cerebral ischemia and vary with time extending. In addition.TLJN can significantly reduce expression of ADAM17, TNF-a in brain in different time.
3. Through observing characteristic expression in different time of AD AM17, TNF-a in CMEC-CM and influence on expression of ADAM17, TNF-a in CMEC-CM by TLJN, we found that OGD can promote CMEC to secrete more AD AM17, TNF-a in different time and TLJN can promote OGD cerebral microvascular endothelial cell to secrete less ADAM17, TNF-αin different time.
Conclusions:
1. TLJN can obviously extenuate cerebral edema, cerebral infarct area, pathological injury of cerebral tissue and restore neuro function. As a result, the founding above can indicate that TLJN boasts a better anti-neuroinjury on brain after cerebral ischemia. Positive control drug injection of Edaravone has the similar effect but its effect is less than TLJN's.
2. After cerebral ischemia, ADAM17 and TNF-αin injured brain coherently and significantly elevate. ADAM17-TNF-αpathway may play a key role in pathgenesis of cerebral ischemia and the mechanism of anti-neuroinjury by TLJN may be related to inhibiting ADAM17-TNF-αpathway in injuried brain after cerebral ischemia.
3. The mechanism of anti-neuroinjury after cerebral ischemia by TLJN through inhibition of ADAM17-TNF-αpathway in cerebral ischemic tissue may be closely related to both ADAM17 and TNF-αsecretion of CMEC.
众所周知,TNF-α作为一种炎症因子在许多疾病,如缺血性脑卒中、中枢神经变性疾病等的发病过程中发挥关键作用。ADAM17是一种在TNF-α分泌成熟过程中起关键作用的脱落酶。在中枢神经系统中,脑微血管内皮细胞、神经元及胶质细胞均可分泌ADAM17和TNF-α。ADAM17-TNF-a通路在中枢神经系统疾病尤其是缺血性脑卒中的发病过程中发挥极其关键的作用。因此,在传统中医络病学说的指导下,我们观察拟缺血状态(脑缺血及细胞氧糖剥夺)下脑内ADAM17-TNF-a通路的变化特点,并且用通络救脑注射液(TLJN)干预来探讨TLJN抗神经损伤机制,进而为“病从络治”提供了现代生物学基础。
目的：
观察ADAM17、TNF-a在MCAO脑缺血大鼠模型脑组织及血清中的时序性表达特征,探索其与缺血性脑损伤的相关性；并且采用TLJN干预,探索该药抗缺血性脑损伤的途径,进而研究TLJN的抗神经损伤机制是否与ADAM17-TNF-a通路有关。此外,通过体外实验来观察ADAM17、TNF-a在正常、缺氧及通络救脑注射液干预下脑微血管内皮细胞条件培养液中表达的时序特征,进一步为传统中医络病学说提供现代医学依据。
方法：
1.对MCAO大鼠模型进行神经功能评分后,采用TTC染色观察MCAO大鼠模型脑损伤的程度、脑组织切片HE染色观察脑组织形态结构的变化,探讨通络救脑注射液在不同时间点的抗神经损伤作用。
2.采用ELISA和免疫组织化学的方法观察MCAO大鼠模型脑组织及血清中ADAM17、TNF-α在不同时间点的变化特征,探讨ADAM17-TNF-a通路在缺血性脑疾病的发病过程中的作用,以及通络救脑注射液是否通过该通路发挥其神经保护作用。
3.观察脑微血管内皮细胞条件培养液(CMEC-CM)中ADAM17、TNF-a的表达情况及通络救脑注射液对CMEC-CM中ADAM17、TNF-a表达的影响。在成功培养并鉴别脑微血管内皮细胞(CMEC)的基础上,制备OGD CMEC模型,采用TLJN干预OGD CMEC后,采用ELISA方法分析CMEC-CM中ADAM17、TNF-a时序变化情况。
结果：
1.通过对MCAO大鼠模型进行神经功能评分以及观察MCAO大鼠模型脑组织脑损伤水平和形态结构状况,我们发现随着脑缺血的进展,脑梗死体积增加,脑组织形态结构损伤恶化。光镜显示,脑梗死灶及梗死灶周围的神经元数量明显减少、细胞水肿、细胞核碎裂、溶解及间质疏松呈水肿样,血管间隙增宽,内皮细胞和胶质细胞水肿,炎性细胞浸润及继发性出血。通络救脑注射液能显著缩减脑梗死面积、减轻脑水肿和上述病理学变化,并能显著恢复神经功能。阳性对照药依达拉奉注射液具有相似的药效但其疗效不如通络救脑注射液。
2. MCAO大鼠模型血清及脑组织中ADAM17、TNF-a在脑缺血早期均显著升高,并具有时序性特征,通络救脑注射液对MCAO大鼠模型各时间点血清及脑组织中均能ADAM17、TNF-a的表达均有显著的降低作用。
3.通过观察脑微血管内皮细胞条件培养液(CMEC-CM)中AD AM17、TNF-a表达时序特征及通络救脑注射液对CMEC-CM中ADAM17、TNF-a含量的影响,我们发现OGD可促进CMEC在不同时间点分泌更多的ADAM17、TNF-α; TLJN能够减少不同时间点OGD脑微血管内皮细胞分泌ADAM17、TNF-α。
结论：
1. TLJN能够改善神经功能、显著缩小脑梗死体积、减轻脑组织病理损害,表明TLJN具有显著的抗脑缺血损伤作用。阳性对照药依达拉奉注射液也具有相似的作用但作用弱于TLJN.
2.脑缺血后,受损脑组织中ADAM 17、TNF-a表达显著增高且呈现同步性ADAM17-TNF-a通路在脑缺血病理过程中起关键作用,TLJN的抗脑缺血损伤机制与抑制缺血后脑组织中ADAM17-TNF-a通路有关。
3. TLJN抑制缺血后脑组织中ADAM17-TNF-a通路抗缺血性脑损伤作用的实现途径,与影响脑微血管内皮细胞分泌ADAM17和TNF-α密切相关。
With the development of modern medicine, Collateral disease in traditional Chinese medicine boasts a new meaning.A great many central nervous system(CNS) disease such as ischemic stroke, AD belong to the category of Collateral disease in trditional Chinese medicine,'toxin attacks brain collaterals'is the key point in its progressive pathogenesis, and in the guide of collateral, effective clinical curative outcome has been acquired. The relationship between Collateral in trditional Chinese medicine and microcirculation is extremely close, especially, the concept of neurovascular unit (NVU) coming up provides Collateral in trditional Chinese medicine with morden medical basis.
It is well known that TNF-αas a imflemation factor plays a important role in the pathgenesis of a great many disease such as ischemic stroke and so on. ADAM17/TACE is a key shadase that play a key role in release of TNF-α. ADAM17 and TNF-αcan be secreted by cerebral microvascular endothelial cells(CMEC), neuron and glial in CNS. ADAM17-TNF-αpathway is extremely immportant for the pathgenesis of CNS disease especially ischemic stroke.As a result, under guide of'collateral theory'in traditional Chinese medicine, we observe change characters of the ADAM17-TNF-αpathway in brain after hypoxia(cerebral ischemia and OGD) and intervention by injection of Tongluojiunao (TLJN) to explore the mechanism of neuroprotection by TLJN, and provide the modern biological basis for'cure from collateral disease'.
Objective:
Observe characteristic changes in time series of ADAM17, TNF-αin serum and brain tissue of middle cerebral artery occlusion (MCAO) rat model to explore the relationship between ADAM17, TNF-αand brain injury,in addition, through intervention by TLJN observe the neuroprotection of TLJN after cerebral ischemia, furthermore, to explore weather there is the relationship between the mechanism neuroprotection of TLJN and the pathway of ADAM17-TNF-αIn addition, in vitro observe characteristic changes in time series of ADAM17,TNF-αin normal, oxygen and gclucose deprivation (OGD) and TLJN intervention CMEC condition medium (CMEC-CM). The researchs above furthermore provide Collateral disease in traditional Chinese medicine with modern medical basis.
Method:
1. Appraise the neurofunction rate of MCAO rat model,and observe morphological stractural changes and information about brain injury of MCAO rat brain tissue to study neuroprotection of TLJN in different time, using brain tissue slice with HE staining and TTC staining
2. Observe characteristic changes in different time of ADAM17, TNF-a of MCAO rat serum and brain tissue using ELISA and immunohistochemistry to explore the role of ADAM17-TNF-a pathway played in pathgenesis of ischemic stroke in vivo and weather TLJN plays its neuroprotective role through ADAM17-TNF-a pathway in ischamic stroke in vivo.
3. Observe expression of ADAM17,TNF-a in CMEC-CM and influence on expression of ADAM 17,TNF-a in CMEC-CM intervented by TLJN.First, successfully cultivate and identify CMEC. Second,make OGD CMEC model. Third, add TLJN to intervene OGD CMEC. Finally, using ELISA to detect changes in time series of ADAM17, TNF-a in CMEC-CM.
Result:
1. Through appraising the neurofunction rate of MCAO rat model,and observing morphological stractural changes and information about brain injury of MCAO rat brain tissue, we found that with cerebral ischemia span extending, neuro function morphological stracture of cerebral tissue and cerebral infarct size become deteriorated. Through light microscope (LM), we found that neuron obviously decrease, cellular swell, karyorrhexis, and matrix swell in ischemic infarct focus. It also can be observed that interspace of blood vessel become large; endothelial cells obviously decrease, cell deflate and karyorrhexis; glia become swell and dropsy and inflaming cell infiltrating around ischemic infarct focus. Hemorrhagic focus also can be observed. TLJN can significantly extenuate cerebral infarct size, brain edema and obviously restore neuro function. Through light microscope, we found that TLJN can significantly extenuate pathological changes. Positive control drug injection of Edaravone has the similar effect but its effect is less than TLJN's.
2. ADAM17 and TNF-a in serum and brain tissue of MCAO rat model significantly elevate in the earlier stage after cerebral ischemia and vary with time extending. In addition.TLJN can significantly reduce expression of ADAM17, TNF-a in brain in different time.
3. Through observing characteristic expression in different time of AD AM17, TNF-a in CMEC-CM and influence on expression of ADAM17, TNF-a in CMEC-CM by TLJN, we found that OGD can promote CMEC to secrete more AD AM17, TNF-a in different time and TLJN can promote OGD cerebral microvascular endothelial cell to secrete less ADAM17, TNF-αin different time.
