重度慢性间歇低氧对大鼠海马神经细胞ERK通路及凋亡的影响
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摘要
目的通过建立重度慢性间歇低氧大鼠模型,观察大鼠海马神经细胞ERK通路及凋亡的变化,探讨ERK通路对神经系统的影响。
方法48只成年雄性Wistar大鼠采用随机数字法分组原则分为2组:5%间歇低氧组(5%CIH组)、空白对照组(UC组),每组按不同时间点分为4个亚组:分别为2、4、6、8w组。将5%CIH组大鼠循环交替给予不同流速的氮气和压缩空气(每一循环120s,使5%CIH组箱内最低氧浓度至5%,然后恢复至21%,8h/d);UC组大鼠不给予任何处理。分别在实验第2、4、6、8w后,采用免疫组化学法检测大鼠海马神经细胞ERK 1/2、c-fos蛋白表达;采用原位细胞凋亡方法检测大鼠海马神经细胞凋亡变化。应用Motic医学图像分析系统对免疫组化结果ERK1/2及c-fos蛋白半定量分析,结果用积分光密度(IOD)值表示。观察各组大鼠第2、4、6、8w大鼠海马神经细胞ERK 1/2、c-fos蛋白的表达和凋亡指数的变化。
统计学处理采用SPSS13.0统计软件包进行数据分析,所得数据用均数±标准差(xˉ±s)表示,组间比较采用独立样本T检验,组内比较采用单因素方差分析,多重比较采用LSD法,以P<0.05为差异有统计学意义。
结果
1重度慢性间歇低氧对海马神经细胞ERK1/2蛋白表达的影响
1.1光学显微镜下观察到大部分阳性表达细胞胞浆呈棕黄色或浅黄色。各组大鼠均有阳性表达细胞,阳性细胞的表达程度不同。UC组可见散在阳性表达细胞;5%CIH组阳性表达细胞明显增多,主要集中在海马CAl区。
1.2 5%CIH组海马CAl区神经细胞ERK1/2蛋白表达IOD值在2、4、6、8w均显著高于UC组(P <0.05),UC组海马CAl区神经细胞ERK1/2蛋白表达IOD值不同时间水平无显著差异(P﹥0.05),5%CIH组海马CAl区神经细胞ERK1/2蛋白表达IOD值不同时间水平有显著差异(P <0.05),表现为:ERK1/2蛋白表达IOD值随时间的延长呈先上升后下降趋势,于第6周达到高峰后下降。
2重度慢性间歇低氧对海马神经细胞c-fos蛋白表达的影响
2.1光学显微镜下观察到大部分阳性表达细胞胞核呈棕黄色或浅黄色,各组大鼠均有阳性表达细胞,阳性细胞的表达程度不同。UC组可见散在阳性表达细胞;5%CIH组阳性表达细胞明显增多,主要集中在海马CAl区。
2.2 5%CIH组海马CAl区神经细胞c-fos蛋白表达IOD值在2、4、6、8w显著高于UC组(P <0.05),UC组海马CAl区神经细胞c-fos蛋白表达IOD值不同时间水平无显著差异(P﹥0.05),5%CIH组海马CAl区神经细胞c-fos蛋白表达IOD值不同时间水平有显著差异(P<0.05),表现为:c-fos蛋白表达IOD值随时间的延长呈先上升后下降趋势,于第6周达到高峰后下降。
3重度慢性间歇低氧对海马神经细胞凋亡的影响
3.1光学显微镜下观察到凋亡细胞形态呈圆形或椭圆形,胞核呈棕黄色或棕褐色,形态呈碎点状,不规整,大小不一致,非凋亡细胞胞核被苏木素复染呈蓝色,核相对较大,形态大小较为一致。光学显微镜下观察到各组大鼠神经细胞均有凋亡, UC组可见散在凋亡细胞, 5%CIH组凋亡细胞明显增多,主要分布在海马CAl区。
3.2 5%CIH组凋亡指数在2、4、6、8w显著高于UC组(P<0.05),UC组海马CAl区神经细胞凋亡指数不同时间水平无显著差异(P﹥0.05),5%CIH组海马CAl区神经细胞凋亡指数不同时间水平有显著差异(P<0.05),表现为:神经细胞凋亡指数随时间的延长呈先上升后下降趋势,于第6周达到高峰后下降。
结论
1重度慢性间歇低氧可激活大鼠海马神经细胞ERK通路,同时诱导大鼠海马神经细胞凋亡。
2 ERK通路可通过介导大鼠海马神经细胞凋亡的发生,进而导致重度慢性间歇低氧早期脑损害的形成。
Objective a rat model of serious chronic intermittent hypoxia was established, the changes of ERK pathway and apoptosis in hippocampal neurocyte was observed, and effects of ERK pathway on nervous injury were explored.
