RELEASE OF CARBON-DISULFIDE IS A CONTRIBUTING MECHANISM IN THE AXONOPATHY PRODUCED BY N,N-DIETHYLDITHIOCARBAMATE

The neurotoxicity of N,N-diethyldithiocarbamate (DEDC) is established, although the mechanisms responsible for its neurotoxicity are not. Pr evious experiments have demonstrated that DEDC has the ability to prod uce CS2-mediated protein cross-linking in vitro and that DEDC releases CS2 in vivo. The release of CS2 with subsequent cross-linking of prot eins presents a potential mechanism through which DEDC may exert its n eurotoxicity. In the present study DEDC (3 mmol/kg po) was given to ra ts every other day for 8 and 16 weeks. At the end of each treatment pe riod, erythrocyte spectrin, hemoglobin, and spinal cord neurofilament preparations were isolated and examined for cross-linking using polyac rylamide gel electrophoresis, reverse phase HPLC, and Western blot tec hniques, respectively. Additional rats were perfused and sections of t he lumbar and cervical spinal cord and the muscular branch of the post erior tibial nerve were removed and examined by light and electron mic roscopy. Relative to controls, significant levels of cross-linking wer e observed in all the proteins examined at both 8 and 16 weeks of trea tment. Morphological changes were not detected at 8 weeks, but at 16 w eeks degenerated and swollen axons filled with disorganized masses of neurofilaments were present in the distal regions of the long tracts o f 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 identi cal to those produced by CS2 is consistent with release of CS2 from DE DC being a contributing mechanism in DEDC-induced neurotoxicity. (C) 1 998 Academic Press.