Conclusions:
1. TLJN can obviously extenuate cerebral edema, cerebral infarct area, pathological injury of cerebral tissue and restore neuro function. As a result, the founding above can indicate that TLJN boasts a better anti-neuroinjury on brain after cerebral ischemia. Positive control drug injection of Edaravone has the similar effect but its effect is less than TLJN's.
2. After cerebral ischemia, ADAM17 and TNF-αin injured brain coherently and significantly elevate. ADAM17-TNF-αpathway may play a key role in pathgenesis of cerebral ischemia and the mechanism of anti-neuroinjury by TLJN may be related to inhibiting ADAM17-TNF-αpathway in injuried brain after cerebral ischemia.
3. The mechanism of anti-neuroinjury after cerebral ischemia by TLJN through inhibition of ADAM17-TNF-αpathway in cerebral ischemic tissue may be closely related to both ADAM17 and TNF-αsecretion of CMEC.
引文
[1]Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease.[J] Nat Rev Neurosci,2004,5:347-360.
[2]Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. [J]Nat Rev Neurosci,2003,4:399-415.
[3]Lok J, Gupta P, Guo S, Kim WJ, Whalen MJ, van Leyen K, Lo EH.Cell-cell signaling in the neurovascular unit. [J]Neurochem Res,2007,32:2032-2045.
[4]Park JA, Choi KS, Kim SY, Kim KW. Coordinated interaction of the vascular and nervous systems:from molecule-to cell-based approaches. [J] Biochem Biophys Res Commun,2003,311:247-253.
[5]Ward NL, Lamanna JC. The neurovascular unit and its growth factors coordinated response in the vascular and nervous systems.[J] Neurol Res,2004,26:870-883.
[6]Zacchigna S, Lambrechts D, Carmeliet P. Neurovascular signaling defects in neurodegeneration.[J] Nat Rev Neurosci,2008,9:169-181.
[7]Buxton RB, Uludag K, Dubowitz DJ, Liu TT. Modeling the hemodynamic response to brain activation. [J] Neuroimage,2004,23(suppl 1):220-233.
[8]Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. [J]Nat Rev Neurosci,2006,7:41-53.
[9]Haydon PG, Carmignoto G. Astrocyte control of synaptic transmission and neurovascular coupling. [J]Physiol Rev,2006,86:1009-1031.
[10]Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G. Neuron-to-astrocyte signaling is central to the dynamic control of brain micrccirculation. [J]Nat Neurosci,2003,6:43-50.
[11]Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. [J] Comp Neurol,2000,425:479-494.
[12]Ohab JJ, Fleming S, Blesch A, Carmichael ST. A neurovascular niche for neurogenesis after stroke. [J] Neurosci,2006,26:13007-13016.
[13]Benarroch EE. Neuron-astrocyte interactions:partnership for normal function and disease in the central nervous system.[J] Mayo Clin Proc,2005,80:1326-1338.
[14]Lobsiger CS, Cleveland DW. Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. [J]Nat Neurosci,2007,10:1355-1360.
[15]Maragakis NJ, Rothstein JD. Mechanisms of disease:astrocytes in neurodegenerative disease. [J]Nat Clin Pract Neurol,2006,2:619-689.
[16]Gu X, Li C, Wei W, Lo V, Gong S, Li SH, Iwasato T, Itohara S, Li XJ, Mody I, Heintz N, Yang XW. Pathological cell-cell interactions elicited by a neuropathogenic form of mutant huntingtin contribute to cortical pathogenesis in HD mice. [J]Neuron,2005,46:433-444.
[17]Gu X, Andre VM, Cepeda C, Li SH, Li XJ, Levine MS, Yang XW. Pathological cell-cell interactions are necessary for striatal pathogenesis in a conditional mouse model of Huntington's disease.[J] Mol Neurodegener,2001,2-8.
[18]Shin JY, Fang ZH, Yu ZX, Wang CE, Li SH, Li XJ. Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity.[J] Cell Biol,2005,171:1001-1012.
[19]Powers WJ, Videen TO, Markham J, McGee-Minnich L, Antenor-Dorsey JV, Hershey T, Perlmutter JS. Selective defect of in vivo glycolysis in early Huntington's disease striatum. [J]Proc Natl Acad Sci U S A,2001,104:2945-2949.
[20]Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M,McMahon AP, Doucette W, Siwek D, Ferrante RJ, Brown RH Jr, Julien JP, Goldstein LS, Cleveland DW. Wild-type nonneuronal cells extend survival of sod1 mutant motor neurons in ALS mice. [J]Science,2003,302:113-117.
[21]Holden C. Neuroscience:astrocytes secrete substance that kills motor neurons in ALS. [J]Science,2007:316-353.
[22]Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, Siklos L, McKercher SR, Appel SH. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. [J]Proc Natl Acad Sci USA,2006,103:16021-16026.
[23]Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. [J]Nat Neurosci. 2007;10:608-614.
[24]Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons.[J] Nat Neurosci,2007,10:615-622.
[25]Patel SC, Suresh S, Kumar U, Hu CY, Cooney A, Blanchette-Mackie EJ, Neufeld EB, Patel RC, Brady RO, Patel YC, Pentchev PG, Ong WY. Localization of Niemann-Pick C1 protein in astrocytes:implications for neuronal degeneration in Niemann-Pick type C disease. [J]Proc Natl Acad Sci U S A,1999,96:1657-1662.
[26]German DC, Quintero EM, Liang CL, Ng B, Punia S, Xie C, Dietschy JM. Selective neurodegeneration, without neurofibrillary tangles, in a mouse model of Niemann-Pick C disease. [J] Comp Neurol,2001,433:415-425.
[27]Chen G, Li HM, Chen YR, Gu XS, Duan S. Decreased estradiol release from astrocytes contributes to the neurodegeneration in a mouse model of Niemann-Pick disease type C. [J]Glia,2007,55:1509-1518.
[28]Zhang M, Strnatka D, Donohue C, Hallows JL, Vincent I, Erickson RP. Astrocyte-only Npcl reduces neuronal cholesterol and triples life span of Npcl(_/_) mice. [J] Neurosci Res, 2008,86:2848-2856.
[29]Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. [J]Neuron,2008,57:178-201.
[30]Desai BS, Monahan AJ, Carvey PM, Hendey B. Blood-brain barrier pathology in Alzheimer's and Parkinson's disease:implications for drug therapy. [J]Cell Transplant,2007,16:285-299.
[31]Rite I, Machado A, Cano J, Venero JL. Blood-brain barrier disruption induces in vivo degeneration of nigral dopaminergic neurons. [J] Neurochem,2007,101:1567-1582.
[32]Grammas P, Moore P, Weigel PH. Microvessels from Alzheimer's disease brains kill neurons in vitro. [J] Am Pathol,1999,154:337-342.
[33]Zlokovic BV. Neurovascular mechanisms of Alzheimer's neurodegeneration. [J]Trends Neurosci,2005,28:202-208.
[34]Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al-Chalabi A, Bornes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermeire S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang-Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R,Morrison KE, Robberecht W, Van Broeckhoven C, Collen D, AndersenPM, Carmeliet P. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death.[J] Nat Genet,2003,34:383-394.
[35]Azzouz M, Ralph GS, Storkebaum E, Walmsley LE, Mitrophanous KA, Kingsman SM, Carmeliet P, Mazarakis ND. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. [J]Nature,2004,429:413-417.
[36]Storkebaum E, Lambrechts D, Dewerchin M, Moreno-Murciano MP, Appelmans S, Oh H, Van Damme P, Rutten B, Man WY, De Mol M, Wyns S, Manka D, Vermeulen K, Van Den Bosch L, Mcrtens N, Schmitz C, Robberecht W, Conway EM, Collen D, Moons L, Carmeliet P.Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS.[J] Nat Neurosci,2005,8:85-92.
[37]Garbuzova-Davis S, Saporta S, Haller E, Kolomey I, Bennett SP, Potter H, Sanberg PR. Evidence of compromised blood-spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS. [J]PLoS ONE,2001,2:1203-1205.
[38]Zhong Z, Deane R, Ali Z, Parisi M, Shapovalov Y, O'Banion MK, Stojanovic K, Sagare A, Boillee S, Cleveland DW, Zlokovic BV. ALScausing SOD1 mutants generate vascular changes prior to motor neuron degeneration. [J]Nat Neurosci,2008,11:420-422.
[39]Guo S, Kim WJ, Lok J, Lee SR, Besancon E, Luo BH, Stins MF, Wang X, Dedhar S, Lo EH. Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons. [J]Proc Natl Acad Sci U S A,2008,105:7582-7587.
[40]ladecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease. [J]Nat Rev Neurosci,2004,5:347-60.
[41]Zonta M, Angulo M, Gobbo S et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation.[J]Nat Neurosci,2003,6:43-50.
[42]Nedergaard M, Ransom BR, Goldman SA. New roles for astrocytes:redefining the functional architecture of the brain.[J] Trends Neurosci,2003,26:523-530.
[43]Koehler RC, Roman RJ, Harder DR. Astrocytes and the regulation of cerebral blood flow. [J]Trends Neurosci,2009,32:160-169.
[44]del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab 2003; 23:879-894.
[45]del Zoppo GJ, Milner R. Integrin-matrix interactions in the cerebral microvasculature. [J]Arterioscler Thromb Vasc Biol,2006,26:1966-1975.
[46]Milner R, Hung S, Wang X, Spatz M, del Zoppo GJ. The rapid decrease in astrocyte-associated dystroglycan expression by focal cerebral ischemia is protease-dependent. [J] Cereb BloodFlow Metab,2008,28:812-823.
[47]Liesi P. Do neurons in the vertebrate CNS migrate on laminin. [J]EMBO,1985,4: 1163-1170.
[48]Engvall E, Davis GE, Dickerson K, Ruoslahti E, Varon S, Manthorpe M. Mapping of domains in human laminin using monoclonalantibodies:localization of the neurite-promoting site.[J] Cell Biol,1986,103:2457-2465.
[49]Herken R, Gotz W, Thies M. Appearance of laminin, heparan sulphate proteoglycan and collagen type IV during initial stages of vascularisation of the neuroepithelium of the mouse embryo. [J]Anat,1990,169:189-195.
[50]David S, Braun PE, Jackson DL, Kottis V, McKerracher L.Laminin overrides the inhibitory effects of peripheral nervous system and central nervous system myelin-derived inhibitors of neurite growth. [J] Neurosci Res,1995,42:594-602.
