Trapidil-mediated inhibition of CNS remyelination results from reduced numbers and impaired differentiation of oligodendrocytes.

Abstract

In a previous study, we described the inhibitory effects of the growth factor-antagonist, trapidil, on spontaneously occurring oligodendrocyte remyelination in the rat spinal cord following lysolecithin-induced demyelination [30]. The objective of the present study was to further investigate the mechanisms of trapidil-mediated impairment of remyelination and thus obtain greater insight into the steps at which growth factors may be involved in remyelination. To this end, an ultrastructural analysis of the cellular composition of lesions from control and trapidil-treated animals was undertaken. Demyelination was created in the dorsal funiculus of 6-week-old female rats by the injection of 1.0 microliter of 1% lysolecithin. The animals received daily intraperitoneal injections of trapidil (80 mg/kg) or saline for 21 days, beginning on the day of lesion induction. Quantitative electron microscopic examination of lesions from both groups of animals showed that trapidil-treated lesions had reduced numbers of oligodendrocytes (P = 0.02) with a higher relative proportion of immature phenotypes, but increased numbers of microglia (P = 0.0009) and dystrophic axons (P0.02). In addition, the numbers of myelin lamellae around remyelinated axons were fewer in trapidil-treated animals. These results suggest that trapidil-mediated impairment of CNS remyelination is due to a blockage of growth factor-mediated proliferation and/or recruitment of remyelinating cells. Furthermore, the presence of oligodendrocytes with a more immature phenotype and the decreased thickness of the myelin sheaths of remyelination in the trapidil-treated animals indicate an impairment of growth factor-mediated differentiation.