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Initial Ultrastructural Abnormalities At The Motor End Plate Produced By A Cholinesterase Inhibitor

M. B. Laskowski, W. Olson, W. Dettbarn
Published 1977 · Chemistry, Medicine

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Abstract Previous studies have demonstrated that paraoxon, an organophosphorous cholinesterase inhibitor, produces a progressive myopathy in diaphragm and leg muscles of the rat within 24 h after subcutaneous injection. Electrophysiological studies revealed augmented transmitter release and rapid spontaneous nerve activity in diaphragm muscles within 30 min after paraoxon. In the present study we examined the ultrastructural changes taking place at motor end plates of diaphragm and soleus muscles during this period of increased neuromuscular activity. Thirty minutes after paraoxon, disorganized cytoarchitecture occurred beneath the motor end plates of diaphragm muscles. This consisted of dilated mitochondria and expanded sarcoplasmic reticulum. The average distance that the pathology extended from the nerve terminal membrane was 8.0 μm. Six hours after paraoxon the first lesions were observable at the light microscopic level. All endplates revealed some subsynaptic disorganization with widely varying severity. Nerve terminals contained accumulations of coated vesicles. Subsynaptic folds were wider and often contained membrane-bound vesicles. The most severely affected end plates were associated with necrotic fibers. End plates of soleus fibers were less severely affected, and no lesions were observed at the light microscopic level at this time. In diaphragm fibers the subsynaptic disorganization continued to expand to 13.5 μm from the nerve terminal 24 and 72 h after paraoxon. Coated vesicles, fold width, and cleft vesicles continued to increase during this time. Reactivation of acetylcholinesterase with pyridine-2-aldoxime methiodide prevented end-plate abnormalities and fiber degeneration if administered 10 min after paraoxon. A delay of 2 h made the aldoxime much less effective. These data indicate that paraoxon produces its initial myopathic effects at the motor-end plate, and that the myopathy can be prevented by reactivation of acetylcholinesterase. The subsynaptic disorganization progresses from the motor end plate, and fiber necrosis may be linked to these subsynaptic abnormalities.
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