benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone and Multiple-Sclerosis

Recent evidence suggests that the oligodendrocyte cell loss observed in multiple sclerosis sufferers is in part mediated by apoptosis. Here we use a human cell line, MO3.13, as a model system to investigate the biochemical processes involved in oligodendroglial cell death. Treatment with staurosporine kills both naive and differentiated cells in a dose-dependent manner; however, much higher concentrations of staurosporine are required to kill differentiated cells compared to their naive progenitors. Dying cells displayed the typical morphological characteristics of apoptosis, including cell shrinkage and chromatin condensation. Biochemical analysis showed that caspases, a group of enzymes intimately involved in the execution of apoptosis, are activated in both naive and differentiated cells. Western blotting analysis revealed that similar subsets of caspase enzymes were operating and that the substrate cleavage patterns were identical in both naive and differentiated cells. Treatment of MO3.13 cells with the general caspase inhibitor zVAD-FMK protected them from toxin-induced cell death. These results indicate that when an oligodendroglial human cell line is exposed to toxin it dies in an apoptotic manner. In addition, we show that cells can be protected from toxin-induced death using an appropriate inhibitor.

Topics: Amino Acid Chloromethyl Ketones; Apoptosis; Caspase Inhibitors; Caspases; Cell Differentiation; Cell Line; Coumarins; Cysteine Proteinase Inhibitors; Enzyme Activation; Enzyme Inhibitors; Fluorescent Dyes; Humans; In Situ Nick-End Labeling; Multiple Sclerosis; Oligodendroglia; Oligopeptides; Staurosporine; Substrate Specificity