ROCK信号转导在大鼠慢性脑低灌注致认知功能障碍中作用研究
摘要
随着人口的老龄化,痴呆发病率逐年增高,已经成为国内外医学界研究的重要课题。痴呆的主要类型阿尔茨海默病(Alzheimer disease,AD)、血管性痴呆(Vascular dementia,VD)和Binswanger病等的早期表现主要是认知功能障碍。研究表明,慢性脑低灌注损伤是导致认知功能障碍的重要原因,是多种疾病发展过程中的一个共同病理过程,最终可导致痴呆,但其损伤机制尚不完全清楚。
本研究在成功制备慢性脑缺血致认知功能障碍模型基础上,以ROCK为靶点,探讨ROCK信号转导参与慢性脑缺血致认知功能障碍损伤机制。研究中利用双侧颈总动脉永久性结扎(2VO)方法制备大鼠慢性脑缺血模型,Morris水迷宫检测大鼠慢性脑缺血不同时间学习记忆能力,HE染色观察额叶皮层、海马病理变化,MAP_2免疫组化观察缺血损伤程度,以评价慢性脑缺血致认知功能障碍模型,进一步采用免疫组化、RT-PCR和Western-blot检测大鼠慢性脑缺血不同时间额叶皮层、海马ROCK2及其下游作用底物肌球蛋白结合亚单位(MBS)和其相关蛋白平滑肌激动蛋白(α-SMA)的表达水平,采用TUNEL染色技术检测细胞凋亡变化,免疫组化和RT-PCR检测凋亡调控基因Caspase-3表达,以上实验同时予以ROCK抑制剂(法舒地尔)进行干预。
结果显示,慢性脑缺血后大鼠逃避潜伏期和游泳距离延长,学习记忆能力下降,ROCK2及其下游作用底物MBS和其相关蛋白α-SMA表达水平均升高,ROCK2及MBS、α-SMA蛋白及基因表达有相似的变化趋势,ROCK2、MBS表达较α-SMA表达高峰提前,法舒地尔干预后,大鼠逃避潜伏期和游泳距离缩短,ROCK2、MBS及α-SMA表达水平均有不同程度降低。慢性脑缺血可致额叶皮层、海马神经细胞凋亡,凋亡调控基因Caspase-3表达增高,法舒地尔干预后凋亡细胞明显减少,Caspase-3表达明显减低。
本研究结果表明ROCK2及其作用底物MBS和其相关蛋白α-SMA可能通过影响细胞凋亡及凋亡调控基因的表达而参与慢性脑缺血后认知功能障碍。提示ROCK转导通路可能成为慢性脑缺血致认知功能障碍防治新的治疗靶点,并为临床ROCK抑制剂(法舒地尔)应用于慢性脑缺血致认知功能障碍防治提供了新的依据。
Chronic cerebral hypoperfusion is a common pathological status in neural impairment,which always contribute to permanent or progressing cognitive dysfunction. Study on mechanism of cognitive dysfunction due to chronic cerebral hypoperfusion has been hot spot for the neurologists both native and abroad, some improvment has been made with animal models, but still more mechaniam remain unaccomplished. We adopted the permanent bilateral carotid arteries occlusion (2VO) medol, target on ROCK( a Small G Protein), observe changes of the related mRNA, protein and neuron apoptosis in frontal cortex and hippocampal area, investigate the effects and mechanism of this pathway on leaming and memory impairment after chronic cerebral hypoperfusion, aim to find new therapeutic target and strategy for ischemic cerebro vascular diseases.
Part 1 Estabilishment and evaluation of cognitive dysfunction model due to chronic cerebral hypoperfusion
Objectives To estabilish and evaluate the cognitive dysfunction model due to chronic cerebral hypoperfusion. Methods After the training of Morris water maze place navigation experiment,150 Wistar rats randomized pseudooperation groupand ischemia group, time point was 3w, 6w and 9w.The chronic ischemia model was established with the method of two-vessel occlusion (2VO),ability of learning and memory measured with Morris water maze including escape latency and swim distance. Pathological change measured with HE staining, degree of ischemia injury was detected with immunohistochemistry of MAP2. Results Compared with pseudooperation group , ischemia group had significant longer escape latency and swim distance at the time of 3w, 6w and 9w after ischemia(P<0.05); 3w after ischemia, in the saline-ischemia group, ischemia changes can be observed in the cortical neuron of frontal lobe with the method of HE staining and MAP2 immunohistochemical staining, the ischemia injury was more sever with the time espectialy in 9w. Conclusion cognitive dysfunction rat model after chronic cerebral ischemia was succeed establishing and evaluating with Morris water maze place navigation experiment, HE dyeing,and immunohistochemistry of MAP2.and shows that it is a good method for immunohistochemistry of MAP2 to investigate neural impairment.
