间歇低氧对大鼠认知功能和p38MAPK/神经细胞凋亡通路影响
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摘要
目的1探讨不同程度慢性间歇性低氧对大鼠认知功能和海马神经元形态结构的影响;2探讨不同程度慢性间歇性低氧对大鼠p38MAPK/神经细胞凋亡通路的影响。方法成年雄性Wistar大鼠256只,随机均分为4组：空白对照组(UC组)、10%持续低氧组(10%CH组)、10%慢性间歇性低氧组(10%CIH组)、5%慢性间歇性低氧组(5%CIH组)。每组分为2周、4周、6周、8周共四个时间点亚组。各组16只大鼠,采用自制低氧舱模拟5%、10%慢性间歇低氧模型及10%持续低氧模型。三组低氧大鼠每日放入自制的低氧舱内暴露8小时。循环交替给予10%CIH组、5%CIH组低氧舱不同流速的氮气和压缩空气(每一循环120s,使两组箱内前30s氧浓度分别降至5%、10%,接着40s氧浓度逐渐恢复至21%,并维持50s,8h/d)；持续向10%CH组低氧舱内充入相同流速氮气和压缩空气,保证舱内氧浓度维持在10%；UC组大鼠放入舱内给予压缩空气。分别暴露2、4、6、8周后,应用Morris水迷宫实验检测大鼠认知功能、电镜和光镜观察脑组织海马区神经细胞形态变化、免疫组化和免疫印迹法检测海马区磷酸化p38MAPK蛋白表达,TUNEL法检测海马区神经细胞凋亡。
结果1. Morris水迷宫实验结果：与空白对照组比较,10%CIH组、10%CH组大鼠在第4、6、8周逃避潜伏期时间延长、跨越目标象限时间缩短；且第六周时变化明显。5%CIH组从第2周开始,随低氧时间延长动物逃避潜伏期时间明显延长、跨越目标象限时间明显缩短,且这种变化比10%CIH组更加显著,与10%CH组比较,10%CIH组动物第6、8周、5%CIH组大鼠第2、4、6、8周避潜伏期时间明显延长、跨越目标象限时间显著缩短。
2.形态学检测结果：①光镜：对照组大鼠海马区神经元结构完整,排列整齐,染色均匀。低氧组海马区出现变性坏死神经元,表现为神经细胞胞体收缩呈三角形,胞浆嗜色性减弱,核皱缩浓染,核溶解及空泡样变。与对照组比较,10%CH组4、6、8周海马CA1区存活神经细胞密度均降低；间歇低氧组大鼠第2、4、6、8周海马CA1区存活神经细胞密度均显著降低；5%CIH组大鼠10%CIH组更明显；10%CH和10%CIH组大鼠存活神经细胞密度降低第六周时变化明显。②电镜：空白对照组动物海马神经元核大圆,核仁清晰,核质均匀,核膜光滑边缘清晰,细胞器丰富完整。低氧组可见神经元细胞水肿、核染色质浓缩聚集、核仁及细胞器消失、核膜断裂；粗面内质网排列紊乱及脱颗粒；线粒体肿胀、空泡变性及嵴消失；突触结构分界不清；轴索排列紊乱、断裂。
3.磷酸化p38MAPK免疫组化结果：与对照组比较,10%CH.10%CIH、5%CIH组大鼠在第2、4、6、8周海马CA1区磷酸化p38MAPK免疫反应性均明显增高,于第6周达高峰；与10%CH组比较,10%CIH组和5%CIH组第2、4、6、8周海马CA1区磷酸化p38MAPK免疫反应性显著增高(P<0.05)、且5%CIH组较10%CIH组增高更明显(P<0.05)。
4.磷酸化p38MAPK免疫印迹结果：对照组中不同时间均有少量磷酸化p38MAPK表达,但无统计学差异(P>0.05)。三组低氧组大鼠海马区磷酸化p38MAPK表达第2、4、6、8周随时间延长明显增高,于第6周达高峰(P<0.05)。与10%CH组比较,10%CIH组和5%CIH组第2、4、6、8周海马CA1区磷酸化p38MAPK表达显著增高(P<0.05)、且5%CIH组较10%CIH组增高更明显(P<0.05)。
5. TUNEL检测结果：与空白对照组比较,10%CH,10%CIH、5%CIH组大鼠在第2、4、6、8周海马CA1区神经细胞凋亡指数明显增高,于第6周达高峰；与10%CH组比较,两组间歇低氧组第2、4、6、8周海马CA1区神经细胞凋亡指数均明显增高；且以5%CIH组凋亡指数最高。
结论：1.慢性间歇性低氧可造成大鼠学习记忆损伤,损伤程度与缺氧时间及程度有关：严重低氧时,早期即可造成学习记忆功能的损害；
2.不同程度慢性间歇性低氧后海马结构损伤是大鼠学习记忆损害的机制之一；
3.大鼠不同程度慢性间歇性低氧后,可激活p38MAPK通路,是导致神经细胞凋亡的重要因素之一；
4.不同程度慢性间歇性低氧可导致p38MAPK/神经细胞凋亡通路激活,是大鼠间歇性低氧后学习记忆损伤重要原因。慢性间歇低氧对大鼠认知功能及神经系统损伤比持续低氧更严重,且以早、中期更明显。提示间歇低氧后期存在低氧应激代偿。
Objective:1Discussion on the effects of intermittent hypoxia on the cognitive function and hippocampus ultra microstructure in Rats;2to observe the effects on the p38MAPK/the neurocyte apoptosis in rats exposed to different degree of intermittent hypoxia. Method:256mature male Wistar rats were randomly assigned to4groups:Control group (UC),10%continued hypoxia group (10%CH),5%intermittent hypoxia group (5%CIH) and10%of chronic intermittent hypoxia Group (10%CIH), and rats in each4groups were assigned to2nd,4th,6th and8th week subgroups (n=16). Rats in each group were suffered8hours everyday. Intermittent hypoxia circulating