Method Adult male Wistar rats (n=48) were randomly divided into 5% intermittent hypoxia group (5%CIH group), control group (UC group), According to different time points each group was divided into four sub-groups:respectively 2、4、6、8w. 5%CIH group were given alternating cycle of different nitrogen and compressed air flow rate (each cycle of 120s, so that 5%CIH group inside the minimum oxygen concentration to 5%, and then recovered to 21%, 8h/d); UC group were not given any treatment. Respectively after 2、4、6、8w of intermittent hypoxia,By immunohistochemical method to detect expression of c-fos and ERK1/2 protein in hippocampal neurocyte;By TUNEL method to detect serious chronic intermittent hypoxia induced neuronal apoptosis in hippocampal neurocyte. To analyze c-fos and ERK1/2 protein semi-quantitatively by Motic Medical image analysis system. The results with the 40 millimeter test optical density (IOD) value indicate. Changes of ERK1/2、c-fos protein and apoptotic index at 2、4、6、8w were observed in hippocampal neurocyte.
Statistical analysis SPSS13.0 statistical package used for data analysis, the data with mean±standard deviation(xˉ±s). Independent-Sample T test was used to the comparison between groups. One-Way ANOVA was used to the comparison within group, LSD method was used on multiple comparisons, P <0.05 was considered statistically significant.
Result
1 Effects on ERK1/2 protein in hippocampal neurocyte after serious chronic intermittent hypoxia.
1.1 Most of the cytoplasm of positive cells stained in brown or pale yellow was observed under Optical microscope. Rats of each group have positive cells. The degrees of positive cells are different. UC group shows scattered positive cells; 5%CIH group of positive cells were significantly increased, most of positive cells were in CA1 of hippocampus.
1.2 In CA1 of hippocampus,expression of ERK1/2 protein in IOD values in CIH 5% Group is more than in UC Group at 2、4、6、8w (P <0.05); Expression of ERK1/2 protein in IOD values in UC Group at different times there was no significant difference in CA1 of hippocampus (P > 0.05); expression of ERK1/2 protein in IOD values in 5%CIH group at different time levels were significantly different in CA1 of hippocampus (P <0.05), as follows: it roses to the peak at 6w and then decreased.
2 Effects on c-fos protein in hippocampal neurocyte after serious chronic intermittent hypoxia.
2.1 Most of the nuclei of positive cells stained in brown or pale yellow were observed under Optical microscope. Rats of each group have positive cells. The degrees of positive cells are different. UC group shows scattered positive cells; 5%CIH group of positive cells were significantly increased, most of positive cells were in CA1 of hippocampus.
2.2 In CA1 of hippocampus,expression of ERK1/2 protein in IOD values in CIH 5% Group is more than in UC Group at 2、4、6、8w (P <0.05); Expression of ERK1/2 protein in IOD values in UC Group at different times there was no significant difference in CA1 of hippocampus (P > 0.05); expression of ERK1/2 protein in IOD values in 5%CIH group at different time levels were significantly different in CA1 of hippocampus (P <0.05), as follows: it roses to the peak at 6w and then decreased.
3. Effects on neuronal apoptosis in hippocampal neurocyte after serious chronic intermittent hypoxia.
3.1 Under Optical microscope , apoptotic cells stained in brown or tan color were round or oval nuclei, shape was broken form, which is not regular, size inconsistency, non-apoptotic cell nuclei were stained with hematoxylin blue, nuclei were relatively large, more consistent shape and size. Rats of each group were apoptotic neurons, UC group showed scattered apoptotic cells, Apoptotic cell of 5%CIH group was significantly increased; Apoptotic cells of 5%CIHare widely distributed, mainly in CAl of hippocampus.
3.2 In CA1 of hippocampus,apoptotic index in 5%CIH Group is more than in UC Group at 2、4、6、8w (P <0.05); Apoptotic index in UC Group at different times there was no significant difference in CA1 of hippocampus (P > 0.05); Apoptotic index in 5%CIH group at different time levels were significantly different in CA1 of hippocampus (P <0.05), as follows: it roses to the peak at 6w and then decreased.
