Antiamnesic and neuroprotective effects of donepezil against learning impairments induced in mice by exposure to carbon monoxide gas
Antiamnesic and neuroprotective effects of donepezil against learning impairments induced in mice by exposure to carbon monoxide gas
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DOI：
10.1124/jpet.106.101527
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发表时间：
2006-06-01
影响因子：
3.5
通讯作者：
Maurice, Tangui
中科院分区：
文献类型：
--
作者：
Meunier, Johann;Ieni, John;Maurice, Tangui
多奈哌齐是一种有效的乙酰胆碱酯酶抑制剂，也与细胞内神经调节蛋白sigma 1受体相互作用。在本研究中，我们分析了多奈哌齐在小鼠缺氧模型中的抗遗忘和神经保护活性，通过重复CO暴露诱导，比较多奈哌齐与其他胆碱酯酶抑制剂他克林，卡巴拉汀，加兰他敏和参考sigma（1）激动剂伊格美新的药理学特征。CO暴露诱导，7天后，海马神经退行性变，甲酚紫染色分析，和行为改变，测量使用自发交替和被动回避反应。当在行为测试前20分钟注射时，即，CO后7 ~ 8天，所有药物均表现出抗遗忘作用。预先给予σ（1）受体拮抗剂N-[2-（3，4-二氯苯基）乙基]-N-甲基2-（二甲氨基）乙胺（BD 1047）仅阻断伊格美新和多奈哌齐的作用。通过在第一次CO暴露前20分钟注射（预损伤保护）或在最后一次CO暴露后1小时注射（后损伤保护）来测试药物的神经保护活性。在CO暴露前注射所有药物均能减轻缺氧诱导的神经退行性变和行为障碍。BD 1047的预给药阻断伊格美新和多奈哌齐的作用。然而，当CO暴露后注射时，只有伊格美新和多奈哌齐诱导有效的神经保护，并且形态学和行为学效应是BD 1047敏感的。这些结果表明，多奈哌齐是一种有效的抗遗忘和神经保护化合物，对兴奋性毒性损伤诱导的神经退行性变，其药理作用作为乙酰胆碱酯酶抑制剂和sigma（1）受体激动剂有助于其显着的疗效。特别是，与更具选择性的胆碱酯酶抑制剂相比，该药物是一种更有效的损伤后保护剂。
Donepezil is a potent acetylcholinesterase inhibitor that also interacts with the sigma 1 receptor, an intracellular neuromodulatory protein. In the present study, we analyzed the antiamnesic and neuroprotective activities of donepezil in a mouse hypoxia model induced by repetitive CO exposure, comparing donepezil's pharmacological profile with other cholinesterase inhibitors tacrine, rivastigmine, and galanthamine, and the reference sigma(1) agonist igmesine. CO exposure induced, after 7 days, hippocampal neurodegeneration, analyzed by Cresyl violet staining, and behavioral alterations, measured using spontaneous alternation and passive avoidance responses. When injected 20 min before the behavioral tests, i.e., 7 to 8 days after CO, all drugs showed antiamnesic properties. Preadministration of the sigma(1) receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl2-(dimethylamino)ethylamine (BD1047) blocked only the igmesine and donepezil effects. The neuroprotective activity of the drugs was tested by injection 20 min before the first CO exposure (preinsult protection) or by injection 1 h after the last CO exposure (postinsult protection). All drugs alleviated the hypoxia-induced neurodegeneration and behavioral impairments when injected before CO exposure. Preadministration of BD1047 blocked both the igmesine and donepezil effects. However, when injected after CO exposure, only igmesine and donepezil induced effective neuroprotection, and the morphological and behavioral effects were BD1047-sensitive. These results showed that donepezil is a potent antiamnesic and neuroprotective compound against the neurodegeneration induced by excitotoxic insult, and its pharmacological actions as both an acetylcholinesterase inhibitor and sigma(1) receptor agonist contribute to its marked efficacy. In particular, the drug is a more potent postinsult protecting agent compared with more selective cholinesterase inhibitors.