to give different flow of nitrogen and compressed air (each cycle120s,at the first30s'keeping oxygen concentration inside at5%and10%for CIH groups, and at following40s'increasing oxygen concentration to21%; and keeping50s'). The same concentration of nitrogen and compressed air was given to the10%CH group to keep the oxygen concentration in room to21%for8hours. The compressed air was given to the UC group. The cognitive functions of rats in each group were assessed with the Morris water maze (MWM) at the end of experiments and hippocampus ultra microstructure was observed. The expression of phosphorylase p38MAPK protein was detected by immunohistochemical and western blot. The apoptosis of hippocampus cell was detected by TUNEL.
Results:1. Morris water maze experimental results:Compared with UC group, in10%CH and10%CIH groups animals showed escape latency obvious extended and the time of through original platform location significantly reduced, especially at6th week. There was different in time that change starting, in5%CIH group, it was occurred at the2nd week, while in the10%CIH and10%CH group, at4th week.
2. The results of morphology.①Mirror microscope:In3hypoxia groups, with the extension of exposure time, the number of hippocampus neurons and synaptic were decreased, the structure injury was significantly in nerve cell nucleus at all duration of experiment4th,6th and8th weeks in10%CH, while in two CIH groups, it occurred at the2nd week, earlier than in10%CH group.②SEM:In3hypoxia groups at early stage, morphological changes of hippocampal neurons are not obvious. With time being, showing increased never system damage in neurons cytoplasm, nuclear membrane, rough endoplasmic, mitochondria, axonal flow, axonal neurofilament otmesis, and so on, especially in5%CIH group.
3. Phosphorylation p38MAPK immunohistochemical results:compared with the UC group, in three hypoxia groups at2nd,4th,6th,8th week, phosphorylation p38MAPK-positive cells in hippocampus increased markedly, to the peak at6th week; Comparing with10%CH, two CIH groups in the2nd,4th,6th,8th,phosphorylation p38MAPK-positive cells in hippocampus increased significantly, especially in5%CIH. group.
4. Phosphorylation p38MAPK Western blot results:compared with the UC group,10%CH and10%CIH5%CIH group in2nd,4th,6th,8th week, phosphorylation p38MAPK expression in hippocampus increased markedly, reaching to the peak in the6th week; Compared with the10%CH group,10%CIH,5%CIH group in2nd,4th,6th,8th week, phosphorylation p38MAPK-positive cells in hippocampus increased significantly, especially in5%CIH. group.
