Positive allosteric modulator of α7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates.
Positive allosteric modulator of α7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates.
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DOI：
10.1016/j.neuropharm.2012.10.019
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发表时间：
2013-04
影响因子：
4.7
通讯作者：
Terry AV Jr
中科院分区：
文献类型：
--
作者：
Callahan PM;Hutchings EJ;Kille NJ;Chapman JM;Terry AV Jr
然而，鉴于老年人口的不断增加，开发用于认知障碍如阿尔茨海默病（AD）的新型治疗剂是至关重要的;对任何可能增强目前可用治疗的临床疗效的策略也有相当大的兴趣。本研究的目的是评价一种记忆增强的连续治疗策略，即联合常用的乙酰胆碱酯酶抑制剂（AChEI）多奈哌齐与α7烟碱乙酰胆碱受体（α7-nAChRs）的正变构调节剂（PAM）PNU-120596。在年轻大鼠的（非空间）自发新物体识别（NOR）任务、老年认知受损大鼠的水迷宫空间学习和回忆程序以及老年恒河猴的延迟样本匹配（工作/短期记忆）任务中评价了治疗策略。在所有三个实验中，观察到类似的药物反应，即单独施用多奈哌齐以剂量依赖性方式改善任务表现;单独施用PNU-120596没有显著效果，但PNU-120596与阈下剂量的多奈哌齐的组合是有效的。药物组合的积极作用似乎是α7-nAChR介导的，因为它在NOR任务中被选择性α7-nAChR拮抗剂甲基乌头碱（MLA）阻断。总之，这些数据表明，PNU-120596增加了多奈哌齐在年轻和年龄受损动物模型中学习/记忆相关任务的有效剂量范围。结果表明，α7-nAChR选择性PAM如PNU-120596具有与乙酰胆碱酯酶抑制剂（例如，多奈哌齐）用于与年龄相关的疾病，如AD以及不一定与高龄相关的记忆障碍。
The development of novel therapeutic agents for disorders of cognition such as Alzheimer’s disease (AD) is of paramount importance given the ever-increasing elderly population, however; there is also considerable interest in any strategy that might enhance the clinical efficacy of currently available treatments. The purpose of this study was to evaluate an adjunctive treatment strategy to memory enhancement, namely combining the commonly prescribed acetylcholinesterase inhibitor (AChEI) donepezil, with a positive allosteric modulator (PAM) of α7 nicotinic-acetylcholine receptors (α7-nAChRs), PNU-120596. The treatment strategy was evaluated in a (non-spatial) spontaneous novel object recognition (NOR) task in young rats; a water maze spatial learning and recall procedure in aged, cognitively-impaired rats, and a delayed match to sample (working/short term memory) task in aged rhesus monkeys. In all three experiments a similar drug response was observed, namely that donepezil administered alone improved task performance in a dose-dependent manner; that PNU-120596 administered alone was without significant effect, but that the combination of PNU-120596 with a subthreshold dose of donepezil was effective. The positive effect of the drug combination appeared to be α7-nAChR mediated given that it was blocked in the NOR task by the selective α7-nAChR antagonist methyllycaconitine (MLA). Collectively, these data indicate that PNU-120596 increases the effective dose range of donepezil in learning/memory-related tasks in young and age-impaired animal models. The results suggest that α7-nAChR-selective PAMs like PNU-120596 have potential as adjunctive treatments with acetylcholinesterase inhibitors (e.g., donepezil) for age-related illnesses such as AD as well memory disorders not necessarily associated with advanced age.
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影响因子：
3.1
作者：
Buccafusco, JJ;Terry, AV
通讯作者：
Terry, AV
影响因子：
2.9
作者：
Geerts, H;Guillaumat, PO;Sachak, S
通讯作者：
Sachak, S
影响因子：
2.7
作者：
ENNACEUR, A;DELACOUR, J
通讯作者：
DELACOUR, J
DOI：
10.1124/jpet.110.173245
发表时间：
2011-02-01
影响因子：
3.5
作者：
Dinklo, Theo;Shaban, Hamdy;Lesage, Anne S. J.
通讯作者：
Lesage, Anne S. J.
影响因子：
4.2
作者：
BACHEVALIER, J;LANDIS, LS;CORK, LC
通讯作者：
CORK, LC