Emulsifier for intravenous cyclosporin inhibits neurite outgrowth, causes deficits in rapid axonal transport and leads to structural abnormalities in differentiating N1E.115 neuroblastoma.
The emulsifier for cyclosporin in clinical i.v. formulations, Cremophor EL, has recently come into question as a possible source of neurotoxic side effects in immunosuppressant therapy. To address this issue we tested Cremophor EL and cyclosporin on an in vitro neuronal model, the differentiating N1E.115 neuroblastoma cell. In terms of effects on elaboration of neurites by these cells, Cremophor accounted for nearly all the neurotoxicity of clinically formulated cyclosporin. At a concentration of 0.005% (v/v), Cremophor EL halved the number of cells that extended neurites after 48 hr in serum-free medium. Average neurite length was also reduced substantially. Inhibition of neurite outgrowth first became apparent 24 hr after exposure to Cremophor EL. Neurites that did grow in the presence of Cremophor were disfigured by a series of regularly spaced, gross dilatations (beads) filled with large (0.2-0.5 microns) lipid vesicles. Abnormalities of rapid axonal transport were documented in the beaded neurites by means of video-enhanced contrast, differential interference-contrast microscopy. Velocity of retrograde transport remained normal, but the velocity of anterograde transport and the total bidirectional flux of organelles were both reduced. It seems likely that the inhibition of neurite outgrowth, the swellings of the neurites and the abnormalities of transport are interrelated phenomena.
Brat
D J
DJ
Department of Pharmacology, Mayo Clinic/Foundation, Rochester, Minnesota.
Windebank
A J
AJ
Brimijoin
S
S
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D016572:Cyclosporine / Q000008:administration & dosage*; D005990:Glycerol / Q000031:analogs & derivatives* / Q000633:toxicity; D051379:Mice; D016501:Neurites / Q000187:drug effects*; D009447:Neuroblastoma / Q000188:drug therapy / Q000648:ultrastructure; D014677:Pharmaceutical Vehicles; D014407:Tumor Cells, Cultured; D014741:Video Recording
D014677:Pharmaceutical Vehicles; C000515:cremophor EL; D016572:Cyclosporine; D005990:Glycerol