Conclusion
l Serious chronic intermittent hypoxia activated ERK pathway and induced apoptosis in hippocampal cells of rats.
2 ERK pathway lead to the formation of early brain damage in serious intermittent hypoxia through which mediated apoptosis in hippocampal cells of rats.
方法48只成年雄性Wistar大鼠采用随机数字法分组原则分为2组:5%间歇低氧组(5%CIH组)、空白对照组(UC组),每组按不同时间点分为4个亚组:分别为2、4、6、8w组。将5%CIH组大鼠循环交替给予不同流速的氮气和压缩空气(每一循环120s,使5%CIH组箱内最低氧浓度至5%,然后恢复至21%,8h/d);UC组大鼠不给予任何处理。分别在实验第2、4、6、8w后,采用免疫组化学法检测大鼠海马神经细胞ERK 1/2、c-fos蛋白表达;采用原位细胞凋亡方法检测大鼠海马神经细胞凋亡变化。应用Motic医学图像分析系统对免疫组化结果ERK1/2及c-fos蛋白半定量分析,结果用积分光密度(IOD)值表示。观察各组大鼠第2、4、6、8w大鼠海马神经细胞ERK 1/2、c-fos蛋白的表达和凋亡指数的变化。
统计学处理采用SPSS13.0统计软件包进行数据分析,所得数据用均数±标准差(xˉ±s)表示,组间比较采用独立样本T检验,组内比较采用单因素方差分析,多重比较采用LSD法,以P<0.05为差异有统计学意义。
结果
1重度慢性间歇低氧对海马神经细胞ERK1/2蛋白表达的影响
1.1光学显微镜下观察到大部分阳性表达细胞胞浆呈棕黄色或浅黄色。各组大鼠均有阳性表达细胞,阳性细胞的表达程度不同。UC组可见散在阳性表达细胞;5%CIH组阳性表达细胞明显增多,主要集中在海马CAl区。
1.2 5%CIH组海马CAl区神经细胞ERK1/2蛋白表达IOD值在2、4、6、8w均显著高于UC组(P <0.05),UC组海马CAl区神经细胞ERK1/2蛋白表达IOD值不同时间水平无显著差异(P﹥0.05),5%CIH组海马CAl区神经细胞ERK1/2蛋白表达IOD值不同时间水平有显著差异(P <0.05),表现为:ERK1/2蛋白表达IOD值随时间的延长呈先上升后下降趋势,于第6周达到高峰后下降。
2重度慢性间歇低氧对海马神经细胞c-fos蛋白表达的影响
2.1光学显微镜下观察到大部分阳性表达细胞胞核呈棕黄色或浅黄色,各组大鼠均有阳性表达细胞,阳性细胞的表达程度不同。UC组可见散在阳性表达细胞;5%CIH组阳性表达细胞明显增多,主要集中在海马CAl区。
2.2 5%CIH组海马CAl区神经细胞c-fos蛋白表达IOD值在2、4、6、8w显著高于UC组(P <0.05),UC组海马CAl区神经细胞c-fos蛋白表达IOD值不同时间水平无显著差异(P﹥0.05),5%CIH组海马CAl区神经细胞c-fos蛋白表达IOD值不同时间水平有显著差异(P<0.05),表现为:c-fos蛋白表达IOD值随时间的延长呈先上升后下降趋势,于第6周达到高峰后下降。
3重度慢性间歇低氧对海马神经细胞凋亡的影响
3.1光学显微镜下观察到凋亡细胞形态呈圆形或椭圆形,胞核呈棕黄色或棕褐色,形态呈碎点状,不规整,大小不一致,非凋亡细胞胞核被苏木素复染呈蓝色,核相对较大,形态大小较为一致。光学显微镜下观察到各组大鼠神经细胞均有凋亡, UC组可见散在凋亡细胞, 5%CIH组凋亡细胞明显增多,主要分布在海马CAl区。
3.2 5%CIH组凋亡指数在2、4、6、8w显著高于UC组(P<0.05),UC组海马CAl区神经细胞凋亡指数不同时间水平无显著差异(P﹥0.05),5%CIH组海马CAl区神经细胞凋亡指数不同时间水平有显著差异(P<0.05),表现为:神经细胞凋亡指数随时间的延长呈先上升后下降趋势,于第6周达到高峰后下降。
结论
1重度慢性间歇低氧可激活大鼠海马神经细胞ERK通路,同时诱导大鼠海马神经细胞凋亡。
2 ERK通路可通过介导大鼠海马神经细胞凋亡的发生,进而导致重度慢性间歇低氧早期脑损害的形成。
Objective a rat model of serious chronic intermittent hypoxia was established, the changes of ERK pathway and apoptosis in hippocampal neurocyte was observed, and effects of ERK pathway on nervous injury were explored.
