Cuprizone induced-demyelination in mice alters brain expression of genes involved in arachidonic acid metabolism .

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.