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Cyclosporine induces neuronal apoptosis and selective oligodendrocyte death in cortical cultures
Author(s) -
McDonald John W.,
Goldberg Mark P.,
Gwag Byoung J.,
Chi ShuIng,
Choi Dennis W.
Publication year - 1996
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410400511
Subject(s) - oligodendrocyte , biology , glutamate receptor , neurotrophic factors , tunel assay , programmed cell death , neuron , neurotoxicity , central nervous system , neurotrophin , apoptosis , endocrinology , microbiology and biotechnology , neuroscience , medicine , toxicity , myelin , receptor , biochemistry
Cyclosporine is used clinically as an immunosuppressant, but carries a risk of central nervous system toxicity due to undefined mechanisms. We examined the abiility of cyclosporine expsure to kill cultured mouse cortical neurons and glia. Mixed neuron/glial cultures exposed to 1 to 20 μM cyclosporine for 24 to 48 hours developed concentration‐dependent neuronal death, with most neurons destroyed by 20 μM cyclosporine. This Neuronal death was characterized by cell body shrinkage and bleebbing, chromatin condenstation, 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 deoxyuridinetriphosphate‐biotin nick end‐labeling) staining and was attenuatd by application of ciliary neurotrophic factor or insulin‐like growth factor I but not glutamate receptro 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.