Part 2 Expression of ROCK,α-SMA and MBS in the rat cognitive dysfunction model with chronic cerebral hypoperfusion
Objective investigate the changes of ROCK and its downstream product asα-SMA、MBS on the cognitive dysfunction in rats after chronic cerebral hypoperfusion. Methods After the training of Morris water maze place navigation experiment, Wistar rats randomized pseudooperation group, saline-ischemia group, and Fasudil-ischemia group, time point was 3w, 6w and 9w, saline-ischemia and Fasudil-ischemia group received intraperitoneal injection of Fasudil (ROCK inhibitor) for 3w. The chronic ischemia model was established with the method of two-vessel occlusion (2VO), ability of learning and memory measured with Morris water maze including escape latency and swim distance. ROCK in frontal lobe cortexand hippocampus at different time point was measured with the method of immunohistochemistry, RT-PCR and Western-blot.α-SMA, as ROCK related protein, in frontal lobe cortex and hippocampus at different time point was measured with the method of immunohistochemistry and RT-PCR . MBS, as ROCK, downstream product, in frontal lobe cortex and hippocampus at different time point was measured with the method of Western-blot. Result Compared with pseudooperation group , the saline-ischemia group had significant longer escape latency and swim distance at the time of 3w, 6w and 9w after ischemia(P<0.05); the Fasudil-ischemia group had significant shortened escape latency and swim distance compared with saline-ischemia group(P<0.05), but still longer than the pseudooperation group(P<0.05). 3w after ischemia, in the saline-ischemia group, ischemia changes can be observed in the cortical neuron of frontal lobe with the method of HE dyeing and MAP2 immunohistochemistry, the ischemia injury was more sever with the time espectialy in 9w. ROCK mRNA and protein expression of saline and Fasudil group was higher than pseudooperation group(P<0.05), peak in 6w and reduced in 9w, but still higher than pseudooperation group (P<0.05). ROCK mRNA and protein expression of Fasudil group was lower than saline group, a-SMA、MBS expression of saline and Fasudil group raised in 3w and peak in 9w,α-SMA、MBS expression of Fasudil group was lower than saline group all the time (P<0.05), but higher than pseudooperation group (P<0.05). Peak of ROCK advancedα-SMA、MBS, there is a significant positive correlation between them(P<0.05). Conclusion ROCK2 and its downstream product asα-SMA、MBS Participate in process of the cognitive dysfunction in rats after chronic cerebral ischemia. ROCK inhibitor(Fasudil) can significantly improve the cognitive function of rat with chronic cerebral ischemia and inhibite the expression of ROCK2 and its downstream product ofα-SMA and MBS.
Part 3 Examination of apoptosis and Caspase-3 expression in the rat cognitive dysfunction model with chronic cerebral hypoperfusion.
Objective To observe the changes of and its controlling gene Caspase-3 on the dysfunction in rats after chronic cerebral ischemia and the effect of ROCK inhibitor(Fasudil). Methods The chronic ischemia model was established with the method of two-vessel occlusion (2VO), Apoptosis measured with TUNEL dyeing. Apoptosis gene Caspase-3 was measured with immunohistochemistry and RT-PCR.Result the investigation of TUNEL shows that Compared with pseudooperation group , the Apoptosis cells in saline-ischemia group significantly increasedat the time of 3w, 6w and 9w after ischemia(P<0.05).The Apoptosis cells in Fasudil-ischemia group, Compared with saline-ischemia group, significantly decreased at the same time point. Caspase-3 expression of saline and Fasudil group was higher than pseudooperation group(P<0.05), peak in 6w and reduced in 9w, but still higher than pseudooperation group (P<0.05). Caspase-3 expression of Fasudil group was lower than saline group, but higher than pseudooperation group (P<0.05). Conclusion The expression of apoptosis and its controlling gene Caspase-3 increased in the cognitive dysfunction in rats after chronic cerebral ischemia.ROCK inhibitor(Fasudil) can significantly decrease the expression of apoptosis and its controlling gene Caspase-3. ROCK2 and its downstream product as a-SMA、MBS Participate in process of apoptosis and its controlling gene Caspase-3 expression that involved in cognitive dysfunction of rat with chronic cerebral ischemia; ROCK pathway may be a new therapeutic target for the cognitive dysfunction after chronic cerebral hypoperfusion.
