Partial inhibition of proteasome activity enhances remyelination after cuprizone-induced demyelination.

We have previously demonstrated that addition of low concentrations of lactacystin (a specific inhibitor of the proteasome) to oligodendroglial cell cultures containing a high percentage of precursor cells induces their exit from the cell cycle and their differentiation. On the other hand, we have recently shown that the mechanism of cuprizone toxicity on oligodendroglial cells involves the recruitment of microglia and their secretion of pro-inflammatory cytokines and in the increased production of oxidant species, which results in a decrease in the activities of the mitochondrial respiratory chain. In the present paper we investigated the effect of a decrease in proteasome activity induced by the injection of lactacystin in the corpus callosum in the remyelination process that normally occurs after cuprizone-induced demyelination. This treatment markedly improves the remyelination process that normally occurs in cuprizone-induced demyelination. It also attenuates the activation of NFkappaB and the recruitment of microglia and astrocytes, thus helping in the recovery of the mitochondrial respiratory chain activities that are affected by cuprizone treatment.