Gk. Matsushima et P. Morell, The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system, BRAIN PATH, 11(1), 2001, pp. 107-116
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.