IDO抑制剂对慢性脑低灌注大鼠海马CA1区细胞凋亡的影响
发布时间：2018-11-25 18:58
【摘要】：目的:观察慢性脑低灌注模型2VO(2-vessel occlusion)大鼠使用犬尿氨酸通路(Kynurenine pathway,KP)限速酶吲哚胺-2,3-双加氧酶(indoleamine2,3-dioxygenase,IDO)抑制剂1-甲基色氨酸(1-MT)后海马CA1区细胞凋亡及凋亡相关蛋白Bcl-2、Bax的表达变化,以及对认知功能水平的改善作用。方法:实验动物随机分入模型、1-MT、假手术三组中,每组10只。模型组及1-MT组行双侧颈总动脉结扎术(Bilateral common carotid artery occlusion,BCCAO)制备2VO模型,假手术组在模型制备术中不结扎颈总动脉。1-MT组予1-MT混悬液灌胃,其余两组予生理盐水灌胃,共14天。Morris水迷宫检测认知功能,TUNEL法观察细胞凋亡,免疫组化法测定凋亡相关蛋白Bcl-2、Bax表达。结果:(1)水迷宫试验:1-MT组第4、5天的逃避潜伏期分别为(17.93±3.24)、(13、11±1.85),低于模型组的(42.31±6.03)、(41.12±4.56)(P0.05),高于假手术组的(13.86±2.84)、(10.59±2.09)(P0.05);1-MT组穿越平台位置次数(4.70±0.60),高于模型组的(2.50±0.45)(P0.05),低于假手术组的(4.90±0.66)(P0.05);1-MT组目标象限停留时间(26.87±1.82),高于模型组的(21.56±1.74)(P0.05),低于假手术组的(28.01±1.44)(P0.05)。(2)Bax蛋白表达分别为假手术组(6.25±1.04)、模型组(56.43±2.62)、1-MT组(30.16±2.17),各组间比较差异均有统计学意义(P0.05);Bcl-2蛋白表达分别为假手术组(9.97±2.66)、模型组(48.67±5.99)、1-MT组(32.67±4.71),模型组及1-MT组比假手术组表达均明显增加,差异有统计学意义(P0.05);凋亡细胞分别为假手术组(1.79±0.41)、模型组(14.13±1.44)、1-MT组(7.80±1.38),各组间比较差异均有统计学意义(P0.05)。结论:(1)2VO大鼠海马CA1区出现细胞凋亡、凋亡蛋白表达增加,提示慢性脑低灌注大鼠病理性改变中存在细胞凋亡,可能与伴随发生的认知功能减低相关;(2)使用1-MT可以减轻2VO大鼠认知功能损害、减少海马CA1区神经细胞的凋亡及凋亡相关蛋白Bax、Bcl-2的表达,但细胞凋亡的改善程度似乎不足以解释认知功能的改善程度,提示1-MT可能是通过细胞凋亡、炎性反应等机制共同作用来影响认知功能。
[Abstract]:Objective: to observe the rate-limiting enzyme indoleamine-3-dioxygenase (indoleamine2,3-dioxygenase,) of canine uremic acid pathway (Kynurenine pathway,KP) in chronic cerebral hypoperfusion model 2VO (2-vessel occlusion) rats. IDO) inhibitor 1-methyltryptophan (1-MT) induced apoptosis and the expression of apoptosis-related protein (Bcl-2,Bax) in hippocampal CA1 and the improvement of cognitive function. Methods: experimental animals were randomly divided into three groups, 1-MTand sham-operation groups, 10 rats in each group. Model group and 1-MT group were treated with bilateral common carotid artery ligation (Bilateral common carotid artery occlusion,BCCAO) to make 2VO model, sham operation group did not ligate common carotid artery during model preparation, and 1-MT group was given 1-MT suspension intragastric perfusion. The other two groups were perfused with normal saline for 14 days. The cognitive function was detected by Morris water maze, apoptosis was observed by TUNEL method, and the expression of apoptosis-related protein Bcl-2,Bax was detected by immunohistochemistry. Results: (1) Water labyrinth test: the escape latency of the 1-MT group was (17.93 卤3.24), () 1311 卤1.85 on the 4th day, which was lower than that of the model group (42.31 卤6.03), (41.12 卤4.56) (P0.05). It was higher than the sham-operated group (13.86 卤2.84), (, 10.59 卤2.09, P0.05). The frequency of crossing the platform position in 1-MT group (4.70 卤0.60) was higher than that in model group (2.50 卤0.45) (P0.05), and lower than that in sham-operated group (4.90 卤0.66) (P0.05). The target quadrant residence time of 1-MT group (26.87 卤1.82) was higher than that of model group (21.56 卤1.74) (P0.05). The expression of Bax protein in sham-operated group (28.01 卤1.44) (P0.05). (2) was (6.25 卤1.04), model group (56.43 卤2.62), 1-MT group (30.16 卤2.17). The differences among groups were statistically significant (P0.05). The expression of Bcl-2 protein in sham-operation group (9.97 卤2.66), model group (48.67 卤5.99) and 1-MT group (32.67 卤4.71) was significantly higher than that in model group and 1-MT group. The difference was statistically significant (P0.05). The apoptotic cells in sham-operated group (1.79 卤0.41), model group (14.13 卤1.44) and 1-MT group (7.80 卤1.38) were significantly different (P0.05). Conclusion: (1) apoptosis and increased expression of apoptotic protein in the CA1 area of hippocampus of 2VO rats suggest that there is apoptosis in the pathological changes of chronic cerebral hypoperfusion rats, which may be related to the associated decreased cognitive function. (2) 1-MT could attenuate the cognitive impairment of 2VO rats, and reduce the apoptosis of neurons and the expression of apoptosis-related protein Bax,Bcl-2 in hippocampal CA1 area. However, the degree of improvement of apoptosis seems to be insufficient to explain the improvement of cognitive function, suggesting that 1-MT may affect cognitive function through the mechanisms of apoptosis and inflammatory response.
