The Neurotoxic Effect of Cuprizone on Oligodendrocytes Depends on the Presence of Pro-inflammatory Cytokines Secreted by Microglia
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In order to further characterize the still unknown mechanism of cuprizone-induced demyelination, we investigated its effect on rat primary oligodendroglial cell cultures. Cell viability was not significantly affected by this treatment. However, when concentrations of IFNγ and/or TNFα having no deleterious effects per se on cell viability were added together with cuprizone, cell viability decreased significantly. In mitochondria isolated from cuprizone-treated glial cells, we observed a marked decrease in the activities of the various complexes of the respiratory chain, indicating a disruption of mitochondrial function. An enhancement in oxidant production was also observed in cuprizone and/or TNFα-treated oligodendroglial cells. In in vivo experiments, inhibition of microglial activation with minocycline prevented cuprizone-induced demyelination. Based on the above-mentioned results we suggest that these microglial cells appear to have a very active role in cuprizone-induced oligodendroglial cell death and demyelination, through the production and secretion of pro-inflammatory cytokines.
KeywordsCuprizone Cytokines Oligodendrocytes Myelin Demyelination Microglia
Contract grant sponsor: Universidad de Buenos Aires B114 and Agencia Nacional de Promoción de Ciencia y Tecnología (PICT 12282). The authors wish to express their gratitude to Dra. Laura Pardo from FUNDALEU, for her help with the flow cytometry data.
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