title: Disulfiram produces a non-carbon disulfide-dependent schwannopathy in the rat.
abstract: Disulfiram is a dithiocarbamate drug used for alcohol aversion therapy that produces a distal sensorimotor peripheral neuropathy in certain individuals. Because carbon disulfide, a disulfiram metabolite, produces a peripheral neuropathy clinically similar to disulfiram, it has been postulated that disulfiram neuropathy results from CS2 release in vivo. The current study evaluated the morphological changes produced by disulfiram and the contribution of CS2-mediated protein cross-linking to disulfiram-induced neuropathy. Male Sprague-Dawley rats were administered 1% w/w disulfiram in their feed for 2, 4, 5, or 7 wk, and erythrocyte spectrin, hemoglobin, and neurofilament preparations were isolated and the extent of cross-linking assessed by SDS-PAGE, RP-HPLC, and Western blotting, respectively. Spinal cord and peripheral nerve sections were obtained from separate treated animals and assessed by light and electron microscopy. Significant protein cross-linking was only detected in neurofilament preparations obtained after 7 wk of exposure. Morphological changes were observed after 4 wk exposure and consisted of vacuoles within the Schwann cell cytoplasm and segmental demyelination. No neurofilamentous axonal swellings were detected and no significant changes were observed in the CNS. Because disulfiram neuropathy lacks both the morphological changes and intermolecular cross-linking characteristic of CS2, we conclude that disulfiram neuropathy is not mediated by the axonal toxicant CS2; instead, disulfiram appears to be a primary Schwann cell toxicant. Recognition of a diethylcarbamoyl adduct on globin and axonal proteins presents a novel putative neurotoxic mechanism for disulfiram.
authors.affiliation: Department of Pathology, Vanderbilt University, Nashville, Tennessee 37232-2561, USA.
authors.forename: E G
authors.initials: EG
authors.lastname: Tonkin
authors.forename: J C
authors.initials: JC
authors.lastname: Erve
authors.forename: W M
authors.initials: WM
authors.lastname: Valentine
mesh_terms: D000284:Administration, Oral; D000427:Alcohol Deterrents / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D001927:Brain Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D002246:Carbon Disulfide / Q000633:toxicity; D004221:Disulfiram / Q000008:administration & dosage / Q000633:toxicity*; D018737:Hand Strength; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016900:Neurofilament Proteins / Q000187:drug effects; D011187:Posture; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology*; D013049:Spectrin / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology*; D013997:Time Factors
chemical_list: D000427:Alcohol Deterrents; D016900:Neurofilament Proteins; D013049:Spectrin; D002246:Carbon Disulfide; D004221:Disulfiram