Symptomatic effect of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model
Symptomatic effect of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model
复制标题
DOI：
10.1007/s00213-004-2132-z
复制
发表时间：
2005-06-01
影响因子：
3.4
通讯作者：
De Deyn, PP
中科院分区：
文献类型：
--
作者：
Van Dam, D;Abramowski, D;De Deyn, PP
基本原理：APP 23小鼠是一种很有前途的阿尔茨海默病模型，表达了人类疾病的几种组织病理学、认知和行为特征。有效的动物模型应该以与人类患者相同的方式对治疗干预做出反应。目的：为了进一步验证APP 23模型，我们检查了多奈哌齐、卡巴拉汀、加兰他敏或美金刚是否可以拮抗认知缺陷，这些药物是批准用于痴呆症对症治疗的药物。方法：在未治疗的APP 23小鼠显示视觉空间学习严重缺陷的年龄对动物进行测试。4月龄APP 23小鼠和对照同窝小鼠通过每日腹膜内注射给予多奈哌齐（0.3或0.6 mg/kg）、卡巴拉汀（0.5或1.0 mg/kg）、加兰他敏（1.25或2.5 mg/kg）、美金刚（2或10 mg/kg）或生理盐水。治疗1周后，开始获得阶段，在认知测试期间继续每日治疗。结果如下：所有胆碱酯酶抑制剂在以下最佳日剂量下均可降低认知缺陷：加兰他敏1.25 mg kg（-1）、卡巴拉汀0.5 mg kg（-1）和多奈哌齐0.3 mg kg（-1）。较高的剂量往往没有发挥有益的效果，根据倒U形剂量-反应曲线描述的拟胆碱。美金刚对认知的症状疗效较轻，在探索试验中有明显改善。结论：这是第一项同时评估这四种化合物在一种特定学习和记忆范例（即Morris水迷宫）中的治疗相关剂量的功效的研究。事实上，对症干预能够减少认知障碍，大大增加了APP 23模型的有效性，作为一个有价值的工具，以评估未来的治疗方法。
Rationale: APP23 mice are a promising model of Alzheimer's disease, expressing several histopathological, cognitive and behavioural hallmarks of the human condition. A valid animal model should respond to therapeutic interventions in an equivalent manner as human patients. Objectives: To further validate the APP23 model, we examined whether cognitive deficits could be antagonised by donepezil, rivastigmine, galantamine or memantine, which are approved drugs for symptomatic treatment of dementia. Methods: Animals were tested at an age at which untreated APP23 mice display severe deficits in visual-spatial learning. Four-month- old APP23 mice and control littermates were administered donepezil (0.3 or 0.6 mg kg(-1)), rivastigmine (0.5 or 1.0 mg kg(-1)), galantamine (1.25 or 2.5 mg kg(-1)), memantine ( 2 or 10 mg kg(-1)) or saline through daily i.p. injections. After 1 week of treatment, acquisition phase commenced, with daily treatment continuing during cognitive testing. Results: All cholinesterase inhibitors reduced cognitive deficits with the following optimal daily doses: galantamine 1.25 mg kg(-1), rivastigmine 0.5 mg kg(-1) and donepezil 0.3 mg kg(-1). Higher dosages often did not exert beneficial effects in accordance with inverted U-shaped dose-response curves described for cholinomimetics. Symptomatic efficacy of memantine on cognition was mild, with significant amelioration manifesting during probe trial. Conclusions: This is the first study to simultaneously evaluate the efficacy of therapeutically relevant doses of these four compounds in one particular learning and memory paradigm, being the Morris water maze. The fact that symptomatic intervention was able to diminish cognitive impairment, substantially adds to the validity of the APP23 model as a valuable tool to evaluate future therapeutic approaches.