[51]Grant DS, Kleinman HK. Regulation of capillary formation by laminin and other components of the extracellular matrix. [J]EXS,1997,79:317-333.
[52]Bernstein JJ, Getz R, Jefferson M, Kelemen M. Astrocytes secrete basal lamina after hemisection of rat spinal cord.[J] Brain Res,1985,327:135-141.
[53]The Persantine-Aspirin Reinfarction Study Research Group.Persantine and aspirin in coronary heart disease.[J] Circulation,1980,62:449-461.
[54]Nagano N, Aoyagi M, Hirakawa K. Extracellular matrix modulates the proliferation of rat astrocytes in serum-free culture.[J]GLIA,1993,8:71-76.
[55]Furuse M, Hirase T, Itoh M et al. Occludin:a novel integral membrane protein localizing at tight junctions. [J] Cell Biol,1993,123:1777-1788.
[56]Itoh M, Nagafuchi A, Yonemura S, Kitani-Yasuda T, Tsukita S, Tsukita S. The 220-kD protein colocalizing with cadherins in non-epithelial cells is identical to ZO-1, a tight junction-associated protein in epithelial cells:cDNA cloning and immunoelectron microscopy. [J]Cell Biol,1993,121:491-502.
[57]Furuse M, Itoh M, Hirase T etal. Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions. [J]Cell Biol,1994,127: 1617-1626.
[58]Furuse M, Sasaki H, Tsukita S. Manner of interaction of heterogeneous claudin species within and between tight junction strands. [J]Cell Biol,1999,147:891-903.
[59]Hurwitz AA, Berman JW, Rashbaum WK, Lyman WD. Human fetal astrocytes induce the expression of blood-brain barrier specific proteins by autologous endothelial cells. [J]Brain Res,1993,625:238-243
[1]Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ,Stocking KL, Reddy P, Srinivasan S, et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. [J]Nature (Lond),1997,385:729-733.
[2]Doedens JR and Black RA. Stimulation-induced down-regulation of tumor necrosis factor-alpha converting enzyme.[J]Biol Chem,2000,275:14598-607.
[3]Reddy P, Slack JL, Davis R, Cerretti DP, Kozlosky CJ, Blanton RA, Shows D,Peschon JJ, and Black RA. Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme. [J]Biol Chem,2000,275:14608-14614.
[4]del Zoppo G, Ginis I, Hallenbeck JM, Iadecola C, Wang X, and Feuerstein GZ.Inflammation and stroke:putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. [J]Brain Pathol,2000,10:95-112.
[5]Wang X and Feuerstein GZ. Role of immune and inflammatory mediators in CNS injury. [J]Drug News Perspect,2000,13:133-140.
[6]Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, and Feuerstein GZ. Tumour necrosis factor-alpha expression in ischemic neurons.[J] Stroke,2001,25:1481-1488.
[7]Wang XK, Yue TL, Barone FC, White RF, Gagnon RC, and Feuerstein GZ.Concomitant cortical expression of TNF-alpha and IL-1 alpha mRNA following transient focal ischemia. [J] Mol Chem Neuropathol,1994,23:103-114.
[8]Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, Lysko PG, and Feuerstein GZ. Tumour necrosis factor-alpha. A mediator of focal ischemic brain injury. [J] Stroke,1997,28:1233-1244.
[9]Dawson DA, Martin D, and Hallenbeck JM. Inhibition of tumour necrosis factor-alpha reduces focal cerebral ischemic injury in the spontaneously hypertensive rat. [J]Neurosci Lett,1996,218:41-44.
[10]Nawashiro H, Martin D, and Hallenbeck JM. Inhibition of tumour necrosis factor and amelioration of brain infarction in mice. [J] Cereb Blood Flow Metab,2000,17:229-232.
[11]Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, Holtsberg FW, and Mattson MP. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors.[J] Nat Med,1996,2:788-794.
[12]Nawashiro H, Tasaki K, Ruetzler CA, and Hallenbeck JM. TNF-alpha pretreatment induces protective effects against focal cerebral ischemia in mice.[J] Cereb Blood Flow Metab,1997,17:483-490.
[13]Liu J, Ginis I, Spatz M and Hallenbeck JM. Hypoxic preconditioning protects cultured neurons against hypoxic stress via TNF-alpha andceramide.[J]AmPhysiol,2000,278:144-153.
[14]Karkkainen I, Rybnikova E, Pelto-Huikko M, and Huovila AP. Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS. [J]Mol Cell Neurosci,2000,15:547-560.
[15]Goddard DR, Bunning RA, and Woodroofe MN. Astrocyte and endothelial cell expression of ADAM 17 (TACE) in adult human CNS.[J] Glia,2001,4:267-271.
[16]Skovronsky DM, Fath S, Lee VM, and Milla ME. Neuronal localization of the TNF-alpha converting enzyme (TACE) in brain tissue and its correlation to amyloid plaques. [J] Neurobiol,2002,49:40-46.
[17]Hurtado O, Cardenas A, Lizasoain I, Bosca L, Leza JC, Lorenzo P, and Moro MA. Up-regulation of TNF-alpha convertase (TACE/ADAM 17) after oxygenglucose deprivation in rat forebrain slices. [J] Neuropharmacology,2001,40:1094-1102.
[18]Xinkang Wang, Giora Z. Feuerstein, Lin Xu, Hugh Wang, William A. Schumacher, Martin L. Inhibition of Tumor Necrosis Factor-alpha-Converting Enzyme by aSelective Antagonist Protects Brain from Focal Ischemic Injury in Rats.[J] Molecular Pharmacology, 2004,65(4):890-897.
[19]Buxbaum JD, Liu KN, Luo Y, Slack JL, Stocking KL, Peschon JJ, Johnson RS,Castner BJ, Cerretti DP, and Black RA. Evidence that tumor necrosis factor-alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. [J] Biol Chem,1998,273:27765-767.
[20]Peschon JJ, Slack JL, Reddy P, Stocking KL, Sunnarborg SW, Lee DC, Russell WE, Castner BJ, Johnson RS, Fitzner JN, et al. An essential role for ectodomain shedding in mammalian development.[J] Science (Wash DC),1998,282:1281-1284.
[21]Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, Haass C, and Fahrenholz F.Constitutive and regulated alpha-secretase cleavage of Alzheimer'samyloid precursor protein by a disintegrin metalloprotease.[J] Proc Natl Acad Sci USA,1999, 96:3922-3927.
[22]Fassbender K, Mossner R, Motsch L, Kischka U, Grau A, and Hennerici M.Circulating selectin-and immunoglobulin-type adhesion molecules in acute ischemic stroke. [J]Stroke,1995,26:1361-1364.
[23]Wang XK, Barone FC, Aiyar NV, and Feuerstein GZ. Interleukin-1 receptor and receptor antagonist gene expression after focal stroke in rats. [J]Stroke,2002,28:155-161.
[24]Ruocco A, Nicole O, Docagne F, Ali C, Chazalviel L, Komesli S, Yablonsky F, Roussel S, MacKenzie ET, Vivien D, et al. A transforming growth factor-beta antagonist unmasks the neuroprotective role of this endogenous cytokine in excitotoxicand ischemic brain injury.[J]Cereb Blood Flow Metab,1999,19:1345-1353.
[25]Citron M. Beta-secretase as a target for the treatment of Alzheimer's disease.[J] Neurosci Res,2002,70:373-379.
[26]Moskowitz MA and Lo EH.Neurogenesis and apoptotic cell death. [J]Stroke 2003,34:324-326.
[27]Gupta S. Molecular steps of tumor necrosis factor receptor-mediated apoptosis.[J]Curr Mol Med,2001,1:317-324.
[28]Cardenas A, Moro MA, Leza JC, O'Shea E, Davalos A, Castillo J, Lorenzo P, and Lizasoain I. Upregulation of TACE/ADAM17 after ischemic preconditioningis involved in brain tolerance.[J] Cereb Blood Flow Metab,2002,22:1297-1302.
[29]Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, Handa N,Fukunaga R, Kimura K, Mikoshiba K. Ischemic tolerance phenomenon found in the brain. [J]Brain Res,1990,528:21-24.
[30]Barone FC, White RF, Spera PA, Ellison J, Currie RW, Wang X, Feurstein GZ. Ischemic preconditioning and brain tolerance.[J] Stroke,1998,29:1937-1951.
[31]Kirino T. Ischemic tolerance.[J]Cereb Blood Flow Metab,2002,22:1283-1296.
[32]Weih M, Kallenberg K, Bergk A, Dirnagl U, Harms L, Wernecke KD, Einhaupl KM. Attenuated stroke severity after prodromal TIA. A role for ischaemic tolerance in the brain? [J]Stroke,2001,30:1851-1854.
[33]Moncayo J, de Freitas GR, Bogousslavsky J, Altieri M, van Melle G. Do transient ischemic attacks have a neuroprotective effect? [J]Neurology,2000,54:2089-2094.
[34]Castillo J, Moro MA, Blanco M, Leira R, Serena J, Lizasozin I, Davzlos A. The release of tumor necrosis factor-alpha is associated with ischemic tolerance in human stroke.[J] Ann Neurol,2003,54:811-819.
[35]Kirino T, Tsujita Y, Tamura A. Induced tolerance to ischemia in gerbil hippocampal neurons. [J] Cereb Blood Flow Metab,2000,11:299-307.
[36]Kato H, Liu Y, Araki T, Kogure K. MK-801, but not anisomycin,inhibits the induction of tolerance to ischemia in the gerbil hippocampus. [J]Neurosic Lett,1992,139:118-121.
[37]Kasischke K, Ludolph AC, Riepe MW.NMDA antagonists reverse increased hypoxic tolerance by preceding chemical hypoxia. [J]Neurosci Lett,1996,214:175-178.
[38]Grabb MC, ChoiDW.Ischemic tolerance in murine cortical cell culture:critical role for NMDA receptors. [J] Neurosci,1999,19:1657-1662.
[39]Shimazaki K, Ishida A, Kawai N. Increase in bcl-2 oncoprotein and the tolerance to ischemia-reduced neuronal death in the gerbil in the gerbil hippocampus. [J]Neurosci Res,1994,20:95-99.
[40]Ohtsuki T, Ruetzler C, Tasaki K, Hallenbeck JM. Interleukin-1 mediates induction of tolerance to global ischemia in gerbil hippocampal CA1 neurons. [J] Cereb Blood Flow Metab,1996,16:1137-1142.