本研究在成功制备慢性脑缺血致认知功能障碍模型基础上,以ROCK为靶点,探讨ROCK信号转导参与慢性脑缺血致认知功能障碍损伤机制。研究中利用双侧颈总动脉永久性结扎(2VO)方法制备大鼠慢性脑缺血模型,Morris水迷宫检测大鼠慢性脑缺血不同时间学习记忆能力,HE染色观察额叶皮层、海马病理变化,MAP_2免疫组化观察缺血损伤程度,以评价慢性脑缺血致认知功能障碍模型,进一步采用免疫组化、RT-PCR和Western-blot检测大鼠慢性脑缺血不同时间额叶皮层、海马ROCK2及其下游作用底物肌球蛋白结合亚单位(MBS)和其相关蛋白平滑肌激动蛋白(α-SMA)的表达水平,采用TUNEL染色技术检测细胞凋亡变化,免疫组化和RT-PCR检测凋亡调控基因Caspase-3表达,以上实验同时予以ROCK抑制剂(法舒地尔)进行干预。
结果显示,慢性脑缺血后大鼠逃避潜伏期和游泳距离延长,学习记忆能力下降,ROCK2及其下游作用底物MBS和其相关蛋白α-SMA表达水平均升高,ROCK2及MBS、α-SMA蛋白及基因表达有相似的变化趋势,ROCK2、MBS表达较α-SMA表达高峰提前,法舒地尔干预后,大鼠逃避潜伏期和游泳距离缩短,ROCK2、MBS及α-SMA表达水平均有不同程度降低。慢性脑缺血可致额叶皮层、海马神经细胞凋亡,凋亡调控基因Caspase-3表达增高,法舒地尔干预后凋亡细胞明显减少,Caspase-3表达明显减低。
本研究结果表明ROCK2及其作用底物MBS和其相关蛋白α-SMA可能通过影响细胞凋亡及凋亡调控基因的表达而参与慢性脑缺血后认知功能障碍。提示ROCK转导通路可能成为慢性脑缺血致认知功能障碍防治新的治疗靶点,并为临床ROCK抑制剂(法舒地尔)应用于慢性脑缺血致认知功能障碍防治提供了新的依据。
Chronic cerebral hypoperfusion is a common pathological status in neural impairment,which always contribute to permanent or progressing cognitive dysfunction. Study on mechanism of cognitive dysfunction due to chronic cerebral hypoperfusion has been hot spot for the neurologists both native and abroad, some improvment has been made with animal models, but still more mechaniam remain unaccomplished. We adopted the permanent bilateral carotid arteries occlusion (2VO) medol, target on ROCK( a Small G Protein), observe changes of the related mRNA, protein and neuron apoptosis in frontal cortex and hippocampal area, investigate the effects and mechanism of this pathway on leaming and memory impairment after chronic cerebral hypoperfusion, aim to find new therapeutic target and strategy for ischemic cerebro vascular diseases.
Part 1 Estabilishment and evaluation of cognitive dysfunction model due to chronic cerebral hypoperfusion
Objectives To estabilish and evaluate the cognitive dysfunction model due to chronic cerebral hypoperfusion. Methods After the training of Morris water maze place navigation experiment,150 Wistar rats randomized pseudooperation groupand ischemia group, time point was 3w, 6w and 9w.The chronic ischemia model was established with the method of two-vessel occlusion (2VO),ability of learning and memory measured with Morris water maze including escape latency and swim distance. Pathological change measured with HE staining, degree of ischemia injury was detected with immunohistochemistry of MAP2. Results Compared with pseudooperation group , ischemia group had significant longer escape latency and swim distance at the time of 3w, 6w and 9w after ischemia(P<0.05); 3w after ischemia, in the saline-ischemia group, ischemia changes can be observed in the cortical neuron of frontal lobe with the method of HE staining and MAP2 immunohistochemical staining, the ischemia injury was more sever with the time espectialy in 9w. Conclusion cognitive dysfunction rat model after chronic cerebral ischemia was succeed establishing and evaluating with Morris water maze place navigation experiment, HE dyeing,and immunohistochemistry of MAP2.and shows that it is a good method for immunohistochemistry of MAP2 to investigate neural impairment.
