The Neurotoxic Effect of Cuprizone on Oligodendrocytes Depends on the Presence of Pro-inflammatory Cytokines Secreted by Microglia
Open accessAbstract
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 IFNgamma and/or TNFalpha 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 TNFalpha-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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Cuprizone-induced apoptosis in in vitro oligodendrocyte culture was successful only after addition of pro-inflammatory cytokines, which are produced by microglia and astrocytes.
“(2), cuprizone-induced apoptosis in in vitro oligodendrocyte culture was successful only after addition of pro-inflammatory cytokines, which are produced by microglia and astrocytes [34];”
From Strain differences in cuprizone induced demyelination (2017) · cites this paper as [34]
Inhibition of microglial activation by minocycline prevented cuprizone induced demyelination in vivo.
“(3), inhibition of microglial activation by minocycline prevented cuprizone induced demyelination in vivo [34];”
From Strain differences in cuprizone induced demyelination (2017) · cites this paper as [34]
In vitro, cuprizone lowers the mitochondrial transmembrane potential of oligodendrocytes, but does not affect microglia, astrocytes, and neurons; cuprizone does not kill rat oligodendrocytes in vitro.
“In vitro, cuprizone lowers the mitochondrial transmembrane potential of oligodendrocytes, but does not affect microglia, astrocytes, and neurons [110] – neither does cuprizone kill rat oligodendrocytes in vitro [111].”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [111]
Cuprizone alone might not be enough to induce oligodendrocyte cell death in vivo, as cuprizone also does not kill oligodendrocytes in vitro.
“Confusingly enough, cuprizone also does not kill oligodendrocytes in vitro [111], suggesting that cuprizone alone might not be enough to induce oligodendrocyte cell death in vivo.”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [111]
Cuprizone disturbs mitochondrial function and compromises the energy metabolism of cells.
“Pasquini et al. reported a marked decrease in the activities of complex I, II, and III of the respiratory chain in oligodendrocyte cultures treated with cuprizone and in mitochondria isolated from cuprizone-treated mice confirming that cuprizone disturbs mitochondrial function and thus compromises the energy metabolism of cells (Pasquini et al., 2007).”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Pasquini et al., 2007
Cites
TNFα promotes proliferation of oligodendrocyte progenitors and remyelination
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Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned
Gudi, V., Gingele, S., Skripuletz, T., & Stangel, M. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00073 · Cited by 375 · see citing works
Regional differences between grey and white matter in cuprizone induced demyelination
Gudi, V., Moharregh-Khiabani, D., Skripuletz, T., Koutsoudaki, P. N., Kotsiari, A., Skuljec, J., Trebst, C., & Stangel, M. (2009) · Brain Research · doi:10.1016/j.brainres.2009.06.005 · Cited by 252 · see citing works
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Cuprizone [Bis(Cyclohexylidenehydrazide)] is Selectively Toxic for Mature Oligodendrocytes
Bénardais, K., Kotsiari, A., Škuljec, J., Koutsoudaki, P. N., Gudi, V., Singh, V., Vulinović, F., Skripuletz, T., & Stangel, M. (2013) · Neurotoxicity Research · doi:10.1007/s12640-013-9380-9 · Cited by 148 · see citing works
Activated microglia drive demyelination via <scp>CSF1R</scp> signaling
Marzan, D. E., Brügger‐Verdon, V., West, B. L., Liddelow, S., Samanta, J., & Salzer, J. L. (2021) · Glia · doi:10.1002/glia.23980 · Cited by 147 · see citing works
“Activated microglia release inflammatory cytokines that may contribute to oligodendrocyte death and demyelination, consistent with earlier in vitro studies (Pasquini et al., 2007).”
BackgroundResultPlatelet-Derived Growth Factor Promotes Repair of Chronically Demyelinated White Matter
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Spatio-Temporal Patterns of Demyelination and Remyelination in the Cuprizone Mouse Model
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IL-17-Induced Act1-Mediated Signaling Is Critical for Cuprizone-Induced Demyelination
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Dynamic Responses of Microglia in Animal Models of Multiple Sclerosis
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Strain differences in cuprizone induced demyelination
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How to Use the Cuprizone Model to Study De- and Remyelination
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“Instead, it has been proposed that a reactive cuprizone–copper responsible for the toxic e ff ects of cuprizone and that various cell types within a ff ected [19–21].”
Background
- Authors
- Pasquini, L. A., Calatayud, C. A., Bertone Uña, A. L., Millet, V., Pasquini, J. M., & Soto, E. F.
- Affiliations
- Universidad de Buenos Aires (AR)
- Corresponding author
- Soto, E. F.
- Venue
- Neurochemical Research
- Published
- 2006-10-25
- Volume
- 32
- Issue
- 2
- Pages
- 279-292
- ISSN
- 0364-3190 (ISSN-L)
- 1573-6903
- OpenAlex
- W2071946866
- Cited by
- 176
- References
- 3
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 7 · 2023: 15 · 2022: 8 · 2021: 11 · 2020: 13 · 2019: 13 · 2018: 8 · 2017: 15 · 2016: 9 · 2015: 12 · 2014: 3 · 2013: 13 · 2012: 7
- FWCI
- 3.30
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- cc-by-nc-sa
- www.springer.com/tdm (tdm)
- Locations
- Neurochemical Research (publishedVersion)
- PubMed (publishedVersion)
- CONICET Digital (CONICET) (submittedVersion, cc-by-nc-sa)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- cuprizone, demyelination, oligodendrocytes, microglia, inflammatory cytokines, interferon-gamma, TNF-α, mitochondrial dysfunction, electron transport chain, reactive oxygen species, minocycline, neuroinflammation
- MeSH terms
- Animals, Cell Survival, Cells, Cultured, Cuprizone, Demyelinating Diseases, Immunohistochemistry, Interferon-gamma, Male, Minocycline, Oligodendroglia, Tumor Necrosis Factor-alpha, Culture Media, Conditioned, Microglia, Mice, Rats
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