Method Adult male Wistar rats (n=48) were randomly divided into 5% intermittent hypoxia group (5%CIH group), control group (UC group), According to different time points each group was divided into four sub-groups:respectively 2、4、6、8w. 5%CIH group were given alternating cycle of different nitrogen and compressed air flow rate (each cycle of 120s, so that 5%CIH group inside the minimum oxygen concentration to 5%, and then recovered to 21%, 8h/d); UC group were not given any treatment. Respectively after 2、4、6、8w of intermittent hypoxia,By immunohistochemical method to detect expression of c-fos and ERK1/2 protein in hippocampal neurocyte;By TUNEL method to detect serious chronic intermittent hypoxia induced neuronal apoptosis in hippocampal neurocyte. To analyze c-fos and ERK1/2 protein semi-quantitatively by Motic Medical image analysis system. The results with the 40 millimeter test optical density (IOD) value indicate. Changes of ERK1/2、c-fos protein and apoptotic index at 2、4、6、8w were observed in hippocampal neurocyte.
Statistical analysis SPSS13.0 statistical package used for data analysis, the data with mean±standard deviation(xˉ±s). Independent-Sample T test was used to the comparison between groups. One-Way ANOVA was used to the comparison within group, LSD method was used on multiple comparisons, P <0.05 was considered statistically significant.
Result
1 Effects on ERK1/2 protein in hippocampal neurocyte after serious chronic intermittent hypoxia.
1.1 Most of the cytoplasm of positive cells stained in brown or pale yellow was observed under Optical microscope. Rats of each group have positive cells. The degrees of positive cells are different. UC group shows scattered positive cells; 5%CIH group of positive cells were significantly increased, most of positive cells were in CA1 of hippocampus.
1.2 In CA1 of hippocampus,expression of ERK1/2 protein in IOD values in CIH 5% Group is more than in UC Group at 2、4、6、8w (P <0.05); Expression of ERK1/2 protein in IOD values in UC Group at different times there was no significant difference in CA1 of hippocampus (P > 0.05); expression of ERK1/2 protein in IOD values in 5%CIH group at different time levels were significantly different in CA1 of hippocampus (P <0.05), as follows: it roses to the peak at 6w and then decreased.
2 Effects on c-fos protein in hippocampal neurocyte after serious chronic intermittent hypoxia.
2.1 Most of the nuclei of positive cells stained in brown or pale yellow were observed under Optical microscope. Rats of each group have positive cells. The degrees of positive cells are different. UC group shows scattered positive cells; 5%CIH group of positive cells were significantly increased, most of positive cells were in CA1 of hippocampus.
2.2 In CA1 of hippocampus,expression of ERK1/2 protein in IOD values in CIH 5% Group is more than in UC Group at 2、4、6、8w (P <0.05); Expression of ERK1/2 protein in IOD values in UC Group at different times there was no significant difference in CA1 of hippocampus (P > 0.05); expression of ERK1/2 protein in IOD values in 5%CIH group at different time levels were significantly different in CA1 of hippocampus (P <0.05), as follows: it roses to the peak at 6w and then decreased.
3. Effects on neuronal apoptosis in hippocampal neurocyte after serious chronic intermittent hypoxia.
3.1 Under Optical microscope , apoptotic cells stained in brown or tan color were round or oval nuclei, shape was broken form, which is not regular, size inconsistency, non-apoptotic cell nuclei were stained with hematoxylin blue, nuclei were relatively large, more consistent shape and size. Rats of each group were apoptotic neurons, UC group showed scattered apoptotic cells, Apoptotic cell of 5%CIH group was significantly increased; Apoptotic cells of 5%CIHare widely distributed, mainly in CAl of hippocampus.
3.2 In CA1 of hippocampus,apoptotic index in 5%CIH Group is more than in UC Group at 2、4、6、8w (P <0.05); Apoptotic index in UC Group at different times there was no significant difference in CA1 of hippocampus (P > 0.05); Apoptotic index in 5%CIH group at different time levels were significantly different in CA1 of hippocampus (P <0.05), as follows: it roses to the peak at 6w and then decreased.
