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 β-amyloid peptide (amino acids 1–14) (Aβ1–14); however, it enhanced the intensity of staining for both ubiquitin and Aβ in cells that were treated with cAMP-stimulating agents. The intensity of staining of amyloid precursor protein (amino acids 44–63) (APP44–63) did not change in any treated group, suggesting that the increase in Aβ staining is due to increased processing of APP to Aβ. We propose that one of the mechanisms of cyclosporin A–induced neurotoxicity involves increased levels of Aβ and ubiquitin.
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1 February 2000
RELATIVE SENSITIVITY OF UNDIFFERENTIATED AND CYCLIC ADENOSINE 3′,5′-MONOPHOSPHATE–INDUCED DIFFERENTIATED NEUROBLASTOMA CELLS TO CYCLOSPORIN A: POTENTIAL ROLE OF β-AMYLOID AND UBIQUITIN IN NEUROTOXICITY
ARUN KUMAR,
ALICIA R. HOVLAND,
FRANCISCO G. LA ROSA,
WILLIAM C. COLE,
JUDITH E. PRASAD,
KEDAR N. PRASAD
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In Vitro Cellular & Developmental Biology - Animal
Vol. 36 • No. 2
February 2000
Vol. 36 • No. 2
February 2000
beta-amyloid
cAMP
Cyclosporine A
degeneration
differentiated neuroblastoma cells
ubiquitin
undifferentiated neuroblastoma cells