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Mefloquine selectively increases asynchronous acetylcholine release from motor nerve terminals.
Joseph J McArdle1, Lawrence C Sellin, Kathleen M Coakley
1Department 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
Neuropharmacology
|November 18, 2005
Summary
Mefloquine, an antimalarial, causes neurologic side effects by disrupting nerve cell communication. This study reveals mefloquine increases intracellular calcium, leading to altered neurotransmitter release and potential neurological impacts.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Mefloquine is a crucial antimalarial drug effective against resistant Plasmodia.
- Neurological adverse effects limit mefloquine's therapeutic use.
- The cellular mechanisms underlying mefloquine's neurotoxicity remain unclear.
Purpose of the Study:
- To investigate mefloquine's effects on cholinergic synaptic transmission.
- To elucidate the cellular mechanisms contributing to mefloquine's neurological side effects.
Main Methods:
- Utilized the Triangularis sterni nerve-muscle preparation from adult mice.
- Employed sharp electrode current clamp techniques to record synaptic activity.
- Investigated the role of calcium and ATP production in mefloquine's action.
Main Results:
- Mefloquine (10 microM) significantly increased miniature endplate potential (mep) frequency (10-fold) in a dose-dependent manner (threshold 0.6 microM).
- Mefloquine-induced mep frequency increase was dependent on intracellular calcium but not extracellular calcium or thapsigargin-sensitive stores.
- Mefloquine's effects mimicked oligomycin's inhibition of mitochondrial ATP synthase, suggesting impaired ATP production and subsequent intracellular calcium elevation.
Conclusions:
- Mefloquine impairs neuronal ATP production, leading to increased intracellular calcium in nerve terminals.
- Elevated intracellular calcium selectively enhances asynchronous neurotransmitter release.
- These findings provide insights into the cellular basis of mefloquine's neurotoxicity.