The effect of 3,4-dimethyl substitution on the neurotoxicity of 2,5-hexanedione: I. Accelerated clinical neuropathy is accompanied by more proximal axonal swellings

The neurotoxicity of the γ-diketone, 3,4-dimethyl-2,5-hexanedione, was studied in rats and compared to the known neurotoxicity of the parent compound, 2,5-hexanedione. The test compound was found to be 20 to 30 times more potent on a molar basis than hexanedione. In addition, unlike the distal axonal changes associated with hexanedione, the neurofilamentous swellings following exposure to the dimethyl analog occurred more proximally in the axon, with a preponderance in the anterior horn and lateral tracts of the spinal cord, and in the anterior roots. Since alkyl substitution causes branched-chain compounds to cyclize more rapidly than unbranched analogs, the greater neurotoxicity of the dimethyl compound implicates pyrrole formation in the pathogenesis of n-hexane neuropathy. Furthermore, the location of the axonal swellings induced with 3,4-dimethyl 2,5-hexanedione suggests that there is a common mechanism of injury for the entire class of neurofilament neuropathies, providing a continuum between the intraspinal swellings of β,β′-iminodipropionitrile (IDPN) and the distal axonopathies of 2,5-hexanedione, carbon disulfide, and acrylamide. In addition, lower doses of 3,4-dimethyl-2,5-hexanedione for longer periods of time led to a shift in the location of the axonal swellings to include more distal sites. These observations support the hypothesis that covalent crosslinking of the stable neurofilament is the primary event in the molecular pathogenesis of these toxic neuropathies, and that the rate of crosslinking of neurofilaments determines the proximodistal location of the axonal swelling.