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 microM cyclosporine for 24 to 48 hours developed concentration-dependent neuronal death, with most neurons destroyed by 20 microM 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 insulin-like 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.
McDonald
J W
JW
Department of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, MO 63110, USA.
Goldberg
M P
MP
Gwag
B J
BJ
Chi
S I
SI
Choi
D W
DW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D002843:Chromatin / Q000187:drug effects; D020934:Ciliary Neurotrophic Factor; D018920:Coculture Techniques; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004247:DNA / Q000032:analysis; D004253:DNA Nucleotidylexotransferase / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005333:Fetus; D007166:Immunosuppressive Agents / Q000633:toxicity; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D019208:Brain-Derived Neurotrophic Factor; D002843:Chromatin; D020934:Ciliary Neurotrophic Factor; D018691:Excitatory Amino Acid Antagonists; D007166:Immunosuppressive Agents; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D007334:Insulin-Like Growth Factor I; D016291:Dizocilpine Maleate; D016572:Cyclosporine; D004247:DNA; D004253:DNA Nucleotidylexotransferase