Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning.
Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning.
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DOI：
10.1073/pnas.98.4.2089
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发表时间：
2001-02
影响因子：
11.1
通讯作者：
D. Woodruff-Pak;R. W. Vogel;Gary L. Wenk
中科院分区：
文献类型：
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作者：
D. Woodruff-Pak;R. W. Vogel;Gary L. Wenk
经典的眨眼条件作用是一个涉及隔-海马胆碱能系统的典型模型。这种形式的联想学习在正常衰老时受损，在阿尔茨海默病(AD)中严重中断。一些烟碱型胆碱能受体亚型在AD中丢失，这使得尼古丁变构增强型配体的使用成为一种有前景的治疗策略。变构增强型配体加兰他明(Gal)调节烟碱型胆碱能受体以增加乙酰胆碱的释放，并作为乙酰胆碱酯酶(AChE)的抑制剂。GAL在两个临床前实验中进行了测试。在实验1中，16只幼兔和16只老年兔在条件反射期间给予Gal(3.0 mg/kg)，连续15天，该药物显著改善学习能力，降低AchE水平，并增加烟碱受体结合。在实验2中，53只退役种兔在四种条件下进行了15周的测试。各组兔在整个15周期间给予0.0mgGal(赋形剂)、1.0mgkg或3.0mgkgGal，或在15d内注射3.0mgkgGal，并在实验的剩余时间内注射赋形剂。每隔1个月进行15次每日条件训练以及随后的保留和再学习评估。连续给予3.0 mg/kg半乳糖组，3.0 mg/kg半乳糖可显著改善习得和记忆过程中的学习障碍。3.0 mg/kg半乳糖处理15天后，烟碱受体结合量显著增加，且所有半乳糖胺处理的兔脑AChE水平均较低。Gal对阿尔茨海默病学习范式严重受损的疗效与临床研究结果一致。
Classical eyeblink conditioning is a well-characterized model paradigm that engages the septohippocampal cholinergic system. This form of associative learning is impaired in normal aging and severely disrupted in Alzheimer's disease (AD). Some nicotinic cholinergic receptor subtypes are lost in AD, making the use of nicotinic allosterically potentiating ligands a promising therapeutic strategy. The allosterically potentiating ligand galantamine (Gal) modulates nicotinic cholinergic receptors to increase acetylcholine release as well as acting as an acetylcholinesterase (AChE) inhibitor. Gal was tested in two preclinical experiments. In Experiment 1 with 16 young and 16 older rabbits, Gal (3.0 mg/kg) was administered for 15 days during conditioning, and the drug significantly improved learning, reduced AChE levels, and increased nicotinic receptor binding. In Experiment 2, 53 retired breeder rabbits were tested over a 15-wk period in four conditions. Groups of rabbits received 0.0 (vehicle), 1.0, or 3.0 mg/kg Gal for the entire 15-wk period or 3.0 mg/kg Gal for 15 days and vehicle for the remainder of the experiment. Fifteen daily conditioning sessions and subsequent retention and relearning assessments were spaced at 1-month intervals. The dose of 3.0 mg/kg Gal ameliorated learning deficits significantly during acquisition and retention in the group receiving 3.0 mg/kg Gal continuously. Nicotinic receptor binding was significantly increased in rabbits treated for 15 days with 3.0 mg/kg Gal, and all Gal-treated rabbits had lower levels of brain AChE. The efficacy of Gal in a learning paradigm severely impaired in AD is consistent with outcomes in clinical studies.