McArdle Joseph J, Sellin Lawrence C, Coakley Kathleen M, Potian Joseph G, Quinones-Lopez Mary C, Rosenfeld Clint A, Sultatos Lester G, Hognason Kormakur
Department of Pharmacology and Physiology, New Jersey Medical School and Graduate School of Biomedical Sciences, UMDNJ, 185 South Orange Avenue, Newark, NJ 07101-1709, USA.
Neuropharmacology. 2005 Dec;49(8):1132-9. doi: 10.1016/j.neuropharm.2005.06.011. Epub 2005 Aug 2.
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 30 min of exposure to 10 microM 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 (3 microM) 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 (100 microM) 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.
甲氟喹对耐药恶性疟原虫有效。这一特性，连同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物。然而，甲氟喹具有神经学效应，抵消了其治疗优势。甲氟喹神经学效应的细胞作用尚不清楚。在此，我们证明甲氟喹可抑制人重组乙酰胆碱酯酶。为探究这一作用的后果，我们在一个模型胆碱能突触——小鼠神经肌肉接头处研究了甲氟喹的作用。使用尖锐电极记录三角肌中的微小终板电位（mepps）。在暴露于10微摩尔甲氟喹的30分钟内，mepps在三个方面发生了改变：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呈线性增加。用胆碱酯酶抑制剂毒扁豆碱（3微摩尔）预处理肌肉可防止甲氟喹诱导的mepp衰减延长。甲氟喹也延长了乙酰胆碱酯酶基因敲除小鼠终板处的mepps。由于选择性丁酰胆碱酯酶抑制剂异-OMPA（100微摩尔）也延长了乙酰胆碱酯酶基因敲除小鼠神经肌肉接头处的mepp衰减，甲氟喹对该酶的抑制在生理上具有相关性。这种非选择性抗胆碱酯酶作用可能导致甲氟喹的神经学效应。
