血管紧张素转化酶抑制剂对β淀粉样蛋白1-42痴呆模型大鼠氧化应激相关因子的影响

Effects of angiotensin converting enzyme inhibitors on oxidative stress related factors in a rat model of beta-amyloid 1-42 dementia

背景:研究表明,血管紧张素转化酶抑制剂降压药能减少活性氧的生成抗氧化应激,使神经元凋亡减少,从而缓解阿尔茨海默病进程。目的:探索血管紧张素转化酶抑制剂类降压药对阿尔茨海默病学习记忆障碍的改善作用及相关机制。方法:将48只SD大鼠随机分为对照组、模型组、卡托普利组、盐酸多奈哌齐组,每组12只;然后,对照组双侧侧脑室注射生理盐水;余实验大鼠注射β淀粉样蛋白1-42制作阿尔茨海默病大鼠模型。造模后对照组及模型组每日给予等量的生理盐水灌胃;卡托普利组给予卡托普利2.5 mg/kg灌胃;盐酸多奈哌齐组给予盐酸多奈哌齐1.0 mg/kg灌胃。2周观察大鼠的一般情况;采用Morris水迷宫对各组大鼠进行定向航行以及空间探索实验,观察卡托普利对模型大鼠学习记忆障碍的影响;利用荧光分光光度法测定阿尔茨海默病模型大鼠大脑海马活性氧水平,免疫组化法检测大鼠海马DNA氧化产物8-羟基脱氧鸟苷及胰岛素降解酶的表达。实验方案经佳木斯大学科研伦理委员会批准。结果与结论:①各组造模后,主观观察发现模型组较前精神明显萎靡、饮食减少,其余3组无明显变化;②Morris水迷宫测试,与对照组比较,模型组大鼠平均逃避潜伏期、游泳路程明显增多,第四象限停留时间及游泳路程百分比明显减少(P<0.01);与模型组比较,卡托普利组和盐酸多奈哌齐组大鼠平均逃避潜伏期、游泳路程明显减少,第四象限停留时间及游泳路程百分比明显增多(P<0.01),而两组之间上述指标差异无显著性意义(P>0.05);③与对照组相比,模型组大鼠海马活性氧水平、8-羟基脱氧鸟苷明显增多,胰岛素降解酶表达明显降低(P<0.01);与模型组比较,卡托普利组及盐酸多奈哌齐组大鼠活性氧水平、8-羟基脱氧鸟苷明显降低,胰岛素降解酶表达明显增高(P<0.01),而两组之间上述指标差异无显著性意义;④结果说明,卡托普利对β淀粉样蛋白1-42致阿尔茨海默病模型大鼠学习记忆能力有明显的改善作用,并提示肾素血管紧张素醛固酮系统的激活具有潜在的对于高风险阿尔茨海默病人群的辅助内分泌治疗价值。

BACKGROUND:Studies have shown that angiotensin-converting enzyme inhibitor(ACEI),an antihypertensive drug,can reduce the production of reactive oxygen species,resist oxidative stress,reduce neuronal apoptosis,and thereby alleviate the procession of Alzheimer’s disease.OBJECTIVE:To explore the effect and mechanism by which ACEI antihypertensive drugs improve learning and memory impairment after Alzheimer’s disease.METHODS:Firstly,48 Sprague-Dawley rats were randomly divided into control group,model group,captopril group and donepezil hydrochloride group,12 in each group.Secondly,rat models of Alzheimer’s disease by injected with beta-amyloid 1-42 were established except the control group injected with normal saline.Then,we offered different intervention treatments for each group and observed the general condition at 2 weeks after intervention.After modeling,the control and model groups were intragastrically given the same amount of normal saline per day;the captopril group was given 2.5 mg/kg captopril;the donepezil hydrochloride group was given 1.0 mg/kg donepezil hydrochloride.Thirdly,the Morris water maze was used to carry out directional navigation and space exploration experiments in rats,in order to explore the effects of captopril on learning and memory impairment in the rat model.In the end,the content of reactive oxygen species in the rat hippocampus was investigated by fluorescence spectrophotometry,and the expression of 8-hydroxy-2’-deoxyguanosine and insulin degrading enzyme in the hippocampus was detected by immunohistochemistry.The study protocol was approved by the Ethics Committee of Jiamusi University.RESULTS AND CONCLUSION:Subjective observation showed that the spirit of rats in the model group was significantly depressed and the diet was reduced after modeling;and there were no significant changes in the other three groups.For the Morris water maze test,compared with the control group,the average escape latency and swimming distance were significantly increased in the model group,while the fourth quadrant dwell time and swimming distance percentage were significantly reduced(P<0.01).Compared with the model group,the average escape latency and swimming distance of captopril group and donepezil hydrochloride group were significantly reduced,while the fourth quadrant dwell time and swimming distance percentage were significantly increased(P<0.01).However,there were no significant difference between the captopril group and donepezil hydrochloride group(P>0.05).Compared with the control group,the levels of reactive oxygen species and 8-hydroxy-2’-deoxyguanosine were significantly increased in the model group,and the expression of insulin degrading enzyme was significantly reduced(P<0.01).Compared with the model group,the levels of reactive oxygen species and 8-hydroxy-2’-deoxyguanosine were significantly reduced in the captopril group and donepezil hydrochloride group,and the expression of insulin degrading enzyme was significantly increased(P<0.01).There was no significant difference between the captopril group and donepezil hydrochloride group.In conclusion,captopril can improve learning and memory impairment in Alzheimer’s disease rat models induced by beta-amyloid 1-42,and our findings also suggest the potentially beneficial effects of certain renin angiotensin aldosterone system activation in high-risk Alzheimer’s disease populations.