Relative sensitivity of undifferentiated and cyclic adenosine 3',5'-monophosphate-induced differentiated neuroblastoma cells to cyclosporin A: potential role of beta-amyloid and ubiquitin in neurotoxicity.
Cyclosporin A is routinely used in transplant therapy following allogeneic or xenogeneic tissue transplantation to prevent rejection. This immunosuppressive drug is also neurotoxic; however, its mechanisms of action for neurotoxicity are poorly understood. Undifferentiated and cyclic adenosine 3',5'-monophosphate (cAMP)-induced differentiated neuroblastoma (NB) cells were used as an experimental model to study the toxicity of cyclosporin A. Results showed that cyclosporin A promoted the outgrowth of neurites and inhibited the growth of undifferentiated NB cells. When cyclosporin A was added simultaneously with RO20-1724, an inhibitor of cyclic nucleotide phosphodiesterase, or with prostaglandin E1, a stimulator of adenylate cyclase, it markedly enhanced the growth inhibitory and differentiation effects of these cAMP-stimulating agents. In addition, cyclosporin A added to cAMP-induced differentiated NB cells caused dose-dependent degeneration of these cells as evidenced by the vacuolization of cytoplasm and the fragmentation of nuclear and cytoplasmic materials; however, neurites remained intact. Cyclosporin A alone did not alter the intensity of cell immunostaining for ubiquitin or beta-amyloid peptide (amino acids 1-14) (Abeta1-14); however, it enhanced the intensity of staining for both ubiquitin and Abeta in cells that were treated with cAMP-stimulating agents. The intensity of staining of amyloid precursor protein (amino acids 44-63) (APP44-66) did not change in any treated group, suggesting that the increase in Abeta staining is due to increased processing of APP to Abeta. We propose that one of the mechanisms of cyclosporin A-induced neurotoxicity involves increased levels of Abeta and ubiquitin.
Kumar
A
A
Center for Vitamins and Cancer Research and Department of Radiology, College of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.
Hovland
A R
AR
La Rosa
F G
FG
Cole
W C
WC
Prasad
J E
JE
Prasad
K N
KN
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000494:pharmacology*; D016572:Cyclosporine / Q000633:toxicity*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D051379:Mice; D016501:Neurites / Q000187:drug effects; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014452:Ubiquitins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007166:Immunosuppressive Agents; D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; D014452:Ubiquitins; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D016572:Cyclosporine; D000242:Cyclic AMP