Study of long-term anticholinesterase therapy: Effects on neuromuscular transmission and on motor end-plate fine structure

Prostigmine (neostigmine methylsulfate) was administered subcutaneously in dosages of 0.4 mg per kilogram twice daily to rats for 42 to 149 days. Motor end-plate fine structure was quantitatively analyzed in red and white muscle fibers, and in vitro microelectrode studies of neuromuscular transmission were performed in diaphragms of treated and control animals. In treated animals degeneration of postsynaptic folds was often observed in end-plates situated on red muscle fibers but infrequently in end-plates situated on white muscle fibers. The abnormal folds became atrophic and collapsed residues of preexisting folds accumulated within the widened synaptic clefts. The postsynaptic membrane profile concentration was decreased by 29 percent in red muscle fibers and by 10 percent in white muscle fibers. The mean nerve terminal area, mean synaptic vesicle count per unit nerve terminal area, and mean postsynaptic area were not significantly affected by prostigmine treatment. Extension of a Schwann cell process into the primary synaptic cleft was observed in one or more regions of eight of 16 soleus, 24 of 38 diaphragm, and two of 23 gastrocnemius end-plates. The niean miniature end-plate potential (MEPP) amplitude in the diaphragm was decreased by 29 percent below the control level. The MEPP frequency, the quantum content of the end-plate potential, and the resting membrane potential were not affected by prostigmine treatment. The findings suggest that long-term an tic ho I in es terase therapy might eventually have an adverse side effect o n neurotnuscular transmission and could contribute to refractoriness in treatment in some cases of myasthenia gravis.