mezerein and Demyelinating-Diseases

In previous work we found that mezerein, a C kinase activator, as well as basic fibroblast growth factor (FGF-2) induce demyelination and partial oligodendrocyte dedifferentiation in highly differentiated aggregating brain cell cultures. Here we show that following protein kinase C activator-induced demyelination, effective remyelination occurs. We found that mezerein or FGF-2 caused a transient increase in DNA synthesis following a pronounced decrease of the myelin markers myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphohydrolase. Both oligodendrocytes and astrocytes were involved in this mitogenic response. Within 17 days after demyelination, myelin was restored to the level of the untreated controls. Transient mitotic activity was indispensable for remyelination. The present results suggest that myelinating oligodendrocytes retain the capacity to reenter the cell cycle, and that this plasticity is important for the regeneration of the oligodendrocyte lineage and remyelination. Although it cannot be excluded that a quiescent population of oligodendrocyte precursor cells was present in the aggregates and able to proliferate, differentiate and remyelinate, we could not find evidence supporting this view.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Becaplermin; Biomarkers; Brain; Cell Division; Cytarabine; Demyelinating Diseases; Diterpenes; DNA; Enzyme Activation; Fetus; Fibroblast Growth Factor 2; In Vitro Techniques; Mitosis; Myelin Basic Protein; Myelin Sheath; Oligodendroglia; Platelet-Derived Growth Factor; Protein Kinase C; Proto-Oncogene Proteins c-sis; Rats; Terpenes

The plasticity of mature oligodendrocytes was studied in aggregating brain cell cultures at the period of maximal expression of myelin marker proteins. The protein kinase C (PKC)-activating tumor promoters mezerein and phorbol 12-myristate 13-acetate (PMA), but not the inactive phorbol ester analog 4alpha-PMA, caused a pronounced decrease of myelin basic protein (MBP) content and 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) activity. In contrast, myelin/oligodendrocyte protein (MOG) content was affected relatively little. Northern blot analyses showed a rapid reduction of MBP and PLP gene expression induced by mezerein, and both morphological and biochemical findings indicate a drastic loss of compact myelin. During the acute phase of demyelination, only a relatively small increase in cell death was perceptible by in situ end labeling and in situ nick translation. Basic fibroblast growth factor (bFGF) also reduced the levels of the oligodendroglial differentiation markers and enhanced the demyelinating effects of the tumor promoters. The present results suggest that PKC activation resulted in severe demyelination and partial loss of the oligodendrocyte-differentiated phenotype.

Topics: Animals; Biomarkers; Brain; Carcinogens; Cell Aggregation; Cell Differentiation; Cells, Cultured; Demyelinating Diseases; Diterpenes; Enzyme Activation; Fibroblast Growth Factor 2; Gene Expression; Myelin Proteins; Oligodendroglia; Protein Kinase C; Rats; Terpenes; Tetradecanoylphorbol Acetate