DEMYELINATION IN EXPERIMENTAL BETA,BETA'-IMINODIPROPIONITRILE AND HEXACARBON NEUROPATHIES - EVIDENCE FOR AN AXONAL INFLUENCE

Abstract

.beta.,.beta.''-Iminodipropionitrile and 2,5-hexanediol are best known for their ability to induce axonal pathology, including formation of giant axonal swellings. During studies of the pathology of rats exposed to these agents for long periods, extensive recurrent demyelination in the spinal roots was found. To determine whether the demyelination occurred in response to the axonal disease or whether it represented a direct toxic effect on Schwann cells, the time course and distribution of axonal changes and demyelination was examined to see whether demyelination correlated with, or was independent of, axonal pathology. Rats were continuously intoxicated with 1 agent and groups were taken for pathologic examination at intervals of up to 2 yr; in both models, the relationship between axonal pathology and demyelination was systematically studied in multiple regions of the L5 spinal roots. In control rats, mild demyelination was present by 14 mo. and increased with age. By 24 mo., untreated animals showed widespread demyelination in the spinal roots; in these animals, there was no predilection for proximal or distal regions of the roots or evidence of recurrent demyelination. Administration of .beta.,.beta.''-iminodipropionitrile produced giant axonal swellings located primarily in the proximal 10 mm of the ventral root and the distal 10 mm of the dorsal root. By 12 mo. of exposure, intramyelinic vacuoles (myelin bubbles) and demyelinated segments were numerous in the same regions. By 24 mo., the affected regions contained elaborate onion bulbs. The regions without axonal swellings showed only mild demyelination. In the 2,5-hexanediol group, giant axonal swellings and axonal degeneration began distally and progressed more proximally with time. By 15 mo., when axonal swellings were present primarily in the distal ventral root, there were numerous myelin bubbles. By 24 mo., onion bulbs, predominantly involving the distal ventral roots, had developed. Semiquantitative analysis of the time course and distribution of demyelination in these toxic models showed a relationship between axonal abnormalities and subsequent development of demyelination. Changes in the axons contributed to the development of demyelination in these models and determined lesion distribution. These experimental neuropathies provided models for studies of the stimulus and mechanisms of secondary demyelination.