5. TUNEL test results:compared with UC, in three hypoxia groups, at2nd,4th,6th,8th week neuron apoptosis was significantly increased in hippocampus, at the6th week to the peak; Compared with the10%CH group,10%CIH,5%CIH group in2nd,4th,6th,8th week, neuron apoptosis increased significantly, especially in5%CIH.group. Conclusion:1. CIH can cause cognitive impairment in rats, it was related with severity and the duration of hypoxia, it occurs at early stage in severe CIH.
2Hippoeampal injuries in the presence of different degrees of CIH was one of the mechanisms of learning and memory impairment in rats;
3.It can activate the p38MAPK pathway in Rats exposure under the varying degrees of CIH and p38MAPK pathway is one of the important factors leading to apoptosis;
4. CIH can cause varying degrees of p38MAPK/neurons apoptosis pathway activation; it is the important reasons of learning and memory impairment in rats after intermittent hypoxia. The cognitive and nerve system damage caused by CIH is severe than CH, especially at early stage.
结果1. Morris水迷宫实验结果：与空白对照组比较,10%CIH组、10%CH组大鼠在第4、6、8周逃避潜伏期时间延长、跨越目标象限时间缩短；且第六周时变化明显。5%CIH组从第2周开始,随低氧时间延长动物逃避潜伏期时间明显延长、跨越目标象限时间明显缩短,且这种变化比10%CIH组更加显著,与10%CH组比较,10%CIH组动物第6、8周、5%CIH组大鼠第2、4、6、8周避潜伏期时间明显延长、跨越目标象限时间显著缩短。
2.形态学检测结果：①光镜：对照组大鼠海马区神经元结构完整,排列整齐,染色均匀。低氧组海马区出现变性坏死神经元,表现为神经细胞胞体收缩呈三角形,胞浆嗜色性减弱,核皱缩浓染,核溶解及空泡样变。与对照组比较,10%CH组4、6、8周海马CA1区存活神经细胞密度均降低；间歇低氧组大鼠第2、4、6、8周海马CA1区存活神经细胞密度均显著降低；5%CIH组大鼠10%CIH组更明显；10%CH和10%CIH组大鼠存活神经细胞密度降低第六周时变化明显。②电镜：空白对照组动物海马神经元核大圆,核仁清晰,核质均匀,核膜光滑边缘清晰,细胞器丰富完整。低氧组可见神经元细胞水肿、核染色质浓缩聚集、核仁及细胞器消失、核膜断裂；粗面内质网排列紊乱及脱颗粒；线粒体肿胀、空泡变性及嵴消失；突触结构分界不清；轴索排列紊乱、断裂。
3.磷酸化p38MAPK免疫组化结果：与对照组比较,10%CH.10%CIH、5%CIH组大鼠在第2、4、6、8周海马CA1区磷酸化p38MAPK免疫反应性均明显增高,于第6周达高峰；与10%CH组比较,10%CIH组和5%CIH组第2、4、6、8周海马CA1区磷酸化p38MAPK免疫反应性显著增高(P<0.05)、且5%CIH组较10%CIH组增高更明显(P<0.05)。
4.磷酸化p38MAPK免疫印迹结果：对照组中不同时间均有少量磷酸化p38MAPK表达,但无统计学差异(P>0.05)。三组低氧组大鼠海马区磷酸化p38MAPK表达第2、4、6、8周随时间延长明显增高,于第6周达高峰(P<0.05)。与10%CH组比较,10%CIH组和5%CIH组第2、4、6、8周海马CA1区磷酸化p38MAPK表达显著增高(P<0.05)、且5%CIH组较10%CIH组增高更明显(P<0.05)。
5. TUNEL检测结果：与空白对照组比较,10%CH,10%CIH、5%CIH组大鼠在第2、4、6、8周海马CA1区神经细胞凋亡指数明显增高,于第6周达高峰；与10%CH组比较,两组间歇低氧组第2、4、6、8周海马CA1区神经细胞凋亡指数均明显增高；且以5%CIH组凋亡指数最高。
结论：1.慢性间歇性低氧可造成大鼠学习记忆损伤,损伤程度与缺氧时间及程度有关：严重低氧时,早期即可造成学习记忆功能的损害；
2.不同程度慢性间歇性低氧后海马结构损伤是大鼠学习记忆损害的机制之一；
3.大鼠不同程度慢性间歇性低氧后,可激活p38MAPK通路,是导致神经细胞凋亡的重要因素之一；
4.不同程度慢性间歇性低氧可导致p38MAPK/神经细胞凋亡通路激活,是大鼠间歇性低氧后学习记忆损伤重要原因。慢性间歇低氧对大鼠认知功能及神经系统损伤比持续低氧更严重,且以早、中期更明显。提示间歇低氧后期存在低氧应激代偿。
Objective:1Discussion on the effects of intermittent hypoxia on the cognitive function and hippocampus ultra microstructure in Rats;2to observe the effects on the p38MAPK/the neurocyte apoptosis in rats exposed to different degree of intermittent hypoxia. Method:256mature male Wistar rats were randomly assigned to4groups:Control group (UC),10%continued hypoxia group (10%CH),5%intermittent hypoxia group (5%CIH) and10%of chronic intermittent hypoxia Group (10%CIH), and rats in each4groups were assigned to2nd,4th,6th and8th week subgroups (n=16). Rats in each group were suffered8hours everyday. Intermittent hypoxia circulating to give different flow of nitrogen and compressed air (each cycle120s,at the first30s'keeping oxygen concentration inside at5%and10%for CIH groups, and at following40s'increasing oxygen concentration to21%; and keeping50s'). The same concentration of nitrogen and compressed air was given to the10%CH group to keep the oxygen concentration in room to21%for8hours. The compressed air was given to the UC group. The cognitive functions of rats in each group were assessed with the Morris water maze (MWM) at the end of experiments and hippocampus ultra microstructure was observed. The expression of phosphorylase p38MAPK protein was detected by immunohistochemical and western blot. The apoptosis of hippocampus cell was detected by TUNEL.