[41]Heurteaux C, Lauritzen I, Widmann C, Lazdunski M. Essential role of adenosine, adenosine A1 receptors, and ATP-sensitive channels in cerebral ischemic preconditioning. [J]Proc Natl Acad Sci USA,1995,92:4666-4670.
[42]Toyoda T, Kassell NF, Lee KS. Induction of ischaemic tolerance and antioxidant activity by brief focal ischaemia.[J] NeuroReport,1997,8:847-851.
[43]Ravati A, Ahlemeyer B, Becker A, Klumpp S, Krieglstein J. Preconditioning-induced neuroprotection is mediated by reactive oxygen species and activation of the transcription factor nuclear factor-kappa B.[J]Neurochem,2001,78:909-919.
[44]Gonza'lez-Zulueta M, Feldman AB, Klesse LJ, Kalb RG, Dillman JF, ParadaLF,Dawson TM, Dawson VL. Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioning. [J]Proc Natl Acad Sci USA,2000,97:436-441.
[45]Wick A, Wick W, Waltenberger W, Weller M, Dichgans J, Schulz JB.Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt.[J]Neurosci,2002,22:6401-6407.
[46]McLaughlin BA, Hartnett KA, Erhardt KA, Legos JL, White RF, Barone FC, Aizenman E. Caspase 3 activation is essential for neuroprotection in preconditioning.[J] Proc Natl Acad Sci USA,2003,100:715-720.
[47]Blondeau N, Widmann C, Lazdunski M, Heurteaux C. Activation of the nuclear factor kappaB is a key event in brain tolerance. [J] Neurosci,2001,21:4668-4677.
[48]Ginis I, Jaiswal R, Klimanis D, Liu J, Geenspon J, Hallenbeck JM. TNF-alpha-Induced tolerance to ischaemic injury involves differential control of NF-kapaaB transactivation:the role of NF-kappaB association with p300 adaptor.[J] Cereb Blood Flow Metab 2002, 22:142-152.
[49]Mattson MP, Culmsee C, Yu Z, Camandola S. Roles of NF-kappaB in neuronal survival and plasticity.[J] Neurochem,2000,74:443-456.
[50]Barone FC, Feuerstein GZ. Inflammatory mediators and stroke:new opportunities for novel therapeutics. [J]Cereb Blood Flow Metab,1999,19:819-834.
[51]Shohami E, Ginis I, Hallenbeck JM. Dual role of tumor necrosis factor-alpha in brain injury.[J] Cytokine Growth Factor Rev,1999,10:119-130.
[52]Del Zoppo G, Ginis I, Hallenbeck JM, Iadecola C, Wang X, Feuerstein GZ. Inflammation and stroke:putative role for cytokines, adhesionmolecules and iNOS in brain response toischemia. [J]Brain Pathol,2000,10:95-112.
[53]Hallenbeck JM. The many faces of tumor necrosis factor in stroke.[J]Nat Med,2002,8:1363-1368.
[54]Liu J, Ginis I, Spatz M, Hallenbeck JM (2000) Hypoxic preconditioning protects cultured neurons against hypoxic stress via TNF-alpha and ceramide. [J] Physiol Cell Physiol,2000, 278:144-153.
[55]Wang X, Li X, Erhardt JA, Barone FC, Feurstein GZ. Detection of TNF-_alpha mRNA induction in ischemic brain tolerance by means of realtime polymerase chain reaction. [J]Cereb Blood Flow Metab,2000,20:15-20.
[56]Hurtado O, Cardenas A, Lizasoain I, Bosca'L, Leza JC, Lorenzo P, Moro MA. Up-regulation of TNF-alpha convertase(TACE/AD AM 17) afteroxygen-glucose deprivation in rat forebrain slices. [J] Neuropharmacology,2001,40:1094-1102.
[57]Hurtado O, Lizasoain I, Ferna'ndez-Tome'P, A'lvarez-Barrientos A, Leza JC,Lorenzo P, Moro MA. TACE/ADAM17-TNF-alpha pathway in rat cortical cultures after exposure to oxygen-glucose deprivation or glutamate.[J]Cereb Blood Flow Metab,2002,22:576-585.
[58]Cardenas A, Moro MA, Leza JC, O'Shea E, Davalos A, Castillo J, Lorenzo P,Lizasoain I. Up-regulation of TACE/ADAM17 after ischemic preconditioning is involved in brain tolerance. [J] Cereb Blood Flow Metab,2002,22:1297-1302.
[59]Cristina Romera.In Vitro Ischemic Tolerance Involves Upregulation of Glutamate Transport Partly Mediated by the TACE/ADAM17-Tumor Necrosis Factor-alpha Pathway. [J] Neuroscience,2004,24(6); 1350-1357
[60]Karkkainen L, Rybnikova E, Pelto-Huikko M, Huovila AP. Metalloprotease disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS.[J] Mol Cell Neurosci,2000,15:547-560.
[61]Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, Feuerstein GZ Tumor necrosis factor-alpha expression in ischemic neurons. [J]Stroke,2000,25:1481-1488.
[62]Choi DW, Rothman SM.The role of glutamate neurotoxicity in hypoxic-ischaemic neuronal death. [J]Annu Rev Neurosci,1999,13:171-182.
[63]Castillo J, Da'valos A, Naveiro J, Noya M. Neuroexcitatory amino acids and their relationship to infarct size and neurological deficit in ischemic stroke. [J] Stroke,1996,27: 1060-1065.
[64]Johns L, Sinclair AJ, Davies JA. Hypoxia/hypoglycemia-induced amino acid release is decreased in vitro by preconditioning. [J]Biochem Biophys Res Commun,2000,276:134-136.
[65]Grabb MC, Lobner D, Turetsky M, Choi DW. Preconditioned resistance to oxygen-glucose deprivation-induced cortical neuronal death:alterations in vesicular GABA and glutamate release. [J]Neuroscience,2002,115:173-183.
[66]Takahashi M, Billups B, Rossi D, Sarantis M, Hamann M, Attwell D. The role of glutamate transporters in glutamate homeostasis in the brain.[J]Exp Biol,1997,200:401-409.
[67]Maragakis NJ, Rothstein JD Glutamate transporters in neurologic diseases. [J]Arch Neurol,2001,58:365-370.
[68]Seal RP, Amara SG. Excitatory amino acid transporters:a family in flux.[J]Annu Rev Pharmacol Toxicol,1999,39:431-456.
[69]Ruscher K, Freyer D, Karsch M, Isaev N, Megow D, Sawitzki B, Priller J, Dirnagl U, Meisel A. Erythropoietin is a paracrine mediator of ischemic tolerance in the brain:evidence from an in vitro model. [J]Neurosci,2002,22:10291-10301.
[70]李翠风.老年性痴呆与信号转导.[J]生命的化学,2000,20(6)：2782-281.
[71]Canet-Aviles RM,Anderton M,Hooper NM,et al. Muscarine enhances soluble amyloid precursor protein secretion in human neuroblastoma SH-SY5 Y by a pat hway dependent on protein kinase C(alpha), src-tyrosine kinase and ext racellular signal-regulated kinase but not phospholipase C. [J] Brain Res Mol Brain Res,2002,102 (122):62-72.
[72]de la Torre JC. Is Alzheimer's disease a neurogegenerative or a vascular disorder? Data, dogma, and dialectics. [J]Lancet Neurol,2004,3 (3):184-190.
[73]Dodart JC,Marr RA,Koistinaho M,et al. Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer's disease. [J] Proc Natl Acad Sci USA,2005,102(4):1211-1216.
[74]Lanni C,Mazzucchelli M, Porrello E, et al. Differential involvement of protein kinase C alpha and epsilon in t he regulated secretion of soluble amyloid precursor protein. [J] Biochem,2004,271 (14):3068-3075.
[75]Zhu G,Wang D,Lin YH,et al. Protein kinase C epsilon suppresses Abeta production and promotes activation of alpha-secretase,[J] Biochem Biophys Res Commun,2001,285 (4):997-1006.
[76]Yeon SW,J ung MW,Ha MJ,et al. Blockade of PKC epsilon activation attenuates phorbol ester-induced increase of alpha-secrease-derived secreted form of amyloid precursor protein. [J] Biochem Biophys Res Commun,2001,280 (3):782-787.
[77]Alkon DL,Sun MK,Nelson TJ. PKC signaling deficit s:a mechanistic hypothesis for the origins of Alzheimer's disease.[J]Trends Pharmacol Sci,2007,28 (2):51-60.
[78]周燕,闫福岭,等.脑慢性低灌注大鼠海马M1受体、ADAM17水平变化及意义.[J]山东医药,2009,49(30)：39-40.
[1]Koo HJ, Lee S, Shin KH, et al. Geniposide, an anti-angiogenic compound from the fruits of Gardemia jas minoides.[J]Planta Med,2004,70(5):467-469.
[2]Longa EZ, Weinstein PR, Carlson S, et al Reverible middle cerebral artery occlusion without cranjectomy in rats.[J]Stroke,1989,20(1):84-91.
[3]张忱等.大鼠局灶性脑缺血再灌注模型的再灌注时间窗.中日友好医院学报,2000,14(5)：255-259.
[4]Suzuki Y, Kondo K, Ikeda Y, et al. Antithrombotic effect of geniposide and genipin in the mouse thrombosis model.[J]Planta Med,2001,67(9):807-810.
[5]Kuo WH, Wang CJ, Young SC, et al. Differential induction of the expression of GST subunits by geniposide in rat hepatocytes. [J]Pharmacology,2004,70(1):15-22.
[6]LeeMJ, HsuJD, WangCJ. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-caused tumor promotion in benzo[a]pyrene-initiated CD-1 mouse skin by geniposide. [J] Anticancer Res,1995,15(2):411-416.
[7]王根发,等.三七皂苷对脑缺血对大鼠再灌注损伤的保护作用.[J]中国临床康复,2002,6(9)：1268-1269.
[8]禺登俊,等.中药三七对脑缺血再灌注损伤后神经可塑性的影响.[J]中国临床康复,2003,5(3)：132-134.
[9]何蔚,朱遵平.三七总皂昔对大鼠脑梗死区ICAMI表达和中性粒细胞浸润的影响.[J]中药材,2005,25(5)：304-306.
