The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system

Myelin of the adult CNS is vulnerable to a variety of metabolic, toxic, and autoimmune insults. That remyelination can ensue, following demyelinating insult, has been well demonstrated. Details of the process of remyelination are, however difficult to ascertain since in most experimental models of d emyelination/remyelination the severity, localization of lesion site, or ti me course of the pathophysiology is variable from animal to animal. In cont rast, an experimental model in which massive demyelination can be reproduci bly induced in large areas of mouse brain is exposure to the copper chelato r, cuprizone, in the diet. We review work from several laboratories over th e past 3 decades, with emphasis on our own recent studies, which suggest an overall picture of cellular events involved in demyelination/remyelination . When 8 week old C57BL/6 mice are fed 0.2% cuprizone in the diet, mature o lidgodendroglia are specifically insulted (cannot fulfill the metabolic dem and of support of vast amounts of myelin) and go through apoptosis. This is closely followed by recruitment of microglia and phagoctytosis of myelin. Studies of myelin gene expression, coordinated with morphological studies, indicate that even in the face of continued metabolic challenge, oligodendr oglial progenitor cells proliferate and invade demyelinated areas. If the c uprizone challenge is terminated, an almost complete remyelination takes pl ace in a matter of weeks. Communication between different cell types by sol uble factors may be inferred. This material is presented in the context of a model compatible with present data and which can be tested more rigorousl y with the cuprizone model. The reproducibility of the model indicates that it may allow for testing of manipulations (e.g. available knockouts or tra nsgenics on the common genetic background, or pharmacological treatments) w hich may accelerate or repress the process of demyelination and or remyelin ation.