The neurotoxic effect of cuprizone on oligodendrocytes depends on the presence of pro-inflammatory cytokines secreted by microglia.
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.
Pasquini
L A
LA
Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, Buenos Aires, C1113AAD, Argentina.
Calatayud
C A
CA
Bertone Uña
A L
AL
Millet
V
V
Pasquini
J M
JM
Soto
E F
EF
D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D003471:Cuprizone / Q000494:pharmacology*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000517:prevention & control; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism*; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D008911:Minocycline / Q000627:therapeutic use; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D017077:Culture Media, Conditioned; D014409:Tumor Necrosis Factor-alpha; D003471:Cuprizone; D007371:Interferon-gamma; D008911:Minocycline