[10]青雪梅,李澎涛,等.通络救脑注射液对大鼠脑微血管内皮细胞活性及其条件培养液影响的初步研究.[J]现代生物医学进展,2006,6(4)：1-4.
[1]Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ,Stocking KL, Reddy P, Srinivasan S, et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. [J] Nature (Lond),1997,385: 729-733.
[2]Doedens JR and Black RA. Stimulation-induced down-regulation of tumor necrosis factor-alpha converting enzyme.[J]Biol Chem,2000,275:14598-607.
[3]Reddy P, Slack JL, Davis R, Cerretti DP, Kozlosky CJ, Blanton RA, Shows D,Peschon JJ, and Black RA. Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme. [J]Biol Chem,2000,275:14608-14614.
[4]del Zoppo G, Ginis I, Hallenbeck JM, Iadecola C, Wang X, and Feuerstein GZ.Inflammation and stroke:putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. [J]Brain Pathol,2000,10:95-112.
[5]Wang X and Feuerstein GZ. Role of immune and inflammatory mediators in CNS injury. [J]Drug News Perspect,2000,13:133-140.
[6]Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, and Feuerstein GZ. Tumour necrosis factor-alpha expression in ischemic neurons.[J] Stroke,2001,25:1481-1488.
[7]Wang XK, Yue TL, Barone FC, White RF, Gagnon RC, and Feuerstein GZ.Concomitant cortical expression of TNF-alpha and IL-lalpha mRNA following transient focal ischemia. [J] Mol Chem Neuropathol,1994,23:103-114.
[8]Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, Lysko PG, and Feuerstein GZ. Tumour necrosis factor-alpha. A mediator of focal ischeic brain injury.[J] Stroke,1997,28:1233-1244.
[9]Dawson DA, Martin D, and Hallenbeck JM. Inhibition of tumour necrosis factor-alpha reduces focal cerebral ischemic injury in the spontaneously hypertensive rat. [J]Neurosci Lett,1996,218:41-44.
[10]Nawashiro H, Martin D, and Hallenbeck JM. Inhibition of tumour necrosis factor and amelioration of brain infarction in mice.[J]Cereb Blood Flow Metab,2000,17: 229-232.
[11]Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, Holtsberg FW, and Mattson MP. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors.[J] Nat Med,1996,2:788-794.
[12]Nawashiro H, Tasaki K, Ruetzler CA, and Hallenbeck JM. TNF-alpha pretreatment induces protective effects against focal cerebral ischemia in mice.[J] Cereb Blood Flow Metab,1997,17:483-490.
[13]Liu J, Ginis I, Spatz M and Hallenbeck JM. Hypoxic preconditioning protects cultured neurons against hypoxic stress via TNF-alpha andceramide.[J]AmPhysiol, 2000,278:144-153.
[14]Karkkainen I, Rybnikova E, Pelto-Huikko M, and Huovila AP. Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS. [J]Mol Cell Neurosci,2000,15:547-560.
[15]Hurtado O, Cardenas A, Lizasoain I, Bosca L, Leza JC, Lorenzo P, and Moro MA. Up-regulation of TNF-alpha convertase (TACE/ADAM17) after oxygenglucose deprivation in rat forebrain slices. [J] Neuropharmacology,2001,40:1094-1102.
[16]Skovronsky DM, Fath S, Lee VM, and Milla ME. Neuronal localization of the TNF-alpha converting enzyme (TACE) in brain tissue and its correlation to amyloid plaques. [J] Neurobiol,2002,49:40-46.
[17]Cardenas A, Moro MA, Leza JC, O'Shea E, Davalos A, Castillo J, Lorenzo P, and Lizasoain I. Upregulation of TACE/ADAM17 after ischemic preconditioningis involved in brain tolerance. J Cereb Blood Flow Metab 22:1297-1302.
[18]Xinkang Wang, Giora Z. Feuerstein, Lin Xu, Hugh Wang, William A. Schumacher,Martin L. Inhibition of Tumor Necrosis Factor-alpha-Converting Enzyme by aSelective Antagonist Protects Brain from Focal Ischemic Injury in Rats.[J] Molecular Pharmacology,2004,65(4):890-897.
[1]Baiguera S, Conconi MT, GuidolinD, et al. Ghrelin inhibits in vitro angiogenic activity of rat brain microvascular endothelial cells. [J] Int J MolMed,2004, 14(5):849-854.
[2]Defazio G, Livrea P, Giorelli M, et al. Interferon beta-1 a downregulates TNF alpha-induced intercellular adhesion molecule 1 expression on brain microvascular endothelial cells through a tyrosine kinase-dependent pathway. [J] Brain Res,2000, 881(2):227-230.
[3]Karkkainen I, Rybnikova E, Pelto-Huikko M, and Huovila AP. Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS. [J]Mol Cell Neurosci,2000,15:547-560.
[4]Goddard DR, Bunning RA, and Woodroofe MN. Astrocyte and endothelial cell expression of ADAM 17 (TACE) in adult human CNS.[J] Glia,2001,4:267-271.
[5]Skovronsky DM, Fath S, Lee VM, and Milla ME. Neuronal localization of the TNF-alpha converting enzyme (TACE) in brain tissue and its correlation to amyloid plaques. [J] Neurobiol,2002,49:40-46.
[6]Hurtado O, Cardenas A, Lizasoain I, Bosca L, Leza JC, Lorenzo P, and Moro MA. Up-regulation of TNF-alpha convertase (TACE/AD AM17) after oxygenglucose deprivation in rat forebrain slices. [J] Neuropharmacology,2001,40:1094-1102.
[7]Cardenas A, Moro MA, Leza JC, O'Shea E, Davalos A, Castillo J, Lorenzo P, and Lizasoain I. Upregulation of TACE/ADAM17 after ischemic preconditioningis involved in brain tolerance. [J] Cereb Blood Flow Metab 22:1297-1302.
[2]Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. [J]Nat Rev Neurosci,2003,4:399-415.
[3]Lok J, Gupta P, Guo S, Kim WJ, Whalen MJ, van Leyen K, Lo EH.Cell-cell signaling in the neurovascular unit. [J]Neurochem Res,2007,32:2032-2045.
[4]Park JA, Choi KS, Kim SY, Kim KW. Coordinated interaction of the vascular and nervous systems:from molecule-to cell-based approaches. [J] Biochem Biophys Res Commun,2003,311:247-253.
[5]Ward NL, Lamanna JC. The neurovascular unit and its growth factors coordinated response in the vascular and nervous systems.[J] Neurol Res,2004,26:870-883.
[6]Zacchigna S, Lambrechts D, Carmeliet P. Neurovascular signaling defects in neurodegeneration.[J] Nat Rev Neurosci,2008,9:169-181.
[7]Buxton RB, Uludag K, Dubowitz DJ, Liu TT. Modeling the hemodynamic response to brain activation. [J] Neuroimage,2004,23(suppl 1):220-233.
[8]Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. [J]Nat Rev Neurosci,2006,7:41-53.
[9]Haydon PG, Carmignoto G. Astrocyte control of synaptic transmission and neurovascular coupling. [J]Physiol Rev,2006,86:1009-1031.
[10]Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G. Neuron-to-astrocyte signaling is central to the dynamic control of brain micrccirculation. [J]Nat Neurosci,2003,6:43-50.
[11]Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. [J] Comp Neurol,2000,425:479-494.
[12]Ohab JJ, Fleming S, Blesch A, Carmichael ST. A neurovascular niche for neurogenesis after stroke. [J] Neurosci,2006,26:13007-13016.
[13]Benarroch EE. Neuron-astrocyte interactions:partnership for normal function and disease in the central nervous system.[J] Mayo Clin Proc,2005,80:1326-1338.
[14]Lobsiger CS, Cleveland DW. Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. [J]Nat Neurosci,2007,10:1355-1360.
[15]Maragakis NJ, Rothstein JD. Mechanisms of disease:astrocytes in neurodegenerative disease. [J]Nat Clin Pract Neurol,2006,2:619-689.
[16]Gu X, Li C, Wei W, Lo V, Gong S, Li SH, Iwasato T, Itohara S, Li XJ, Mody I, Heintz N, Yang XW. Pathological cell-cell interactions elicited by a neuropathogenic form of mutant huntingtin contribute to cortical pathogenesis in HD mice. [J]Neuron,2005,46:433-444.
[17]Gu X, Andre VM, Cepeda C, Li SH, Li XJ, Levine MS, Yang XW. Pathological cell-cell interactions are necessary for striatal pathogenesis in a conditional mouse model of Huntington's disease.[J] Mol Neurodegener,2001,2-8.
[18]Shin JY, Fang ZH, Yu ZX, Wang CE, Li SH, Li XJ. Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity.[J] Cell Biol,2005,171:1001-1012.
[19]Powers WJ, Videen TO, Markham J, McGee-Minnich L, Antenor-Dorsey JV, Hershey T, Perlmutter JS. Selective defect of in vivo glycolysis in early Huntington's disease striatum. [J]Proc Natl Acad Sci U S A,2001,104:2945-2949.
[20]Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M,McMahon AP, Doucette W, Siwek D, Ferrante RJ, Brown RH Jr, Julien JP, Goldstein LS, Cleveland DW. Wild-type nonneuronal cells extend survival of sod1 mutant motor neurons in ALS mice. [J]Science,2003,302:113-117.
[21]Holden C. Neuroscience:astrocytes secrete substance that kills motor neurons in ALS. [J]Science,2007:316-353.
[22]Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, Siklos L, McKercher SR, Appel SH. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. [J]Proc Natl Acad Sci USA,2006,103:16021-16026.
[23]Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. [J]Nat Neurosci. 2007;10:608-614.
[24]Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons.[J] Nat Neurosci,2007,10:615-622.
[25]Patel SC, Suresh S, Kumar U, Hu CY, Cooney A, Blanchette-Mackie EJ, Neufeld EB, Patel RC, Brady RO, Patel YC, Pentchev PG, Ong WY. Localization of Niemann-Pick C1 protein in astrocytes:implications for neuronal degeneration in Niemann-Pick type C disease. [J]Proc Natl Acad Sci U S A,1999,96:1657-1662.
[26]German DC, Quintero EM, Liang CL, Ng B, Punia S, Xie C, Dietschy JM. Selective neurodegeneration, without neurofibrillary tangles, in a mouse model of Niemann-Pick C disease. [J] Comp Neurol,2001,433:415-425.
[27]Chen G, Li HM, Chen YR, Gu XS, Duan S. Decreased estradiol release from astrocytes contributes to the neurodegeneration in a mouse model of Niemann-Pick disease type C. [J]Glia,2007,55:1509-1518.