【学位授予单位】：山西医科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R749.1
[Abstract]:Objective: to observe the rate-limiting enzyme indoleamine-3-dioxygenase (indoleamine2,3-dioxygenase,) of canine uremic acid pathway (Kynurenine pathway,KP) in chronic cerebral hypoperfusion model 2VO (2-vessel occlusion) rats. IDO) inhibitor 1-methyltryptophan (1-MT) induced apoptosis and the expression of apoptosis-related protein (Bcl-2,Bax) in hippocampal CA1 and the improvement of cognitive function. Methods: experimental animals were randomly divided into three groups, 1-MTand sham-operation groups, 10 rats in each group. Model group and 1-MT group were treated with bilateral common carotid artery ligation (Bilateral common carotid artery occlusion,BCCAO) to make 2VO model, sham operation group did not ligate common carotid artery during model preparation, and 1-MT group was given 1-MT suspension intragastric perfusion. The other two groups were perfused with normal saline for 14 days. The cognitive function was detected by Morris water maze, apoptosis was observed by TUNEL method, and the expression of apoptosis-related protein Bcl-2,Bax was detected by immunohistochemistry. Results: (1) Water labyrinth test: the escape latency of the 1-MT group was (17.93 卤3.24), () 1311 卤1.85 on the 4th day, which was lower than that of the model group (42.31 卤6.03), (41.12 卤4.56) (P0.05). It was higher than the sham-operated group (13.86 卤2.84), (, 10.59 卤2.09, P0.05). The frequency of crossing the platform position in 1-MT group (4.70 卤0.60) was higher than that in model group (2.50 卤0.45) (P0.05), and lower than that in sham-operated group (4.90 卤0.66) (P0.05). The target quadrant residence time of 1-MT group (26.87 卤1.82) was higher than that of model group (21.56 卤1.74) (P0.05). The expression of Bax protein in sham-operated group (28.01 卤1.44) (P0.05). (2) was (6.25 卤1.04), model group (56.43 卤2.62), 1-MT group (30.16 卤2.17). The differences among groups were statistically significant (P0.05). The expression of Bcl-2 protein in sham-operation group (9.97 卤2.66), model group (48.67 卤5.99) and 1-MT group (32.67 卤4.71) was significantly higher than that in model group and 1-MT group. The difference was statistically significant (P0.05). The apoptotic cells in sham-operated group (1.79 卤0.41), model group (14.13 卤1.44) and 1-MT group (7.80 卤1.38) were significantly different (P0.05). Conclusion: (1) apoptosis and increased expression of apoptotic protein in the CA1 area of hippocampus of 2VO rats suggest that there is apoptosis in the pathological changes of chronic cerebral hypoperfusion rats, which may be related to the associated decreased cognitive function. (2) 1-MT could attenuate the cognitive impairment of 2VO rats, and reduce the apoptosis of neurons and the expression of apoptosis-related protein Bax,Bcl-2 in hippocampal CA1 area. However, the degree of improvement of apoptosis seems to be insufficient to explain the improvement of cognitive function, suggesting that 1-MT may affect cognitive function through the mechanisms of apoptosis and inflammatory response.
【学位授予单位】：山西医科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R749.1
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