Anti-Malaria Drug Mefloquine Induces Motor Learning Deficits in Humans

Chris I De Zeeuw,David Overbosch,Frans Vanderwerf,Marcel T G De Jeu,Perry J J Van Genderen,Ruben S Van Der Giessen,Sebastiaan K E Koekkoek,Thomas A Van Essen

doi:10.3389/fnins.2010.00191

Abstract

Mefloquine (a marketed anti-malaria drug) prophylaxis has a high risk of causing adverse events. Interestingly, animal studies have shown that mefloquine imposes a major deficit in motor learning skills by affecting the connexin 36 gap junctions of the inferior olive. We were therefore interested in assessing whether mefloquine might induce similar effects in humans. The main aim of this study was to investigate the effect of mefloquine on olivary-related motor performance and motor learning tasks in humans. We subjected nine participants to voluntary motor timing (dart throwing task), perceptual timing (rhythm perceptual task) and reflex timing tasks (eye-blink task) before and 24 h after the intake of mefloquine. The influence of mefloquine on motor learning was assessed by subjecting participants with and without mefloquine intake (controls: n = 11 vs mefloquine: n = 8) to an eye-blink conditioning task. Voluntary motor performance, perceptual timing, and reflex blinking were not affected by mefloquine use. However, the influence of mefloquine on motor learning was substantial; both learning speed as well as learning capacity was impaired by mefloquine use. Our data suggest that mefloquine disturbs motor learning skills. This adverse effect can have clinical as well as social clinical implications for mefloquine users. Therefore, this side-effect of mefloquine should be further investigated and recognized by clinicians.

Highlights

The quinolone derivative mefloquine is widely used in the treatment and prophylaxis of malaria in travelers to areas with chloroquine-resistant falciparum malaria (Palmer et al, 1993)
Nine participants volunteered for the performance experiments and 19 for the motor learning experiments (8 used mefloquine; 11 individuals served as control participants [no mefloquine use])
The unconditioned stimulus (US) is indicated by the vertical black line, ranging from 1000 to 1020 ms. (C) Histogram of the total number of conditioned response (CR) in % observed in control subject and mefloquine users

Summary

Introduction

The quinolone derivative mefloquine is widely used in the treatment and prophylaxis of malaria in travelers to areas with chloroquine-resistant falciparum malaria (Palmer et al, 1993). It is known that mefloquine interacts with an array of protein targets and cellular signaling pathways no studies have been performed regarding the nature of the origin of these adverse events (Lim and Go, 1985; Gribble et al, 2000; Maertens et al, 2000; Kang et al, 2001; Dow et al, 2003; Weiss et al, 2003; Cruikshank et al, 2004). Mefloquine has been shown to block connexin 36 (Cx36) gap junction very potently (Cruikshank et al, 2004; Margineanu and Klitgaard, 2006). The IO gives rise to the climbing fibers projecting to the Purkinje cells in the cerebellar cortex and functionally integrates sensory information and motor output resulting in well coordinated motor performance, motor learning, and cognitive processes (Simpson et al, 1996; Strick et al, 2009)

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