title: Mefloquine inhibits cholinesterases at the mouse neuromuscular junction.
abstract: 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.
authors.affiliation: 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. mcardle@umdnj.edu
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: McArdle
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Sellin
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Coakley
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Potian
authors.forename: Mary C
authors.initials: MC
authors.lastname: Quinones-Lopez
authors.forename: Clint A
authors.initials: CA
authors.lastname: Rosenfeld
authors.forename: Lester G
authors.initials: LG
authors.lastname: Sultatos
authors.forename: Kormakur
authors.initials: K
authors.lastname: Hognason
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000502:physiology; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006801:Humans; D015767:Mefloquine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009045:Motor Endplate / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects*; D010275:Parasympathetic Nervous System / Q000187:drug effects; D010830:Physostigmine / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects
chemical_list: D000962:Antimalarials; D002800:Cholinesterase Inhibitors; D010830:Physostigmine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D015767:Mefloquine