Release of carbon disulfide is a contributing mechanism in the axonopathy produced by N,N-diethyldithiocarbamate.

Johnson DJ, Graham DG, Amarnath V, Amarnath K, Valentine WM
Toxicol Appl Pharmacol. 1998 148 (2): 288-96

PMID: 9473537 · DOI:10.1006/taap.1997.8344

The neurotoxicity of N,N-diethyldithiocarbamate (DEDC) is established, although the mechanisms responsible for its neurotoxicity are not. Previous experiments have demonstrated that DEDC has the ability to produce CS2-mediated protein cross-linking in vitro and that DEDC releases CS2 in vivo. The release of CS2 with subsequent cross-linking of proteins presents a potential mechanism through which DEDC may exert its neurotoxicity. In the present study DEDC (3 mmol/kg po) was given to rats every other day for 8 and 16 weeks. At the end of each treatment period, erythrocyte spectrin, hemoglobin, and spinal cord neurofilament preparations were isolated and examined for cross-linking using polyacrylamide gel electrophoresis, reverse phase HPLC, and Western blot techniques, respectively. Additional rats were perfused and sections of the lumbar and cervical spinal cord and the muscular branch of the posterior tibial nerve were removed and examined by light and electron microscopy. Relative to controls, significant levels of cross-linking were observed in all the proteins examined at both 8 and 16 weeks of treatment. Morphological changes were not detected at 8 weeks, but at 16 weeks degenerated and swollen axons filled with disorganized masses of neurofilaments were present in the distal regions of the long tracts of the lumbar and cervical spinal cord and also in the muscular branch of the posterior tibial nerve. The ability of DEDC to covalently cross-link proteins in vivo and to produce axonal structural changes identical to those produced by CS2 is consistent with release of CS2 from DEDC being a contributing mechanism in DEDC-induced neurotoxicity.

Copyright 1998 Academic Press.

MeSH Terms (15)

Animals Axons Carbon Disulfide Chelating Agents Cross-Linking Reagents Ditiocarb Erythrocytes Hemoglobins Male Neurofilament Proteins Rats Rats, Sprague-Dawley Spectrin Spinal Cord Tibial Nerve

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