氯肟衍生物对记忆障碍模型动物空间学习记忆障碍改善作用及其机制研究

Effects and mechanisms of chloro-oxime derivatives on spatial learning and memory dysfunction in two dementia animal models

目的研究氯肟衍生物arimoclomol和TCO-2对记忆障碍动物学习记忆能力的影响并初步探讨其机制。方法采用东莨菪碱致记忆获得性障碍小鼠模型和侧脑室注射Aβ1-42所致记忆障碍大鼠模型。动物分为正常组、模型组、多奈哌齐对照组、arimoclomol干预组和TCO-2干预组。正常组与模型组动物每日相同时间腹腔注射相应剂量的药物溶剂(生理盐水);多奈哌齐对照组及待测药物干预组分别给予相应剂量的药物。给药8 d后,采用Morris水迷宫方法检测动物的空间学习记忆能力,并且检测动物海马组织的乙酰胆碱酯酶活性;检测侧脑室注射Aβ1-42大鼠海马组织的Aβ1-42含量,并测定磷酸化tau蛋白表达。结果与模型对照组相比,给予两种氯肟衍生物的动物搜索平台潜伏期缩短,穿越平台次数增加,表明氯肟衍生物可以明显改善注射东莨菪碱或Aβ1-42引起的记忆障碍;给予氯肟化合物还能够明显降低脑内乙酰胆碱酯酶活性和Aβ1-42含量,下调磷酸化tau蛋白的表达。结论氯肟衍生物可改善东莨菪碱以及侧脑室注射Aβ1-42所致的记忆障碍,其作用机制可能与增强中枢胆碱能系统功能、降低脑内Aβ蛋白和磷酸化tau蛋白含量有关。

Aim To explore the effects and mechanisms of choro-oxime derivatives on spatial learning and memory impairment in Kunming mice and SD rats induced by scopolamine and Aβ1-42, respectively. Methods 40 Kunming mice were randomly divided into 5 groups ： control group, model group, donepezil treatment group, arimoclomol treatment group and TCO-2 treatment group. There were 8 mice in each group. Mice of control group were established by intraperitoneal injection of saline, and mice of other groups were injected with scopolamine and caused memory impairment. Both control group and model group were treated with solvent by intraperitoneal administration; donepezil treatment group received donepezil by intragastric administration; arimoclomol treatment group and TCO-2 treatment group were given the corresponding drugs by abdominal injection, respectively. The solvent and drugs were given at the same time every moming for 8 days. Spatial learning and memory ability were tested by Morris water maze from the fifth day of the drugs administration. 40 SD rats were divided into 5 groups the same as the dementia model mentioned above. Mice of control group were established by intracerebroventricular injection of saline, and mice of other groups were injected with insoluble Aβ1-42 to be induced of memory impairment. Solvent and drugs were also delivered as mentioned above. Morris water maze was carried out from the fifth day of the drug delivery. After that, acetyl cholinesterase activity of hippocampus was tested with acetyl cholinesterase reagent kit; the content of Aβ1-42 in hippocampus was measured by ELISA assay kit; the expression of phosphorylated tau proteins was detected by Western Blot. Results In both two dementia models, choro-oxime derivatives could improve the spatial learning and memory ability, shorten the escape latency and increase the times of crossing the former platform. Choro-oxime derivatives could also inhibit the acetyl cholinesterase activity in animal brain, decrease the concentration of Aβ1-42 and the expression of phosphorylated tan proteins in the dementia rats＇ hippocampus. Conclusions Spatial learning and memory deficits induced by scopolamine and Aβ1-42 could be reversed by choro-oxime derivatives. It may be concerned with enhancement of the cholinergic system functions and reduction of the levels of Aβ1-42 and phosphorylated tan proteins in the brain.