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 μM 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 μM) 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 μM) 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.