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 γ-diketone neuropathies, and that the proximodistal pattern to axonal enlargements represents pharmacokinetic variables rather than differences in mode of action. The neurotoxicity of γ-diketones probably arises from pyrrolation of lysine ε{lunate}-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 γ-diketone-induced NF accumulation results primarily from a progressive cross-linking of NF occuring subsequent to pyrrole formation. © 1990.