CYCLOSPORINE INDUCES NEURONAL APOPTOSIS AND SELECTIVE OLIGODENDROCYTEDEATH 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 mous e cortical neurons and glia. Mixed neuron/glial cultures exposed to 1 to 20 mu M cyclosporine for 24 to 48 hours developed concentration-dep endent neuronal death, with most neurons destroyed by 20 mu M cyclospo rine. This neuronal death was characterized by cell body shrinkage and blebbing, chromatin condensation, and internucleosomal DNA fragmentat ion, 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 r eceptor antagonists. Oligodendrocytes were more sensitive to cyclospor ine-induced damage than were neurons, but astrocytes were relatively r esistant. Oligodendrocyte death was accompanied by positive TUNEL (ter minal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate- biotin nick end-labeling) staining and was attenuated by application o f ciliary neurotrophic factor or insulinlike growth factor I but not g lutamate receptor antagonists. Present observations raise the possibil ity that the central nervous system toxicity syndrome associated with cyclosporine may be caused by the drug-induced death of oligodendrocyt es and neurons.