Conclusion
l Serious chronic intermittent hypoxia activated ERK pathway and induced apoptosis in hippocampal cells of rats.
2 ERK pathway lead to the formation of early brain damage in serious intermittent hypoxia through which mediated apoptosis in hippocampal cells of rats.
引文
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27.陈万欣,张志民,张凤侠等.脑损伤大鼠皮质神经细胞凋亡过程中细胞外调节激酶通路的作用[J].中国组织工程研究与临床康复,2007,11(29):15765-15768.
28.Choi DW, Rothman SM. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death [J]. Annu Rev Neurosci, 1990, 13 (3) : 171-182.
29.Gao J, Duan B, Wang DG, et al. Coupling between NMDA receptor and acid-sensing ion channel contributes to ischemic neuronal death[J].Neuron, 2005, 48 ( 4) : 635- 646.
30. Park ER, Eblen ST, Catling AD. MEK1 activation by PAK: A novel mechanism [J]. Cell Signal, 2007, 19 (7) : 1488-1496.
31. Marchetti S, Gimond C, Chambard JC, et al. Extracellular signal- regulated kinases phosphorylate mitogen activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation [J]. Mol Cell Biol, 2005, 25 ( 2 ) :854-864.
32. Johansson IM,Wester P,Hakova M,et a1.Early and delayed induction of immediate early gene expression in a novel focal cerebral is chemia model in the rat[J].Eur J Neurosci,2000,12(10):3615.
33.Cui J,Hu PK.Neuronal NOS inhibitor that reduce oxidative DNA lesions and neuronal sensitivity increases the expression of intact c-fos transcripts after brain injury[J].J Biomed Sci,2001,8(4):336.
34.刘亚玲、马永丰.丙泊酚对大鼠肝脏缺血再灌注损伤c-fos、c-jun蛋白及细胞凋亡的影响[J].临床麻醉学杂志,2008,6(24):525-526
35. Tanaka K,Wada N,Ogawa N.Chronic cerebral hypoperfusion in duces transient eversible rnonoaminegic changes in the rat brain[J]. Neurochem Res. 2000,25(3):313-319.
36. Makoto,Funahashi,Yifen He,et a1.Noxious tooth pulp stimulation suppresses c-fos expression in the rat hippocampal formatrion[J].Brain Research,1999,827:215.
37. Phillps LL,Belairdo ET.Expression of c-fos in the hippoearopus following mild and moderate fluid percussion brain injury.J Neuratrama,1992,9(4):323.
38.王政伟,尹彦玲,赵春平等.脑血管痉挛后血管平滑肌细胞中c-fos基因表达及意义[J].中华神经外科疾病研究杂志,2002,l(2):173-175.
39.Hafezi F,Steinbach JP,Marti A,et a1.The absence of c-fos prevents light-induced apoptotic cell death of photoraceptors in retinal degenration in vivo[J],Nat Med,1997,3:346-348.
40.高俊玲、田艳霞、陈万欣等.大鼠脑创伤后ERK通路对皮质神经细胞c-fos蛋白表达及凋亡的影响[J].天津医药,2008, 36(1):46-48.
41. Gillardon F , Lenz C , Waschke KF , et al. Altered expression of bcl-2 , bcl-x, bax and c-fos colocalizes with DNA fragenttation and ischemic cell damage following miggle cerebral artery occlusion in rats[J].Mol Brain Res , 1996 , 40 :254
42.Kinoshita Y,Ucyama T,Senba E, et al. Expression of c-fos,heat shock protein 70,neurotrphins,and cyclooxyenase-2 mRNA in response to focal cerebral ischemia/reperfusion in rats and their modification by magnesium sulface[J]. J Neurotrauma, 2001,18(4):435-445.
43.任广立,王玲,刘莹等.缺氧缺血再灌注后海马神经元凋亡与c-fos的表达[J].实用儿科临床杂志,2002,17(6):621-623.
44. J Colotta F,Polentarutti N,Sironi M,et a1.Expression and invol- vement of c-fes and c-jun protooneogenes in programmed cell death induced by growth factor deprivation in cympboid cell lines[J].J Biol Chen,1992,267(26):18278.
45.Paula M,James E,Christopher S.Dextmmethorphan inhibits ischemia-induced c-fos expression and delayed neurontal death in hippocampal neurons.Anesthesiology.1994,87:470-477.
