Mefloquine inhibits cholinesterases at the mouse neuromuscular junction.
Mefloquine inhibits cholinesterases at the mouse neuromuscular junction.
复制标题
甲氟喹抑制小鼠神经肌肉接头处的胆碱酯酶。
DOI：
10.1016/j.neuropharm.2005.06.011
复制
发表时间：
2005
影响因子：
4.7
通讯作者：
Hognason,Kormakur
中科院分区：
文献类型：
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作者：
McArdle,JosephJ;Sellin,LawrenceC;Coakley,KathleenM;Potian,JosephG;Quinones-Lopez,MaryC;Rosenfeld,ClintA;Sultatos,LesterG;Hognason,Kormakur
甲氟喹对抗药性恶性疟原虫有效。这种性质，沿着其独特的药代动力学特征，使甲氟喹成为一种广泛使用的抗疟药。然而，甲氟喹具有抵消其治疗优势的神经学作用。甲氟喹的神经学效应的细胞作用知之甚少。在这里，我们证明甲氟喹抑制人重组乙酰胆碱酯酶。为了探索这种作用的后果，我们研究了甲氟喹在模型胆碱能突触（小鼠神经肌肉接头）中的作用。用尖电极记录胸骨三角肌的微终板电位。在10μM甲氟喹作用30分钟内，mepps有三种变化：10-90%上升时间，90-10%衰减时间和幅度显著增加。Mepp衰减时间随甲氟喹浓度线性增加。用胆碱酯酶抑制剂毒扁豆碱（3μM）预处理肌肉可阻止甲氟喹诱导的mepp衰减延长。甲氟喹也延长乙酰胆碱酯酶基因敲除小鼠终板的mepps。由于选择性丁酰胆碱酯酶抑制剂iso-OMPA（100μM）也延长了乙酰胆碱酯酶敲除小鼠神经肌肉接头处的mepp衰减，因此甲氟喹对该酶的抑制具有生理相关性。甲氟喹的非选择性抗胆碱酯酶作用可能有助于其神经学效应。
Mefloquine is effective against drug-resistant Plasmodium falciparum. This property, along with its unique pharmacokinetic profile, makes mefloquine a widely prescribed antimalarial drug. However, mefloquine has neurologic effects which offset its therapeutic advantages. Cellular actions underlying mefloquine's neurologic effects are poorly understood. Here, we demonstrate that mefloquine inhibits human recombinant acetylcholinesterase. To explore the consequences of this action, we investigated mefloquine's actions at a model cholinergic synapse, the mouse neuromuscular junction. Sharp electrode recording was used to record miniature endplate potentials (mepps) in the Triangularis sterni muscle. Within 30min of exposure to 10μM mefloquine, mepps were altered in three ways: 10–90% rise time, 90–10% decay time and amplitude significantly increased. Mepp decay time increased linearly with mefloquine concentration. Pretreatment of muscles with the cholinesterase inhibitor physostigmine (3μM) precluded the mefloquine-induced prolongation of mepp decay. Mefloquine also prolonged mepps at endplates of acetylcholinesterase knock-out mice. Since the selective butyrylcholinesterase inhibitor iso-OMPA (100μM) also prolonged mepp decay at the neuromuscular junction of acetylcholinesterase knock-out mice, mefloquine inhibition of this enzyme is physiologically relevant. The non-selective anti-cholinesterase action can contribute to the neurologic effects of mefloquine.