Taxol-induced neuropathy after nerve crush: long-term effects on regenerating axons.

Previous studies have shown that newly derived axonal sprouts are sensitive to the effect of taxol. Taxol induced an accumulation of microtubules in axonal sprouts, which resulted in giant axonal bulbs with the subsequent excessive proliferation of distorted axonal twigs from the distal end of swollen axonal bulbs 3 weeks after the nerve crush. The present study was performed to evaluate the chronic effects of taxol upon regenerative axons and the morphological changes have now been followed up to 40 weeks post injection (PI). The results showed that 1 month PI, the giant axonal bulbs with the conglomerations of haphazardly arranged axonal twigs were numerous at the lesion site. Later on, the axonal twigs, filled with axoplasmic microtubules, elongated and showed more longitudinal orientation as they grew distally. After 8 weeks PI the axonal elongation progressed and the majority of the original small axonal twigs disappeared and several larger diameter axonal branches developed. Some of the axonal branches emerging from the giant axonal bulbs became myelinated and survived while others degenerated. Ultrastructurally, the number of microtubules remained high in the surviving axonal branches up to 3 months PI. The degenerating branches showed an unexpected loss of microtubules 2 months onwards with the subsequent accumulation of degenerative axoplasmic material. However, neurofilaments were numerous in the degenerating axonal branches even when degenerative axoplasmic material was present. The present results show that some of the taxol-induced axonal twigs develop into larger diameter axonal branches which persist for up to 10 months. The cytoskeletal differences in the surviving versus the degenerating axonal branches suggests local regulatory mechanisms for regulation of axonal cytoskeleton in axons.(ABSTRACT TRUNCATED AT 250 WORDS)

Taxol-induced neuropathy after nerve crush: long-term effects on Schwann and endoneurial cells.

The present investigation is a continuation of previous studies showing taxol-induced changes up to 4 weeks after a nerve crush. To evaluate the long-term cellular response to taxol, we have extended our morphological analysis of these changes in the taxol-treated nerve crush for up to 40 weeks after a single injection of taxol (PI). The results showed that Schwann cells exhibited a long-lasting and marked response when taxol was injected into the crushed peripheral nerve. During the first 2 months PI, taxol-induced giant axonal bulbs showed the formation of primitive nodes of Ranvier as a result of Schwann cell invaginations. The Schwann cell invaginations developed into nodes of Ranvier after 3-4 months PI together with the recovery of axonal bulbs. Ultrastructurally, cytoplasmic microtubule-related abnormalities were numerous up to 3 months PI and microtubules were seen to enclose degenerative myelin. Taxol-induced abnormalities in Schwann cells did not prevent their ability to produce myelin sheaths, although the accumulation of microtubules between myelin lamellae caused swellings of Schmidt-Lanterman incisures and paranodal myelin loops. Abnormal, extracellular collagen-like 5-nm-thin fibrils were noted closely associated with Schwann cells up to 10 weeks PI. Endoneurial cells, present as long rows without interconnections were noted in areas devoid of axonal sprouts up to 6-8 weeks PI. These cells showed marked cytoplasmic elongations and were covered by thickened basal lamina and contained several microtubule-related cytoplasmic structures, some of which have not been described previously. Taxol, when injected into crushed sciatic nerve induced a long-lasting response upon the Schwann cells with several ultrastructural abnormalities which correlate with changes in myelination and the development of nodes of Ranvier. These findings suggest that normal microtubule turnover is necessary for Schwann cells during nerve fiber regeneration.