参乌胶囊对微泵恒速灌注叠氮钠致痴呆大鼠行为学及胆碱能系统的影响

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0.45,0.9,1.8g· 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.

Effects of Shenwu capsule on learning-memory ability and cholinergic function of brain in AD-like rat model induced by chronic infusion of sodium azide by minipump

Because of the proposed importance of mitochondrial cytochrome C oxidase (COX) decrease in Alzheimer's disease (AD), the protective effect of Shenwu capsule on mitochondrial deficiency model rats and its pharmacological mechanism were investigated in present study.Rats were administered with azide at 1 mg·kg^-1·h^-1 subcutaneously via an Alzet minipump for 30 days.Tweny-four hours after the operation, the rats were administered intragastrically by Shenwu capsule with the dose of 0.45, 0.9 and 1.8 g·kg^-1·d^-1 for one month.Then learning-memory ability was determined by the watermaze test and passive avoidance tests.The activity of choline-acetyl-transfertase(ChAT) and acetylcholinesterase (AChE) in hippocampus and cortex of rats were measured by radiochemical method and hydroxylamine colorimetry separately.M-cholinergic receptor binding ability (M-binding) was assayed by radio binding.Chronic infusion of sodium azide via minipump induced learning-memory deficiency of rats.Both ChAT activity and M-binding decreased in hippocampus and cortex of model rats, however, the activity of AChE increased in hippocampus and was not affected at the cortex.As the result, the cholinergic function of the brain decreased in model rats.Shenwu capsule significantly improved learning and memory ability and the mechanism may be related with the improved cholinergic function in model brain: ChAT activity and M-binding significantly increased in Shenwu treated groups compared with model group; and the increased activity of AChE in hippocampus returned to normal.Mitochondria, especially mitochondrial cytochrome C oxidase, may play the key role in the early event of AD.Chronic, partial in vivo inhibition of mitochondrial cytochrome C oxidase in rats provides a suitable model mimicking several aspects of AD.Shenwu capsule indicate effectiveness in AD-like mitochondrial deficiency model rats, so it would be applied in the treatment of AD.