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该研究的目的是利用线粒体细胞色素C氧化酶抑制剂叠氮钠致痴呆动物模型,观察参乌胶囊对模型大鼠学习记忆障碍的改善作用及其机制。应用SD大鼠皮下埋植Alzet微泵,连续恒速给予叠氮钠(1 mg.kg-1.h-1)共30 d造模。手术后24 h开始给药,参乌胶囊低、中、高剂量组(干粉0.45,0.9,1.8 g.kg-1)每日灌胃给药1次。应用水迷宫、避暗试验检测动物学习记忆能力。放射免疫法测定大脑皮层和海马胆碱乙酰基转移酶(ChAT)活性,羟胺比色法检测乙酰胆碱酯酶(AChE)活性,放射配基结合试验测定M-胆碱能受体结合力。结果显示,微泵恒速灌注叠氮钠导致模型大鼠水迷宫游出时间及距离延长,避暗潜伏期缩短、错误次数增加。模型大鼠大脑皮层和海马ChAT活性降低,海马区AChE活性升高,皮层和海马M-胆碱能受体结合力明显下降。参乌胶囊灌胃给药能够明显减少模型大鼠水迷宫游出时间及距离,延长避暗潜伏期、减少错误次数;并且降低模型大鼠脑内AChE活性,升高ChAT活性及M-胆碱能受体结合力。实验结果表明,参乌胶囊明显改善线粒体缺陷致痴呆模型大鼠学习记忆能力,其药理作用机制与改善脑内胆碱能系统功能相关。提示参乌胶囊可干预线粒体缺陷这一AD早期的病理改变,进而拮抗其后出现的AD特征性病理变化,对于AD的治疗具有重要的应用价值。
The aim of this study was to investigate the effect and mechanism of Shen-wu capsule on learning and memory impairments in model rats by using sodium azide, a mitochondrial cytochrome C oxidase inhibitor, as an animal model of dementia. SD rats were subcutaneously implanted with Alzet micropumps and continuously treated with sodium azide (1 mg.kg-1.h-1) for 30 days. 24 h after surgery, Shenwu capsule low, medium and high dose group (dry powder 0.45,0.9,1.8 g.kg-1) administered orally once daily. Application of water maze, dark avoidance test animal learning and memory ability. The activity of choline acetyltransferase (CHAT) in the cerebral cortex and hippocampus was detected by radioimmunoassay. The activity of acetylcholinesterase (AChE) was detected by hydroxylamine colorimetry and the binding ability of M-cholinergic receptor by radioligand binding assay. The results showed that the constant infusion of sodium azide by micro-pump resulted in prolonged swimming time and distance of water maze in model rats, shortening the latency of avoiding darkness and increasing the number of errors. The activity of ChAT in the cerebral cortex and hippocampus of model rats decreased, the activity of AChE in hippocampus increased, and the binding capacity of M-cholinergic receptor in cortex and hippocampus decreased significantly. Administration of Shenwu capsule intragastrically could significantly reduce the time and distance of water maze excursion in model rats, prolong the avoidance latency and reduce the number of errors; and reduce AChE activity, increase ChAT activity and M-cholinergic Receptor binding. The experimental results show that Shenwu capsule can obviously improve the learning and memory abilities of rats with dementia caused by mitochondrial defects, and its pharmacological mechanism is related to improving the function of the cholinergic system in the brain. It suggests that Shen-wu capsule can intervene mitochondrial defects early pathological changes of AD, and then antagonize the subsequent occurrence of AD pathological changes, the treatment of AD has important application value.