[28]Zhang M, Strnatka D, Donohue C, Hallows JL, Vincent I, Erickson RP. Astrocyte-only Npcl reduces neuronal cholesterol and triples life span of Npcl(_/_) mice. [J] Neurosci Res, 2008,86:2848-2856.
[29]Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. [J]Neuron,2008,57:178-201.
[30]Desai BS, Monahan AJ, Carvey PM, Hendey B. Blood-brain barrier pathology in Alzheimer's and Parkinson's disease:implications for drug therapy. [J]Cell Transplant,2007,16:285-299.
[31]Rite I, Machado A, Cano J, Venero JL. Blood-brain barrier disruption induces in vivo degeneration of nigral dopaminergic neurons. [J] Neurochem,2007,101:1567-1582.
[32]Grammas P, Moore P, Weigel PH. Microvessels from Alzheimer's disease brains kill neurons in vitro. [J] Am Pathol,1999,154:337-342.
[33]Zlokovic BV. Neurovascular mechanisms of Alzheimer's neurodegeneration. [J]Trends Neurosci,2005,28:202-208.
[34]Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al-Chalabi A, Bornes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermeire S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang-Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R,Morrison KE, Robberecht W, Van Broeckhoven C, Collen D, AndersenPM, Carmeliet P. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death.[J] Nat Genet,2003,34:383-394.
[35]Azzouz M, Ralph GS, Storkebaum E, Walmsley LE, Mitrophanous KA, Kingsman SM, Carmeliet P, Mazarakis ND. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. [J]Nature,2004,429:413-417.
[36]Storkebaum E, Lambrechts D, Dewerchin M, Moreno-Murciano MP, Appelmans S, Oh H, Van Damme P, Rutten B, Man WY, De Mol M, Wyns S, Manka D, Vermeulen K, Van Den Bosch L, Mcrtens N, Schmitz C, Robberecht W, Conway EM, Collen D, Moons L, Carmeliet P.Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS.[J] Nat Neurosci,2005,8:85-92.
[37]Garbuzova-Davis S, Saporta S, Haller E, Kolomey I, Bennett SP, Potter H, Sanberg PR. Evidence of compromised blood-spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS. [J]PLoS ONE,2001,2:1203-1205.
[38]Zhong Z, Deane R, Ali Z, Parisi M, Shapovalov Y, O'Banion MK, Stojanovic K, Sagare A, Boillee S, Cleveland DW, Zlokovic BV. ALScausing SOD1 mutants generate vascular changes prior to motor neuron degeneration. [J]Nat Neurosci,2008,11:420-422.
[39]Guo S, Kim WJ, Lok J, Lee SR, Besancon E, Luo BH, Stins MF, Wang X, Dedhar S, Lo EH. Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons. [J]Proc Natl Acad Sci U S A,2008,105:7582-7587.
[40]ladecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease. [J]Nat Rev Neurosci,2004,5:347-60.
[41]Zonta M, Angulo M, Gobbo S et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation.[J]Nat Neurosci,2003,6:43-50.
[42]Nedergaard M, Ransom BR, Goldman SA. New roles for astrocytes:redefining the functional architecture of the brain.[J] Trends Neurosci,2003,26:523-530.
[43]Koehler RC, Roman RJ, Harder DR. Astrocytes and the regulation of cerebral blood flow. [J]Trends Neurosci,2009,32:160-169.
[44]del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab 2003; 23:879-894.
[45]del Zoppo GJ, Milner R. Integrin-matrix interactions in the cerebral microvasculature. [J]Arterioscler Thromb Vasc Biol,2006,26:1966-1975.
[46]Milner R, Hung S, Wang X, Spatz M, del Zoppo GJ. The rapid decrease in astrocyte-associated dystroglycan expression by focal cerebral ischemia is protease-dependent. [J] Cereb BloodFlow Metab,2008,28:812-823.
[47]Liesi P. Do neurons in the vertebrate CNS migrate on laminin. [J]EMBO,1985,4: 1163-1170.
[48]Engvall E, Davis GE, Dickerson K, Ruoslahti E, Varon S, Manthorpe M. Mapping of domains in human laminin using monoclonalantibodies:localization of the neurite-promoting site.[J] Cell Biol,1986,103:2457-2465.
[49]Herken R, Gotz W, Thies M. Appearance of laminin, heparan sulphate proteoglycan and collagen type IV during initial stages of vascularisation of the neuroepithelium of the mouse embryo. [J]Anat,1990,169:189-195.
[50]David S, Braun PE, Jackson DL, Kottis V, McKerracher L.Laminin overrides the inhibitory effects of peripheral nervous system and central nervous system myelin-derived inhibitors of neurite growth. [J] Neurosci Res,1995,42:594-602.
[51]Grant DS, Kleinman HK. Regulation of capillary formation by laminin and other components of the extracellular matrix. [J]EXS,1997,79:317-333.
[52]Bernstein JJ, Getz R, Jefferson M, Kelemen M. Astrocytes secrete basal lamina after hemisection of rat spinal cord.[J] Brain Res,1985,327:135-141.
[53]The Persantine-Aspirin Reinfarction Study Research Group.Persantine and aspirin in coronary heart disease.[J] Circulation,1980,62:449-461.
[54]Nagano N, Aoyagi M, Hirakawa K. Extracellular matrix modulates the proliferation of rat astrocytes in serum-free culture.[J]GLIA,1993,8:71-76.
[55]Furuse M, Hirase T, Itoh M et al. Occludin:a novel integral membrane protein localizing at tight junctions. [J] Cell Biol,1993,123:1777-1788.
[56]Itoh M, Nagafuchi A, Yonemura S, Kitani-Yasuda T, Tsukita S, Tsukita S. The 220-kD protein colocalizing with cadherins in non-epithelial cells is identical to ZO-1, a tight junction-associated protein in epithelial cells:cDNA cloning and immunoelectron microscopy. [J]Cell Biol,1993,121:491-502.
[57]Furuse M, Itoh M, Hirase T etal. Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions. [J]Cell Biol,1994,127: 1617-1626.
[58]Furuse M, Sasaki H, Tsukita S. Manner of interaction of heterogeneous claudin species within and between tight junction strands. [J]Cell Biol,1999,147:891-903.
[59]Hurwitz AA, Berman JW, Rashbaum WK, Lyman WD. Human fetal astrocytes induce the expression of blood-brain barrier specific proteins by autologous endothelial cells. [J]Brain Res,1993,625:238-243
[1]Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ,Stocking KL, Reddy P, Srinivasan S, et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. [J]Nature (Lond),1997,385:729-733.
[2]Doedens JR and Black RA. Stimulation-induced down-regulation of tumor necrosis factor-alpha converting enzyme.[J]Biol Chem,2000,275:14598-607.
[3]Reddy P, Slack JL, Davis R, Cerretti DP, Kozlosky CJ, Blanton RA, Shows D,Peschon JJ, and Black RA. Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme. [J]Biol Chem,2000,275:14608-14614.
[4]del Zoppo G, Ginis I, Hallenbeck JM, Iadecola C, Wang X, and Feuerstein GZ.Inflammation and stroke:putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. [J]Brain Pathol,2000,10:95-112.
[5]Wang X and Feuerstein GZ. Role of immune and inflammatory mediators in CNS injury. [J]Drug News Perspect,2000,13:133-140.
[6]Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, and Feuerstein GZ. Tumour necrosis factor-alpha expression in ischemic neurons.[J] Stroke,2001,25:1481-1488.
[7]Wang XK, Yue TL, Barone FC, White RF, Gagnon RC, and Feuerstein GZ.Concomitant cortical expression of TNF-alpha and IL-1 alpha mRNA following transient focal ischemia. [J] Mol Chem Neuropathol,1994,23:103-114.
[8]Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, Lysko PG, and Feuerstein GZ. Tumour necrosis factor-alpha. A mediator of focal ischemic brain injury. [J] Stroke,1997,28:1233-1244.
[9]Dawson DA, Martin D, and Hallenbeck JM. Inhibition of tumour necrosis factor-alpha reduces focal cerebral ischemic injury in the spontaneously hypertensive rat. [J]Neurosci Lett,1996,218:41-44.
[10]Nawashiro H, Martin D, and Hallenbeck JM. Inhibition of tumour necrosis factor and amelioration of brain infarction in mice. [J] Cereb Blood Flow Metab,2000,17:229-232.
[11]Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, Holtsberg FW, and Mattson MP. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors.[J] Nat Med,1996,2:788-794.
[12]Nawashiro H, Tasaki K, Ruetzler CA, and Hallenbeck JM. TNF-alpha pretreatment induces protective effects against focal cerebral ischemia in mice.[J] Cereb Blood Flow Metab,1997,17:483-490.
[13]Liu J, Ginis I, Spatz M and Hallenbeck JM. Hypoxic preconditioning protects cultured neurons against hypoxic stress via TNF-alpha andceramide.[J]AmPhysiol,2000,278:144-153.
[14]Karkkainen I, Rybnikova E, Pelto-Huikko M, and Huovila AP. Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS. [J]Mol Cell Neurosci,2000,15:547-560.
[15]Goddard DR, Bunning RA, and Woodroofe MN. Astrocyte and endothelial cell expression of ADAM 17 (TACE) in adult human CNS.[J] Glia,2001,4:267-271.
[16]Skovronsky DM, Fath S, Lee VM, and Milla ME. Neuronal localization of the TNF-alpha converting enzyme (TACE) in brain tissue and its correlation to amyloid plaques. [J] Neurobiol,2002,49:40-46.
[17]Hurtado O, Cardenas A, Lizasoain I, Bosca L, Leza JC, Lorenzo P, and Moro MA. Up-regulation of TNF-alpha convertase (TACE/ADAM 17) after oxygenglucose deprivation in rat forebrain slices. [J] Neuropharmacology,2001,40:1094-1102.
[18]Xinkang Wang, Giora Z. Feuerstein, Lin Xu, Hugh Wang, William A. Schumacher, Martin L. Inhibition of Tumor Necrosis Factor-alpha-Converting Enzyme by aSelective Antagonist Protects Brain from Focal Ischemic Injury in Rats.[J] Molecular Pharmacology, 2004,65(4):890-897.
