Chronic feeding with the copper chelator cuprizone in mice
causes oligodendrocyte death and subsequent reversible
demyelination. Although the mechanism of demyelination is
unknown, activation of glia is integral to the process. Since
metabolism of arachidonic acid (AA) is involved in glial
activation, we hypothesized that cuprizone exposure would
alter expression of AA cascade genes. Mice were fed 0.2 %
cuprizone in the diet for 6 weeks and then returned to a normal
diet. Histochemistry with the myelin stains Black Gold and
Fluoromyelin demonstrated that frank demyelination and
influx of glial cells into the corpus collosum begins at week 3
and peaks at week 5. A decrease in myelin and oligodendrocyte
markers, accompanied by increased expression of markers of
microglia (CD11b) and astrocytes (glial acidic fibrillary
protein), was evident at week one. Gene expression of
cyclooxygenase-2 and 15-lipoxygenase (LOX) was also changed
at week one, suggesting that these genes are either involved
in or respond to early demyelination. Expression of 5-LOX was
not changed during early demyelination but it peaked during
week 5, when glial markers and frank demyelination also
reached their peak, suggesting that 5-LOX expression is a
consequence of the massive influx of inflammatory cells into
the area of demyelination. Our study is the first to demonstrate
that multiple enzymes involved in arachidonic acid metabolism are altered in the cuprizone model of demyelination and
remyelination. These data may help to develop new therapeutic
targets to treat human demyelinating diseases, such as multiple
sclerosis.
Supported by the Intramural Research Program of the NIH,
NIA
