THE NEUROTOXIC EFFECT OF CUPRIZONE ON OLIGODENDROCYTES REQUIRES THE PRESENCE OF TNFalpha AND IFNgamma

PASQUINI LA, CALATAYUD C, MILLET V, SOTO E, AND PASQUINI J.

Pinamar, Buenos Aires, Argentina

Congreso; SAIB -PABMB-SAN; 2005

Sociedad Argentina de Neuroquimica

Cuprizone(CPZ) intoxication model has been widely used to induce demyelination. To explain the unknown mechanism of demyelination caused by CPZ, primary oligodendroglial cell (OLGc) cultures were treated with a wide range of CPZ concentrations, for 0/7 days and in presence or absence of conditioned medium from astrocytes previously treated with CPZ. Cell viability, evaluated by the MTT assay doesn¡¦t showed changes. The effect of CPZ on OLGc cell cycle and differentiation was also evaluated and no variations were detected. The inflammatory process plays a key role in the pathogenesis of degenerative disorders such as Multiple Sclerosis so we tested the effect of cytokines such as IFNg and TNFa and none of them affected cell viability. However, in presence of cytokines and CPZ, we observed an important diminish in cell viability. Activities of mitochondrial complexes I/I-III evaluated on mitochondrias from glial cell cultures treated with CPZ (72h) show a decrease relative to controls. Production of free radicals evaluated using DCDCDHF, in cells treated with TNFa, CPZ or both, is significantly increased. Results suggest that CPZ demyelination is not a direct effect of the drug on OLGcs. Myelin loss and OLGc death seems to be mediated by molecules such as TNFa and IFNg secreted by recruited microglia/macrophages and could be also consequence of a mitochondrial complexes activity diminish, with a loss in energy production and an increase in the production of free radicals.