Morphological and electrophysiological study of distal motor nerve fiber degeneration and sprouting after irreversible cholinesterase inhibition.
A single subcutaneous injection of a sublethal dose of the irreversible organophosphate sarin (0.08 mg/kg) in rats induced a non-Wallerian-type axonal degeneration of the neuromuscular synapse in the slow twitch, soleus muscle. These alterations of the endplate region were more obvious in the soleus than in the fast extensor digitorum longus muscle and were slowly reversible, complete recovery requiring about 10 days. Silver-cholinesterase staining and electrophysiological techniques were used to define the spatiotemporal evolution of prejunctional abnormalities. The non-Wallerian-type axonal degeneration of the neuromuscular synapse was characterized by bead or balloon-like varicosities of the focal, distal, and terminal nerve fibers and a retraction of terminal axons. Axonal degeneration was accompanied by junctional and extrajunctional membrane depolarization and was followed by nerve sprouting at focal, distal, and terminal nerve fibers. Transients similar to miniature endplate potentials were recorded along the muscle fiber at distances of 800-2500 microns away from the parent endplate. New ectopic endings, originating from the same endplate, were discovered adjacent to the terminal axon and also distant from the parent endplate. Very elaborate terminal arborization and occasional multibranching arose from a progressive growth sprout. The new sprouting may have served to compensate for the loss of synaptic contact caused by sarin. Thus the present study demonstrates a direct cytotoxic effect of sarin and indicates that this organophosphate agent may be an important neurotoxicological tool to understand the mechanisms involved in nerve sprouting.
Kawabuchi
M
M
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201.
Cintra
W M
WM
Deshpande
S S
SS
Albuquerque
E X
EX
D000818:Animals; D001369:Axons / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004594:Electrophysiology; D005260:Female; D008564:Membrane Potentials / Q000187:drug effects; D009045:Motor Endplate / Q000187:drug effects / Q000648:ultrastructure; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*; D009132:Muscles / Q000187:drug effects / Q000201:enzymology / Q000294:innervation*; D009410:Nerve Degeneration / Q000187:drug effects*; D009416:Nerve Regeneration / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D012524:Sarin / Q000633:toxicity
D002800:Cholinesterase Inhibitors; D012524:Sarin