Beta, beta'-Iminodipropionitrile and 2,5-hexanedione are neurotoxins that produce neurofilamentous axonal swellings. The swellings produced experimentally with these agents are similar in structure but different in distribution. Neither the relationships between these agents nor the mechanisms of action are known. In this study local effects on nerve fibers were compared following injection of beta, beta'-iminodipropionitrile and 2,5-hexanedione beneath the perineurium of rat sciatic nerves. Soon after injection, 2,5-hexanedione reproduced the distinctive cytoskeletal disorganization previously described with beta, beta'-iminodipropionitrile: microtubules collected into a central channel, with neurofilaments segregated in a surrounding subaxolemmal ring. Later, the beta, beta'-iminodipropionitrile-injected nerves developed local neurofilaments accumulations, reproducing the neurofilamentous axonal swellings characteristic of systemic intoxication with these agents. The results indicate that both these agents have direct local effects on the axonal cytoskeleton and probably are similar in mechanism of action. Both these agents appear to segregate neurofilaments from the rest of the axonal cytoskeleton. This segregation may prevent the normal proximal-to-distal transport of neurofilaments, resulting in the formation of neurofilamentous axonal swellings.

Schwann cell division, meticulously regulated throughout development, occurs at an extremely low level in normal adult nerves. Loss of the myelin sheath in disease results in active proliferation of Schwann cells. The dividing cells are usually thought to be the Schwann cells of the demylinated fibres and their daughters. In this study we asked if other populations of Schwann cells might also divide following focal monophasic demyelination, and if the proliferating Schwann cells would be found only in the foci of demyelination. [3H]thymidine incorporation was examined by autoradiography at intervals after topical application of lysolecithin (lysophosphatidyl choline) to rat sciatic nerves. The postlabelling intervals were set to identify premitotic cells, cells shortly after mitosis (perimitotic cells) and postmitotic cells, as well as to provide cumulative labelling over 3 days. The affected nerves had three distinct zones. The first was a zone of nearly complete demyelination immediately beneath the perineurium. The subjacent zone was normal morphologically except for numerous supernumerary Schwann cells, displacement of some Schwann cell perikarya, ultrastructural changes in a few myelinated fibres, and rare demyelinated and remyelinated fibres. The third zone, beneath the first two, was normal. In the focus of demyelination there were large numbers of Schwann cells in S phase on days 4 and 6. These cells included premyelinating Schwann cells that were contacting or ensheathing demyelinated axons or collateral axonal sprouts. The subjacent region also contained dividing Schwann cells, most of which were Schwann cells of unmyelinated Remak fibres. In addition, occasional Schwann cells of thickly myelinated fibres (fibres that had not previously undergone demyelination) were labelled by the premitotic schedule; most of these fibres had morphological abnormalities in the Schwann cell perikaryon or myelin sheath. In many, the perikaryon of the Schwann cell was beginning to separate from the rest of the Schwann cell cytoplasm and the myelin sheath. These changes suggested that these fibres were destined to undergo subsequent demyelination, a hypothesis supported by the absence of any normal myelinated fibres with labelled Schwann cell nuclei in nerves removed 1 week after labelling. Thus, this model provided no evidence for division by Schwann cells that continued to maintain myelin sheaths. Taken together, these results suggest that there is a 'surround' of Schwann cell proliferation around foci of demyelination; in this surround multiple populations of Schwann cells are recruited to proliferate, including Schwann cells of intact unmyelinated fibres. Structurally normal unmyelinated fibres appear to provide an unexpected source of new Schwann cells in nerve disease.

No abstract