Induction of neurofibrillary degeneration following treatment with maytansine in vivo.

The effects of maytansine (MYT), a naturally occurring ansa macrolide and potent antimitotic drug that binds to tubulin, were studied by light and electron microscopy in the central nervous system of rabbits. Respectively, 17 and 5 animals were sacrified at various time intervals following a single intrathecal or intraocular injection of the agent. The rabbits responded to the intrathecal injection with progressively severe weakness. By 19 h following injection the neurons of the cervical spinal cord, medulla and pons showed, by light microscopy, a marked clumping of the Nissl substance, while on the third day and later the nerve cell perikarya and dendrites displayed severe neurofibrillary changes. By electron microscopy several cytological alterations were observed as early as 19 h; among them were the clumping of the rough endoplasmic reticulum, the reduction in number of microtubules, and the presence of a fine, floccular and amorphous material. The perikaryonal and dendritic neurofibrillary changes appeared as tangles and/or bundles of10 nm neurofilaments. In the intraocularly injected rabbits the earliest changes observed in retinal ganglion cells were the severe reduction in microtubule number and the presence of an amorphous material. The neurofibrillary changes seen at later times were comparable with those observed in the cervical cord and brain stem. Although the molecular events occurring between the formation of the intracytoplasmic MYT-tubulin complexes and the accumulation of filaments are not known, the present results indicate that the proliferation of neurofilaments is chronologically preceded by the reduction in number of the microtubules and by the appearance of an amorphous floccular material in the cytoplasm. It is emphasized that despite differences in binding characteristics and physico-chemical properties, maytansine, colchicine and the Vinca alkaloids have, as a common denominator, the property of interfering with the process of utilization of tubulin and in that way they seem to differ from other chemical agents known to induce neurofibrillary degeneration.