Results:1. Morris water maze experimental results:Compared with UC group, in10%CH and10%CIH groups animals showed escape latency obvious extended and the time of through original platform location significantly reduced, especially at6th week. There was different in time that change starting, in5%CIH group, it was occurred at the2nd week, while in the10%CIH and10%CH group, at4th week.
2. The results of morphology.①Mirror microscope:In3hypoxia groups, with the extension of exposure time, the number of hippocampus neurons and synaptic were decreased, the structure injury was significantly in nerve cell nucleus at all duration of experiment4th,6th and8th weeks in10%CH, while in two CIH groups, it occurred at the2nd week, earlier than in10%CH group.②SEM:In3hypoxia groups at early stage, morphological changes of hippocampal neurons are not obvious. With time being, showing increased never system damage in neurons cytoplasm, nuclear membrane, rough endoplasmic, mitochondria, axonal flow, axonal neurofilament otmesis, and so on, especially in5%CIH group.
3. Phosphorylation p38MAPK immunohistochemical results:compared with the UC group, in three hypoxia groups at2nd,4th,6th,8th week, phosphorylation p38MAPK-positive cells in hippocampus increased markedly, to the peak at6th week; Comparing with10%CH, two CIH groups in the2nd,4th,6th,8th,phosphorylation p38MAPK-positive cells in hippocampus increased significantly, especially in5%CIH. group.
4. Phosphorylation p38MAPK Western blot results:compared with the UC group,10%CH and10%CIH5%CIH group in2nd,4th,6th,8th week, phosphorylation p38MAPK expression in hippocampus increased markedly, reaching to the peak in the6th week; Compared with the10%CH group,10%CIH,5%CIH group in2nd,4th,6th,8th week, phosphorylation p38MAPK-positive cells in hippocampus increased significantly, especially in5%CIH. group.
5. TUNEL test results:compared with UC, in three hypoxia groups, at2nd,4th,6th,8th week neuron apoptosis was significantly increased in hippocampus, at the6th week to the peak; Compared with the10%CH group,10%CIH,5%CIH group in2nd,4th,6th,8th week, neuron apoptosis increased significantly, especially in5%CIH.group. Conclusion:1. CIH can cause cognitive impairment in rats, it was related with severity and the duration of hypoxia, it occurs at early stage in severe CIH.
2Hippoeampal injuries in the presence of different degrees of CIH was one of the mechanisms of learning and memory impairment in rats;
3.It can activate the p38MAPK pathway in Rats exposure under the varying degrees of CIH and p38MAPK pathway is one of the important factors leading to apoptosis;
4. CIH can cause varying degrees of p38MAPK/neurons apoptosis pathway activation; it is the important reasons of learning and memory impairment in rats after intermittent hypoxia. The cognitive and nerve system damage caused by CIH is severe than CH, especially at early stage.
引文
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