[19]Buxbaum JD, Liu KN, Luo Y, Slack JL, Stocking KL, Peschon JJ, Johnson RS,Castner BJ, Cerretti DP, and Black RA. Evidence that tumor necrosis factor-alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. [J] Biol Chem,1998,273:27765-767.
[20]Peschon JJ, Slack JL, Reddy P, Stocking KL, Sunnarborg SW, Lee DC, Russell WE, Castner BJ, Johnson RS, Fitzner JN, et al. An essential role for ectodomain shedding in mammalian development.[J] Science (Wash DC),1998,282:1281-1284.
[21]Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, Haass C, and Fahrenholz F.Constitutive and regulated alpha-secretase cleavage of Alzheimer'samyloid precursor protein by a disintegrin metalloprotease.[J] Proc Natl Acad Sci USA,1999, 96:3922-3927.
[22]Fassbender K, Mossner R, Motsch L, Kischka U, Grau A, and Hennerici M.Circulating selectin-and immunoglobulin-type adhesion molecules in acute ischemic stroke. [J]Stroke,1995,26:1361-1364.
[23]Wang XK, Barone FC, Aiyar NV, and Feuerstein GZ. Interleukin-1 receptor and receptor antagonist gene expression after focal stroke in rats. [J]Stroke,2002,28:155-161.
[24]Ruocco A, Nicole O, Docagne F, Ali C, Chazalviel L, Komesli S, Yablonsky F, Roussel S, MacKenzie ET, Vivien D, et al. A transforming growth factor-beta antagonist unmasks the neuroprotective role of this endogenous cytokine in excitotoxicand ischemic brain injury.[J]Cereb Blood Flow Metab,1999,19:1345-1353.
[25]Citron M. Beta-secretase as a target for the treatment of Alzheimer's disease.[J] Neurosci Res,2002,70:373-379.
[26]Moskowitz MA and Lo EH.Neurogenesis and apoptotic cell death. [J]Stroke 2003,34:324-326.
[27]Gupta S. Molecular steps of tumor necrosis factor receptor-mediated apoptosis.[J]Curr Mol Med,2001,1:317-324.
[28]Cardenas A, Moro MA, Leza JC, O'Shea E, Davalos A, Castillo J, Lorenzo P, and Lizasoain I. Upregulation of TACE/ADAM17 after ischemic preconditioningis involved in brain tolerance.[J] Cereb Blood Flow Metab,2002,22:1297-1302.
[29]Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, Handa N,Fukunaga R, Kimura K, Mikoshiba K. Ischemic tolerance phenomenon found in the brain. [J]Brain Res,1990,528:21-24.
[30]Barone FC, White RF, Spera PA, Ellison J, Currie RW, Wang X, Feurstein GZ. Ischemic preconditioning and brain tolerance.[J] Stroke,1998,29:1937-1951.
[31]Kirino T. Ischemic tolerance.[J]Cereb Blood Flow Metab,2002,22:1283-1296.
[32]Weih M, Kallenberg K, Bergk A, Dirnagl U, Harms L, Wernecke KD, Einhaupl KM. Attenuated stroke severity after prodromal TIA. A role for ischaemic tolerance in the brain? [J]Stroke,2001,30:1851-1854.
[33]Moncayo J, de Freitas GR, Bogousslavsky J, Altieri M, van Melle G. Do transient ischemic attacks have a neuroprotective effect? [J]Neurology,2000,54:2089-2094.
[34]Castillo J, Moro MA, Blanco M, Leira R, Serena J, Lizasozin I, Davzlos A. The release of tumor necrosis factor-alpha is associated with ischemic tolerance in human stroke.[J] Ann Neurol,2003,54:811-819.
[35]Kirino T, Tsujita Y, Tamura A. Induced tolerance to ischemia in gerbil hippocampal neurons. [J] Cereb Blood Flow Metab,2000,11:299-307.
[36]Kato H, Liu Y, Araki T, Kogure K. MK-801, but not anisomycin,inhibits the induction of tolerance to ischemia in the gerbil hippocampus. [J]Neurosic Lett,1992,139:118-121.
[37]Kasischke K, Ludolph AC, Riepe MW.NMDA antagonists reverse increased hypoxic tolerance by preceding chemical hypoxia. [J]Neurosci Lett,1996,214:175-178.
[38]Grabb MC, ChoiDW.Ischemic tolerance in murine cortical cell culture:critical role for NMDA receptors. [J] Neurosci,1999,19:1657-1662.
[39]Shimazaki K, Ishida A, Kawai N. Increase in bcl-2 oncoprotein and the tolerance to ischemia-reduced neuronal death in the gerbil in the gerbil hippocampus. [J]Neurosci Res,1994,20:95-99.
[40]Ohtsuki T, Ruetzler C, Tasaki K, Hallenbeck JM. Interleukin-1 mediates induction of tolerance to global ischemia in gerbil hippocampal CA1 neurons. [J] Cereb Blood Flow Metab,1996,16:1137-1142.
[41]Heurteaux C, Lauritzen I, Widmann C, Lazdunski M. Essential role of adenosine, adenosine A1 receptors, and ATP-sensitive channels in cerebral ischemic preconditioning. [J]Proc Natl Acad Sci USA,1995,92:4666-4670.
[42]Toyoda T, Kassell NF, Lee KS. Induction of ischaemic tolerance and antioxidant activity by brief focal ischaemia.[J] NeuroReport,1997,8:847-851.
[43]Ravati A, Ahlemeyer B, Becker A, Klumpp S, Krieglstein J. Preconditioning-induced neuroprotection is mediated by reactive oxygen species and activation of the transcription factor nuclear factor-kappa B.[J]Neurochem,2001,78:909-919.
[44]Gonza'lez-Zulueta M, Feldman AB, Klesse LJ, Kalb RG, Dillman JF, ParadaLF,Dawson TM, Dawson VL. Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioning. [J]Proc Natl Acad Sci USA,2000,97:436-441.
[45]Wick A, Wick W, Waltenberger W, Weller M, Dichgans J, Schulz JB.Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt.[J]Neurosci,2002,22:6401-6407.
[46]McLaughlin BA, Hartnett KA, Erhardt KA, Legos JL, White RF, Barone FC, Aizenman E. Caspase 3 activation is essential for neuroprotection in preconditioning.[J] Proc Natl Acad Sci USA,2003,100:715-720.
[47]Blondeau N, Widmann C, Lazdunski M, Heurteaux C. Activation of the nuclear factor kappaB is a key event in brain tolerance. [J] Neurosci,2001,21:4668-4677.
[48]Ginis I, Jaiswal R, Klimanis D, Liu J, Geenspon J, Hallenbeck JM. TNF-alpha-Induced tolerance to ischaemic injury involves differential control of NF-kapaaB transactivation:the role of NF-kappaB association with p300 adaptor.[J] Cereb Blood Flow Metab 2002, 22:142-152.
[49]Mattson MP, Culmsee C, Yu Z, Camandola S. Roles of NF-kappaB in neuronal survival and plasticity.[J] Neurochem,2000,74:443-456.
[50]Barone FC, Feuerstein GZ. Inflammatory mediators and stroke:new opportunities for novel therapeutics. [J]Cereb Blood Flow Metab,1999,19:819-834.
[51]Shohami E, Ginis I, Hallenbeck JM. Dual role of tumor necrosis factor-alpha in brain injury.[J] Cytokine Growth Factor Rev,1999,10:119-130.
[52]Del Zoppo G, Ginis I, Hallenbeck JM, Iadecola C, Wang X, Feuerstein GZ. Inflammation and stroke:putative role for cytokines, adhesionmolecules and iNOS in brain response toischemia. [J]Brain Pathol,2000,10:95-112.
[53]Hallenbeck JM. The many faces of tumor necrosis factor in stroke.[J]Nat Med,2002,8:1363-1368.
[54]Liu J, Ginis I, Spatz M, Hallenbeck JM (2000) Hypoxic preconditioning protects cultured neurons against hypoxic stress via TNF-alpha and ceramide. [J] Physiol Cell Physiol,2000, 278:144-153.
[55]Wang X, Li X, Erhardt JA, Barone FC, Feurstein GZ. Detection of TNF-_alpha mRNA induction in ischemic brain tolerance by means of realtime polymerase chain reaction. [J]Cereb Blood Flow Metab,2000,20:15-20.
[56]Hurtado O, Cardenas A, Lizasoain I, Bosca'L, Leza JC, Lorenzo P, Moro MA. Up-regulation of TNF-alpha convertase(TACE/AD AM 17) afteroxygen-glucose deprivation in rat forebrain slices. [J] Neuropharmacology,2001,40:1094-1102.
[57]Hurtado O, Lizasoain I, Ferna'ndez-Tome'P, A'lvarez-Barrientos A, Leza JC,Lorenzo P, Moro MA. TACE/ADAM17-TNF-alpha pathway in rat cortical cultures after exposure to oxygen-glucose deprivation or glutamate.[J]Cereb Blood Flow Metab,2002,22:576-585.
[58]Cardenas A, Moro MA, Leza JC, O'Shea E, Davalos A, Castillo J, Lorenzo P,Lizasoain I. Up-regulation of TACE/ADAM17 after ischemic preconditioning is involved in brain tolerance. [J] Cereb Blood Flow Metab,2002,22:1297-1302.
[59]Cristina Romera.In Vitro Ischemic Tolerance Involves Upregulation of Glutamate Transport Partly Mediated by the TACE/ADAM17-Tumor Necrosis Factor-alpha Pathway. [J] Neuroscience,2004,24(6); 1350-1357
[60]Karkkainen L, Rybnikova E, Pelto-Huikko M, Huovila AP. Metalloprotease disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS.[J] Mol Cell Neurosci,2000,15:547-560.
[61]Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, Feuerstein GZ Tumor necrosis factor-alpha expression in ischemic neurons. [J]Stroke,2000,25:1481-1488.
[62]Choi DW, Rothman SM.The role of glutamate neurotoxicity in hypoxic-ischaemic neuronal death. [J]Annu Rev Neurosci,1999,13:171-182.
[63]Castillo J, Da'valos A, Naveiro J, Noya M. Neuroexcitatory amino acids and their relationship to infarct size and neurological deficit in ischemic stroke. [J] Stroke,1996,27: 1060-1065.
[64]Johns L, Sinclair AJ, Davies JA. Hypoxia/hypoglycemia-induced amino acid release is decreased in vitro by preconditioning. [J]Biochem Biophys Res Commun,2000,276:134-136.
