Giant axonopathy characterized by intermediate location of axonal enlargements and acceleration of neurofilament transport.

It has previously been shown that 2,5-hexanedione (2,5-HD) and its 3,4-dimethyl derivative (3,4-DMHD) induce neurofilamentous accumulations at prenodal sites in distal and proximal, respectively, regions of peripheral axons. For 2,5-HD, neurofilament (NF) transport is accelerated and this is thought to be directly related to the appearance of the axonal enlargements. For 3,4-DMHD, however, the rate of NF transport cannot be assessed owing to the very proximal position of NF accumulation. In the present study, it is shown that administration to rats of 3-methyl-2,5-hexanedione, the structural 'average' of 2,5-HD and 3,4-DMHD, induces NF accumulations at midway axonal positions of the sciatic and optic systems, and results in acceleration of NF in the sections of optic axons proximal to the enlargements. These results suggest that a common mechanism underlies all gamma-diketone neuropathies, and that the proximodistal pattern of axonal enlargements represents pharmacokinetic variables rather than differences in mode of action. The neurotoxicity of gamma-diketones probably arises from pyrrolation of lysine epsilon-amino groups in crucial regions of NF or related proteins responsible for maintaining the proper supramolecular organization of the cytoskeleton. Acceleration of NF transport appears to be a common characteristic of chemically induced axonopathies, regardless of location, and this is contrary to the theory that gamma-diketone-induced NF accumulation results primarily from a progressive cross-linking of NF occurring subsequent to pyrrole formation.

beta,beta'-Iminodipropionitrile (IDPN) neurotoxicity: a mechanistic hypothesis for toxic activation.

beta,beta'-Iminodipropionitrile (IDPN) induces neurobehavioral aberrations in experimental animals and massive focal accumulations of neurofilaments in proximal regions of axons. A hypothesis is presented to explain the neurotoxic activity of IDPN in terms of oxidative amine metabolism, wherein a resonance-stabilized cyanoenamine 3-(2-cyanoethylamino)acrylonitrile (dehydro-IDPN, 5) could be generated. Chemical studies were conducted to verify the likelihood of the proposed enzymatic transformations and their consistency with the known excreted metabolites. Dehydro-IDPN gives rise to a slow hydrolytic release of cyanoacetaldehyde at pH 7, which can transform protein-based amino groups to cyanoenamines, though the latter derivatives could be formed directly through a relatively rapid transamination reaction with dehydro-IDPN at pH 7. Kinetic studies were conducted to assess the balance between competing hydrolysis (pseudo-first order) and transamination (second order) of cyanoenamines as a function of pH. Cyanoethenylation of the epsilon-amino groups of critical lysine residues in the "tail-piece" domains of neurofilament (NF) subunit proteins could disrupt the supramolecular coulombic interactions thought to contribute to maintenance of cytoskeletal caliber. This could result in a defect in the slow axonal transport of NF, and subsequently in the formation of proximal axonal enlargements.

Structural basis of gamma-diketone neurotoxicity: non-neurotoxicity of 3,3-dimethyl-2,5-hexanedione, a gamma-diketone incapable of pyrrole formation.

The chronic exposure to gamma-diketones results in the formation of giant neurofilament (NF)-containing axonal enlargements, followed by axonal degeneration in peripheral axons. Based on the specific ability of gamma-diketones to react with primary amino groups to form pyrroles, and the observation of such reaction with NF protein in vitro and with other proteins in vivo, it has been proposed that pyrrole formation at primary amino groups of NF protein is responsible for the neurotoxicity of gamma-diketones. We have tested this hypothesis through an investigation of the neurotoxicity in rats of 3,3-dimethyl-2,5-hexanedione (3,3-DMHD), a gamma-diketone which is incapable of forming pyrroles. 3,3-DMHD was found to produce only a slight alteration of axonal caliber and no clinical neurotoxicity after up to 12 weeks of administration, at a dose over 20 times that for which its isomer 3,4-dimethyl-2,5-hexanedione (3,4-DMHD) produced massive focal NF-containing axonal enlargements and complete paralysis in 4 weeks. These results support the view that the pyrrole-forming capability of gamma-diketones is the initial molecular event in the pathogenesis of gamma-diketone neurotoxicity.