46.Itoh H,Yagi M,Fushida S,et al.Activation of immediate early gene, c-fos,and c-jun in the rat small intestine after ischemia/reperfusion[J]. Transplantation,2000,69(4):598-604.
47. Kerr JFR , Wyllie AH , Curne AR. Apoptosis : a basic biological phenomenon with wide ranging implication in tissue kinetics [J] . Brit Cancer , 1972 , 26: 239-257
48. Van English M , Nieland LJ ,Ramaejers FC ,et al. AnnexinV-affinity assay : A review on an apoptosis detection system based on phosphatidylserine exposure [J].Cytometry, 1998, 31:1-4.
49.李文斌,华子春.胞浆死亡信号衔接蛋白FADD[J] .药物生物技术,2003,10 (5) :317-324.
50. Padosch SA,Vogel P,Bottiger Bw, et a1.Neuronal apoptosis following cerebra/ischemia.Basis,physiopathology and treatment streatment strategies[J].Anesthesist,2001,50L:905-920.
51. Linnik MD, Miller JA,Sprinle CA, et al. Apoptotic DNA fragmentation in the rat cerebral cortex induced by permanent middle cerebral artery occlusion[J]. Brain Res Mol Brain Rea,1995,32(1);116-124.
52. Ferrer I. Cell death in the normal developing brain,and following ionizing radiation, methy-azoxymethanol acctatc, and hypoxia-ischacmia in the rat[J].Neuropathol Appol Neuro-biol, 1996,22(6);489-494.
53.Dell Auna E , Chen Y, Engidawork E ,et al. Delayed neuronal death following perinatal asphyxia in rat [J] . Exp Brain Res ,1997 ,115 (1) :110 -115.
54.刘辉国、张志锋、张珍祥等.间歇缺氧大鼠海马神经元凋亡及其机制[J].中华结核和呼吸杂志,2007,30(5):368-371.
55.Hu BR,Wieloch T.Tyrosine phosphorylation and activation of mitogen -activated protein kinase in the rat brain following transient cerebral ischemia[J].J Neurochem,1994,62(3):1357-1367.
56. Alessandrini A.Namura S.Bonventre JV,et a1.MEKl protein kinaseinhibition protects against damage resulting from focal cerebral ischemia [J].Proc Natl Acad Sci USA,1999.96(11):12866-12869.
57.Mori T.Wang XY,Jung JC,et a1.Mitogen—activated protein kinase inhibition in traumatic brain injury:in vitro and in vivo effeets[J].Journal of Cerebral Blood Flow&Metabolism,2002,22(4):444-452.
58.Zhuang S, Schnellmann RG. A death-promoting role for extracellular signal- regulated kinase[J]. J Pharm acol Exp Ther, 2006, 319(3) : 991- 997.
59. Yamashita M, Shinnakasu R, Asou H, et al. Ras-ERK MAPK cascade regulates GATA3 stability and Th2 differentiation through ubiquitin -proteasome pathway[J]. J Biol Chem, 2005, 280(33):29409-29419.
1. Boulton TG,Nye SH,Robbins DJ,et al. ERKs:a family of Protein- serine/threonine kinases that are activated and tyrosine Phosphorylated in response in insulin and NGF[J].Cell,1991,165:663-675.
2. Courehesne WE,Kunisawa R,ThornerJ. A Putative Protein kinase overeomes pheromone-induced arrest of eell cycling in S. cerevisiae[J]. Cell,1989,58:1107-1119.
3.郑铭,韩启德.β肾上腺素受体的丝裂原蛋白激酶信号途径[J].生理科学进展, 2003, 33: 111.
4.Inoue T, Suzuki Y, Mizuno K, et al. SHP-1 exhibits a proapoptotic functi on in antigerr stimulated mast cells: positive regulation of mitochondrial death pathways and negative regulation of survival signaling pathways [J] . Mol Immunol,2009, 47( 2-3) : 222-232.
5. Osuga H,Hakin AM. Relevance of interstital Glutamate to selectice vulnerability in focal Cerebral ischemia [J] . J Cereb Blood Flow Metab , 1994,14 (2) :343.
6.杨惠玲主编.高级病理生理学[M] .北京:科学出版社,1998. 24-38.
7. Lewen A, Mlewen A , Mqtz P ,Chan PH. Free radial Pathways in CNS injury[J] . J neurotrauma ,2000 ,17 (10) :871-890.
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