[65]Grabb MC, Lobner D, Turetsky M, Choi DW. Preconditioned resistance to oxygen-glucose deprivation-induced cortical neuronal death:alterations in vesicular GABA and glutamate release. [J]Neuroscience,2002,115:173-183.
[66]Takahashi M, Billups B, Rossi D, Sarantis M, Hamann M, Attwell D. The role of glutamate transporters in glutamate homeostasis in the brain.[J]Exp Biol,1997,200:401-409.
[67]Maragakis NJ, Rothstein JD Glutamate transporters in neurologic diseases. [J]Arch Neurol,2001,58:365-370.
[68]Seal RP, Amara SG. Excitatory amino acid transporters:a family in flux.[J]Annu Rev Pharmacol Toxicol,1999,39:431-456.
[69]Ruscher K, Freyer D, Karsch M, Isaev N, Megow D, Sawitzki B, Priller J, Dirnagl U, Meisel A. Erythropoietin is a paracrine mediator of ischemic tolerance in the brain:evidence from an in vitro model. [J]Neurosci,2002,22:10291-10301.
[70]李翠风.老年性痴呆与信号转导.[J]生命的化学,2000,20(6)：2782-281.
[71]Canet-Aviles RM,Anderton M,Hooper NM,et al. Muscarine enhances soluble amyloid precursor protein secretion in human neuroblastoma SH-SY5 Y by a pat hway dependent on protein kinase C(alpha), src-tyrosine kinase and ext racellular signal-regulated kinase but not phospholipase C. [J] Brain Res Mol Brain Res,2002,102 (122):62-72.
[72]de la Torre JC. Is Alzheimer's disease a neurogegenerative or a vascular disorder? Data, dogma, and dialectics. [J]Lancet Neurol,2004,3 (3):184-190.
[73]Dodart JC,Marr RA,Koistinaho M,et al. Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer's disease. [J] Proc Natl Acad Sci USA,2005,102(4):1211-1216.
[74]Lanni C,Mazzucchelli M, Porrello E, et al. Differential involvement of protein kinase C alpha and epsilon in t he regulated secretion of soluble amyloid precursor protein. [J] Biochem,2004,271 (14):3068-3075.
[75]Zhu G,Wang D,Lin YH,et al. Protein kinase C epsilon suppresses Abeta production and promotes activation of alpha-secretase,[J] Biochem Biophys Res Commun,2001,285 (4):997-1006.
[76]Yeon SW,J ung MW,Ha MJ,et al. Blockade of PKC epsilon activation attenuates phorbol ester-induced increase of alpha-secrease-derived secreted form of amyloid precursor protein. [J] Biochem Biophys Res Commun,2001,280 (3):782-787.
[77]Alkon DL,Sun MK,Nelson TJ. PKC signaling deficit s:a mechanistic hypothesis for the origins of Alzheimer's disease.[J]Trends Pharmacol Sci,2007,28 (2):51-60.
[78]周燕,闫福岭,等.脑慢性低灌注大鼠海马M1受体、ADAM17水平变化及意义.[J]山东医药,2009,49(30)：39-40.
[1]Koo HJ, Lee S, Shin KH, et al. Geniposide, an anti-angiogenic compound from the fruits of Gardemia jas minoides.[J]Planta Med,2004,70(5):467-469.
[2]Longa EZ, Weinstein PR, Carlson S, et al Reverible middle cerebral artery occlusion without cranjectomy in rats.[J]Stroke,1989,20(1):84-91.
[3]张忱等.大鼠局灶性脑缺血再灌注模型的再灌注时间窗.中日友好医院学报,2000,14(5)：255-259.
[4]Suzuki Y, Kondo K, Ikeda Y, et al. Antithrombotic effect of geniposide and genipin in the mouse thrombosis model.[J]Planta Med,2001,67(9):807-810.
[5]Kuo WH, Wang CJ, Young SC, et al. Differential induction of the expression of GST subunits by geniposide in rat hepatocytes. [J]Pharmacology,2004,70(1):15-22.
[6]LeeMJ, HsuJD, WangCJ. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-caused tumor promotion in benzo[a]pyrene-initiated CD-1 mouse skin by geniposide. [J] Anticancer Res,1995,15(2):411-416.
[7]王根发,等.三七皂苷对脑缺血对大鼠再灌注损伤的保护作用.[J]中国临床康复,2002,6(9)：1268-1269.
[8]禺登俊,等.中药三七对脑缺血再灌注损伤后神经可塑性的影响.[J]中国临床康复,2003,5(3)：132-134.
[9]何蔚,朱遵平.三七总皂昔对大鼠脑梗死区ICAMI表达和中性粒细胞浸润的影响.[J]中药材,2005,25(5)：304-306.
[10]青雪梅,李澎涛,等.通络救脑注射液对大鼠脑微血管内皮细胞活性及其条件培养液影响的初步研究.[J]现代生物医学进展,2006,6(4)：1-4.
[1]Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ,Stocking KL, Reddy P, Srinivasan S, et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. [J] Nature (Lond),1997,385: 729-733.
[2]Doedens JR and Black RA. Stimulation-induced down-regulation of tumor necrosis factor-alpha converting enzyme.[J]Biol Chem,2000,275:14598-607.
[3]Reddy P, Slack JL, Davis R, Cerretti DP, Kozlosky CJ, Blanton RA, Shows D,Peschon JJ, and Black RA. Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme. [J]Biol Chem,2000,275:14608-14614.
[4]del Zoppo G, Ginis I, Hallenbeck JM, Iadecola C, Wang X, and Feuerstein GZ.Inflammation and stroke:putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. [J]Brain Pathol,2000,10:95-112.
[5]Wang X and Feuerstein GZ. Role of immune and inflammatory mediators in CNS injury. [J]Drug News Perspect,2000,13:133-140.
[6]Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, and Feuerstein GZ. Tumour necrosis factor-alpha expression in ischemic neurons.[J] Stroke,2001,25:1481-1488.
[7]Wang XK, Yue TL, Barone FC, White RF, Gagnon RC, and Feuerstein GZ.Concomitant cortical expression of TNF-alpha and IL-lalpha mRNA following transient focal ischemia. [J] Mol Chem Neuropathol,1994,23:103-114.
[8]Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, Lysko PG, and Feuerstein GZ. Tumour necrosis factor-alpha. A mediator of focal ischeic brain injury.[J] Stroke,1997,28:1233-1244.
[9]Dawson DA, Martin D, and Hallenbeck JM. Inhibition of tumour necrosis factor-alpha reduces focal cerebral ischemic injury in the spontaneously hypertensive rat. [J]Neurosci Lett,1996,218:41-44.
[10]Nawashiro H, Martin D, and Hallenbeck JM. Inhibition of tumour necrosis factor and amelioration of brain infarction in mice.[J]Cereb Blood Flow Metab,2000,17: 229-232.
[11]Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, Holtsberg FW, and Mattson MP. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors.[J] Nat Med,1996,2:788-794.
[12]Nawashiro H, Tasaki K, Ruetzler CA, and Hallenbeck JM. TNF-alpha pretreatment induces protective effects against focal cerebral ischemia in mice.[J] Cereb Blood Flow Metab,1997,17:483-490.
[13]Liu J, Ginis I, Spatz M and Hallenbeck JM. Hypoxic preconditioning protects cultured neurons against hypoxic stress via TNF-alpha andceramide.[J]AmPhysiol, 2000,278:144-153.
[14]Karkkainen I, Rybnikova E, Pelto-Huikko M, and Huovila AP. Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS. [J]Mol Cell Neurosci,2000,15:547-560.
[15]Hurtado O, Cardenas A, Lizasoain I, Bosca L, Leza JC, Lorenzo P, and Moro MA. Up-regulation of TNF-alpha convertase (TACE/ADAM17) after oxygenglucose deprivation in rat forebrain slices. [J] Neuropharmacology,2001,40:1094-1102.
[16]Skovronsky DM, Fath S, Lee VM, and Milla ME. Neuronal localization of the TNF-alpha converting enzyme (TACE) in brain tissue and its correlation to amyloid plaques. [J] Neurobiol,2002,49:40-46.
[17]Cardenas A, Moro MA, Leza JC, O'Shea E, Davalos A, Castillo J, Lorenzo P, and Lizasoain I. Upregulation of TACE/ADAM17 after ischemic preconditioningis involved in brain tolerance. J Cereb Blood Flow Metab 22:1297-1302.
[18]Xinkang Wang, Giora Z. Feuerstein, Lin Xu, Hugh Wang, William A. Schumacher,Martin L. Inhibition of Tumor Necrosis Factor-alpha-Converting Enzyme by aSelective Antagonist Protects Brain from Focal Ischemic Injury in Rats.[J] Molecular Pharmacology,2004,65(4):890-897.
[1]Baiguera S, Conconi MT, GuidolinD, et al. Ghrelin inhibits in vitro angiogenic activity of rat brain microvascular endothelial cells. [J] Int J MolMed,2004, 14(5):849-854.
[2]Defazio G, Livrea P, Giorelli M, et al. Interferon beta-1 a downregulates TNF alpha-induced intercellular adhesion molecule 1 expression on brain microvascular endothelial cells through a tyrosine kinase-dependent pathway. [J] Brain Res,2000, 881(2):227-230.
[3]Karkkainen I, Rybnikova E, Pelto-Huikko M, and Huovila AP. Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS. [J]Mol Cell Neurosci,2000,15:547-560.
[4]Goddard DR, Bunning RA, and Woodroofe MN. Astrocyte and endothelial cell expression of ADAM 17 (TACE) in adult human CNS.[J] Glia,2001,4:267-271.
[5]Skovronsky DM, Fath S, Lee VM, and Milla ME. Neuronal localization of the TNF-alpha converting enzyme (TACE) in brain tissue and its correlation to amyloid plaques. [J] Neurobiol,2002,49:40-46.
[6]Hurtado O, Cardenas A, Lizasoain I, Bosca L, Leza JC, Lorenzo P, and Moro MA. Up-regulation of TNF-alpha convertase (TACE/AD AM17) after oxygenglucose deprivation in rat forebrain slices. [J] Neuropharmacology,2001,40:1094-1102.
[7]Cardenas A, Moro MA, Leza JC, O'Shea E, Davalos A, Castillo J, Lorenzo P, and Lizasoain I. Upregulation of TACE/ADAM17 after ischemic preconditioningis involved in brain tolerance. [J] Cereb Blood Flow Metab 22:1297-1302.