Morphological and electrophysiological study of distal motor nerve fiber degeneration and sprouting after irreversible cholinesterase inhibition

Abstract

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.

Compartmental neurodegeneration and synaptic plasticity in the Wlds mutant mouse

“…For instance, blocking fast axonal transport with batrachotoxin causes nerve terminals to withdraw from endplates within 18 h; but they then grow back (Hudson et al 1984). Nerve terminals also retract in a ‘non‐Wallerian’ fashion following a single subcutaneous injection of the organophosphate sarin (Kawabuchi et al 1991). Rich & Lichtman (1989) observed comparable, reversible nerve terminal withdrawal from degenerating muscle fibres.…”

Ultrastructural Morphology of Motor Endplate Neurotoxicities in Rats

“…Decreases of synaptic vesicles in the motor endplates are i n d u c e d b y t h e t r e a t m e n t o f v e n o m s s u c h a s β -bungarotoxin 7,15 , notexin and taipoxin 16 , Vacor 10,17 and DTBHQ 13,14 . Accumulations of smooth endoplasmic reticulum and bead or balloon-like varicosities are observed in the animals toxicated with sarin 8 and DTB 2,3 . In this stage, no abnormal changes such as streaming of the Z-line and the degeneration of myofibrils are observed in the skeletal muscles of treated animals (Fig.…”

“…A single subcutaneous injection of a sublethal dose of sarin (0.08 mg/ kg) in rats induced a non-Wallerian-type axonal degeneration of the neuromuscular synapse in the slow twitch, soleus muscle 8 . The degeneration of the neuromuscular synapse was characterized by bead or balloon-like varicosities of the distal and terminal nerve fibers and a retraction of terminal axons.…”

A Re-Examination of Neuropsychological Functioning in Persian Gulf War Era Veterans

“…Polycyclic aromatic hydrocarbons (PAHs) from oil smoke generate in vitro genotoxicity, adversely impacting immune and respiratory functions (e.g., Klaassen, Amdur, & Doull, 1986;Kelsey et al, 1994) and depleted uranium has been cited as having carcinogenic effects in addition to adverse effects on kidney functioning (Doucet, 1994). Other purported environmental exposures such as kerosene and diesel fuel (Andrews & Snyder, 1986); pyridostigmine (Almog et al, 1991;Keeler, Hurst, & Dunn, 1991); metals and volatile organics found in smoke (Klaassen et al, 1986); and sarin (Burchfiel & Duffy, 1982;Kawabuchi, Cintra, Deshpande, & Dlbuquerque, 1991;Husain, Vijayaraghavan, Pant, Raza, & Pandey, 1993), exert both acute and chronic neurotoxicant effects in animals and humans. Although, an incidence study of admissions to an Army hospital during the PGW reported no admissions for exposure to chemical or biological weapons (Wintermeyer, 1994), it is possible that chronic low level exposures may be the cause of cognitive and physiological changes as long-term sequelae are unknown in humans.…”