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The Neurotoxic Effect of Cuprizone on Oligodendrocytes Depends on the Presence of Pro-inflammatory Cytokines Secreted by Microglia

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Abstract

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.

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Acknowledgments

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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Authors and Affiliations

  1. Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, Buenos Aires, C1113AAD, Argentina

    L. A. Pasquini, C. A. Calatayud, A. L. Bertone Uña, V. Millet, J. M. Pasquini & E. F. Soto

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  1. L. A. Pasquini
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  2. C. A. Calatayud
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  3. A. L. Bertone Uña
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  4. V. Millet
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  5. J. M. Pasquini
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  6. E. F. Soto
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Correspondence to E. F. Soto.

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This work is dedicated with sincere friendship to Celia and Tony Campagnoni.

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Pasquini, L.A., Calatayud, C.A., Bertone Uña, A.L. et al. The Neurotoxic Effect of Cuprizone on Oligodendrocytes Depends on the Presence of Pro-inflammatory Cytokines Secreted by Microglia. Neurochem Res 32, 279–292 (2007). https://doi.org/10.1007/s11064-006-9165-0

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  • DOI: https://doi.org/10.1007/s11064-006-9165-0

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