Cyclosporine induces neuronal apoptosis and selective oligodendrocyte death in cortical cultures

Cyclosporine is used clinically as an immunosuppressant, but carries a risk of central nervous system toxicity due to undefined mechanisms. We examined the ability of cyclosporine exposure to kill cultured mouse cortical neurons and glia. Mixed neuron/glial cultures exposed to 1 to 20 mu M cyclosporine for 24 to 48 hours developed concentration-dependent neuronal death, with most neurons destroyed by 20 mu M cyclosporine. This neuronal death was characterized by cell body shrinkage and blebbing, chromatin condensation, and internucleosomal DNA fragmentation, consistent with apoptosis. Neuronal death was reduced by addition of cycloheximide, brain-derived neurotrophic factor, or insulin-like growth factor I but not N-methyl-D-aspartate- or AMPA-type glutamate receptor antagonists. Oligodendrocytes were more sensitive to cyclosporine-induced damage than were neurons, but astrocytes were relatively resistant. Oligodendrocyte death was accompanied by positive TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling) staining and was attenuated by application of ciliary neurotrophic factor or insulinlike growth factor I but not glutamate receptor antagonists. Present observations raise the possibility that the central nervous system toxicity syndrome associated with cyclosporine may be caused by the drug-induced death of oligodendrocytes and neurons.