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Severance of a peripheral nerve leads to a characteristic series of events in the distal stump, including the dissolution of axons and myelin and the proliferation of Schwann cells within their basal lamina. This study examines the relationship between the spatial-temporal pattern of the induction of the Schwann cell S phase, loss of the structural and functional properties of axolemma, and the clearance of myelin debris in the cat tibial nerve. Nerve transection stimulated a monophasic increase in [3H]thymidine incorporation that peaked at 4 days post-transection throughout an 80-mm length of distal stump. Light microscope autoradiography revealed prominent incorporation into Schwann cells of myelinated fibres. Treatment of distal stumps with mitomycin C at the time of nerve transection greatly retarded thymidine incorporation and clearance of myelin debris, but not the time course of axonal degeneration, decline in the synthesis of the major myelin glycoprotein, P0, or the onset of ovoid formation. Nerve transection also greatly reduced the specific uptake of [3H]saxitoxin (STX), a ligand which binds to voltage-sensitive sodium channels. Binding in the distal stump fell precipitously to 20% of the normal at 4 days post-transection, concurrent with the peak of thymidine incorporation. This low level of binding was maintained for periods of up to 70 days, demonstrating that some STX binds to structures other than axons in denervated distal stumps. Prior treatment with mitomycin C delayed the loss of specific STX binding. In conclusion, these studies suggest that: (a) Schwann cell DNA replication- and/or mitosis regulates other events during Wallerian degeneration, including myelin degeneration, catabolism of P0 and the clearance of sodium channels from nodal axolemma; (b) the decline in P0 synthesis and/or shift to synthesis of less extensively processed P0 is independent of the induction of Schwann cell S phase; and (c) Schwann cells enveloping myelinated axons enter S phase within a 24-h period throughout the entire 80-mm length of distal stump.

This paper describes a surgical method of manipulating feline peripheral nerve regeneration to separate spatially the temporal sequence of events of axon-Schwann cell interaction during nerve fibre formation. The method allows regenerating axons from the peroneal nerve to reinnervate the distal stump of a axon- and myelin-free, Schwann cell-enriched, chronically denervated tibial nerve distal stump. Three zones can be morphologically delineated in the tibial nerve stump after three weeks of reinnervation: (1) a proximal myelinated zone, (2) a more distal, non-myelinated, axon-Schwann cell contact zone, and (3) a distal axon-free Schwann cell non-contact zone. The distal limit of the second zone can be determined accurately by the front of an axonally transported label. The large volume of available tissue makes this method suitable for interdisciplinary studies to elucidate the control of axon elongation, axon growth, and axon-Schwann cell inter-relationships.

This study examined the thesis that 2,5-dexanedione (2,5-HD) produces distal (dying-back) axonopathy by direct toxic action on nerve fibers. Single or repeated application of undiluted or 10% 2,5-HD to exposed rat sciatic nerves caused some fibres to develop focal axonal swellings filled with abnormally large numbers of 10 nm neurofilaments. Such changes occurred within four days of application and were especially prominent in equivalently treated nerve segments obtained from animals orally exposed to 0.5% 2,5-HD before surgery. Nerve fibers along the perimeter of tibial nerve fascicles exposed to 2,5-HD or 2,4-hexanedione (2,4-HD), a compound unable to produce systemic neuropathy, underwent non-specific breakdown and Schwann cell necrosis. Nerve fibres located in the centre of such fascicles only developed an hypertrophied paranuclear Schwann cell cytoplasm and did not proliferate intermediate filaments. Saline, hydrochloric acid and 1,6-hexanediol, a water-soluble hexacarbon also lacking systemic neurotoxic properties, produced no intra-fascicular changes when locally applied to the sciatic nerve. It is concluded (1) that 2,5-HD causes a giant axonal swellings by direct toxic action on the nerve fibre, (2) 2,5-HD does not induce a generalized disorder of cytoplasmic intermediate filaments and (3) primary Schwann cell changes produced by locally applied 2,5-HD or 2,4-HD are non-specific and unrelated to the formation of the giant axonal swellings.