Part 2 Expression of ROCK,α-SMA and MBS in the rat cognitive dysfunction model with chronic cerebral hypoperfusion
Objective investigate the changes of ROCK and its downstream product asα-SMA、MBS on the cognitive dysfunction in rats after chronic cerebral hypoperfusion. Methods After the training of Morris water maze place navigation experiment, Wistar rats randomized pseudooperation group, saline-ischemia group, and Fasudil-ischemia group, time point was 3w, 6w and 9w, saline-ischemia and Fasudil-ischemia group received intraperitoneal injection of Fasudil (ROCK inhibitor) for 3w. The chronic ischemia model was established with the method of two-vessel occlusion (2VO), ability of learning and memory measured with Morris water maze including escape latency and swim distance. ROCK in frontal lobe cortexand hippocampus at different time point was measured with the method of immunohistochemistry, RT-PCR and Western-blot.α-SMA, as ROCK related protein, in frontal lobe cortex and hippocampus at different time point was measured with the method of immunohistochemistry and RT-PCR . MBS, as ROCK, downstream product, in frontal lobe cortex and hippocampus at different time point was measured with the method of Western-blot. Result Compared with pseudooperation group , the saline-ischemia group had significant longer escape latency and swim distance at the time of 3w, 6w and 9w after ischemia(P<0.05); the Fasudil-ischemia group had significant shortened escape latency and swim distance compared with saline-ischemia group(P<0.05), but still longer than the pseudooperation group(P<0.05). 3w after ischemia, in the saline-ischemia group, ischemia changes can be observed in the cortical neuron of frontal lobe with the method of HE dyeing and MAP2 immunohistochemistry, the ischemia injury was more sever with the time espectialy in 9w. ROCK mRNA and protein expression of saline and Fasudil group was higher than pseudooperation group(P<0.05), peak in 6w and reduced in 9w, but still higher than pseudooperation group (P<0.05). ROCK mRNA and protein expression of Fasudil group was lower than saline group, a-SMA、MBS expression of saline and Fasudil group raised in 3w and peak in 9w,α-SMA、MBS expression of Fasudil group was lower than saline group all the time (P<0.05), but higher than pseudooperation group (P<0.05). Peak of ROCK advancedα-SMA、MBS, there is a significant positive correlation between them(P<0.05). Conclusion ROCK2 and its downstream product asα-SMA、MBS Participate in process of the cognitive dysfunction in rats after chronic cerebral ischemia. ROCK inhibitor(Fasudil) can significantly improve the cognitive function of rat with chronic cerebral ischemia and inhibite the expression of ROCK2 and its downstream product ofα-SMA and MBS.
Part 3 Examination of apoptosis and Caspase-3 expression in the rat cognitive dysfunction model with chronic cerebral hypoperfusion.
Objective To observe the changes of and its controlling gene Caspase-3 on the dysfunction in rats after chronic cerebral ischemia and the effect of ROCK inhibitor(Fasudil). Methods The chronic ischemia model was established with the method of two-vessel occlusion (2VO), Apoptosis measured with TUNEL dyeing. Apoptosis gene Caspase-3 was measured with immunohistochemistry and RT-PCR.Result the investigation of TUNEL shows that Compared with pseudooperation group , the Apoptosis cells in saline-ischemia group significantly increasedat the time of 3w, 6w and 9w after ischemia(P<0.05).The Apoptosis cells in Fasudil-ischemia group, Compared with saline-ischemia group, significantly decreased at the same time point. Caspase-3 expression of saline and Fasudil group was higher than pseudooperation group(P<0.05), peak in 6w and reduced in 9w, but still higher than pseudooperation group (P<0.05). Caspase-3 expression of Fasudil group was lower than saline group, but higher than pseudooperation group (P<0.05). Conclusion The expression of apoptosis and its controlling gene Caspase-3 increased in the cognitive dysfunction in rats after chronic cerebral ischemia.ROCK inhibitor(Fasudil) can significantly decrease the expression of apoptosis and its controlling gene Caspase-3. ROCK2 and its downstream product as a-SMA、MBS Participate in process of apoptosis and its controlling gene Caspase-3 expression that involved in cognitive dysfunction of rat with chronic cerebral ischemia; ROCK pathway may be a new therapeutic target for the cognitive dysfunction after chronic cerebral hypoperfusion.
引文
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