Exposure of mice to the copper chelator, cuprizone, results in CNS demyelination. There is remyelination after removal of the metabolic insult. We present brain regional studies identifying corpus callosum as particularly severely affected; 65% of cerebroside is lost after 6 weeks of exposure. We examined recovery of cerebroside and ability to synthesize cerebroside and cholesterol following removal of the toxicant. The temporal pattern for concentration of myelin basic protein resembled that of cerebroside. We applied Affymetrix GeneChip technology to corpus callosum to identify temporal changes in levels of mRNAs during demyelination and remyelination. Genes coding for myelin structural components were greatly down-regulated during demyelination and up-regulated during remyelination. Genes related to microglia/macrophages appeared in a time-course (peaking at 6 weeks) correlating with phagocytosis of myelin and repair of lesions. mRNAs coding for many cytokines had peak expression at 4 weeks, compatible with intercellular signaling roles. Of interest were other genes with temporal patterns correlating with one of the three above patterns, but of function not obviously related to demyelination/remyelination. The ability to correlate gene expression with known pathophysiological events should help in elucidating further function of such genes as related to demyelination/remyelination.
Exposure of mice to the copper chelator, Cuprizone, results in a CNS demyelination; remyelination occurs following removal of this metabolic insult. Using this model, we have demonstrated changes in content and metabolism of myelin lipids in whole brain. We now extend these biochemical studies to brain regions and identify corpus callosum as particularly severely affected; 65% of cerebroside is lost after 6 weeks of exposure. Animals can be rescued by removal of the toxicant and the extent of recovery of myelin, as well as recovery of ability to synthesize cerebroside and cholesterol, can be determined. The temporal pattern for concentration of myelin basic protein tracked that of cerebroside, supporting the assumption that cerebroside level is a good surrogate for myelin concentration. We also applied Affymetrix microarray technology to corpus callosum to track temporal changes in steady‐state levels of mRNA species related to demyelination and remyelination. Genes coding for myelin structural components were greatly down‐regulated during demyelination and up‐regulated during remyelination. Genes related to microglia/macrophages appeared in a time course (peaking at 6 weeks) correlating with that expected for phagocytosis of myelin. mRNAs coding for many cytokine genes had peak expression at 4 weeks, compatible with an intercellular signaling role. Of interest were other genes with temporal patterns correlating with one of the three patterns mentioned above, but with functions not obviously related to demyelination/remyelination. The ability to correlate gene expression with known pathophysiological and regenerative events should be of utility in elucidating further function of such genes. Acknowledgements: Supported by USPHS & NMSS grants.
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