The long-term cellular response to taxol in peripheral nerve: Schwann cell and endoneurial cell changes.

Abstract

Taxol, an agent known to stabilize and increase the assembly of microtubules, causes long-lasting nerve damage when injected into peripheral nerve. In the present study, the cellular response to taxol in rat sciatic nerve was studied for up to 6 months after a single injection. The initial response of Schwann cells to taxol at the lesion site involved the accumulation of cytoplasmic microtubules which persisted up to 4 months after injection. Some novel microtubule-related cytoplasmic structures were also noted; these included microtubule-lined cytoplasmic crypts and channels. Despite these structural abnormalities, Schwann cells were able to produce myelin sheaths around taxol-induced axonal bulbs. This myelination showed some anomalies up to 4 months consisting of the widening of myelin lamellae, variability in sheath thickness, paranodal myelin infoldings and myelin protrusions. With time the diameter of the axonal bulbs decreased and, concomitant with this, more normal-appearing remyelination occurred. By 5 months, the previously noted myelin abnormalities were rare. By 6 months only a few naked axonal segments occurred at the lesion site. In endoneurial fibroblasts and macrophages cytoplasmic lamellar microtubule formations were frequent at 10 weeks. Needle-like cytoplasmic structures appeared within endoneurial cells at the site of the lesion after 10 weeks. By 3 months these inclusions were numerous and were often surrounded by extended cytoplasmic processes. The needles were up to 50 microns long and 3 microns wide and probably represented cholesterol. By 4 months the number of cytoplasmic needles decreased and at 5 months onwards none was observed. The present findings confirm and extend previous findings that taxol has a long-lasting effect upon both Schwann cells and endoneurial cells and that this is related to abnormal tubulin synthesis.