Abstract
Racemic mefloquine activates spontaneous vesicle release (SVR) from motor nerve endings and inhibits endplate acetylcholinesterase (AChE). Such cholinergic effects may reduce mefloquine's safety as an antimalarial drug. We tested the hypothesis that (+) and (‐) mefloquine differentially affect the neuromuscular junction (NMJ). Intracellular recordings at NMJs of mouse Triangularis sterni muscles suggested that 30 min exposure to 10 μM (+) or (‐) enantiomer alters the frequency of miniature endplate potentials (mEPPs). Quantitative comparisons were not possible since (+) reduced mEPP amplitude. Therefore, we recorded miniature endplate currents (mEPCs). (+) and (‐) significantly (p<0.01) increased mEPC frequency to 59.7 ± 20.05 Sec‐1 (mean ± SEM, N=21 NMJs) and 17.2 ± 1.98 Sec‐1 (N=14), respectively, from the control value of 5.6 ± 0.76 Sec‐1 (N=25). (+) also reduced amplitude (p<0.01) to 2.9 ± 0.18 nAmps (N=21) from the control value of 3.4 ± 0.18 nAmps (N=25); (‐) did not affect mEPC amplitude. (+), but not (‐), significantly (p<0.01) prolonged the endplate current decay time constant to 2.5 ± 0.16 mSec (N=12) from the control value of 1.1 ± 0.05 mSec (N=16). Thus, (+) may reduce conductance and prolong open time of the endplate acetylcholine receptor (AChR) as well as activate SVR. Neither (+) nor (‐) altered stimulus‐evoked quantal release. Assay of whole muscle homogenates revealed that while both enantiomers (1 to 100 μM) inhibit AChE, (‐) is more potent. The data suggest that (‐) is a less potent activator of SVR but a more potent inhibitor of AChE than (+) mefloquine. Supported by the Kirby Foundation.
Published Version
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