PATHOGENETIC STUDIES OF HEXANE AND CARBON-DISULFIDE NEUROTOXICITY

Two commonly employed solvents, n-hexane and carbon disulfide (CS2), a lthough chemically dissimilar, result in identical neurofilament-fille d swellings of the distal axon in both the central and peripheral nerv ous systems. Whereas CS2 is itself a neurotoxicant, hexane requires me tabolism to the gamma-diketone, 2,5-hexanedione (HD). Both HD and CS2 react with protein amino functions to yield initial adducts (pyrrolyl or dithiocarbamate derivatives, respectively), which then undergo oxid ation or decomposition to an electrophile (oxidized pyrrole ring or is othiocyanate), that then reacts with protein nucleophiles to result in protein crosslinking. It is postulated that progressive cross-linking of the stable neurofilament during its anterograde transport in the l ongest axons ultimately results in the accumulation of neurofilaments within axonal swellings. Reaction with additional targets appears to b e responsible for the degeneration of the axon distal to the swellings .