Ultrastructure of peripheral neuropathy induced in rabbits by 2',3'-dideoxycytidine.
The nucleoside analogue, 2',3'-dideoxycytidine (ddC), an inhibitor of human immunodeficiency virus reverse transcriptase, mediates virologic and immunologic improvements in acquired immunodeficiency syndrome patients. However, in clinical studies ddC treatment is associated with a dose-limiting peripheral neuropathy. The purpose of this study was to characterize the ultrastructural features of the peripheral neuropathy induced in rabbits. Rabbits received 0, 10, 50, or 100 mg/kg/day of ddC for 18 weeks. A prominent ultrastructural change induced by ddC in sciatic nerve and ventral root was separation of myelin lamellae at the intraperiod line and vacuolation and fragmentation of myelin sheaths. Many demyelinated and remyelinated axons were observed. Although pathologic alterations in Schwann cells were evident by the presence of lipid droplets and myelin figures, their formation was not considered a primary event. Axons containing abnormal cytoplasmic components were occasionally observed. Other changes included redundance of Schwann cell basal lamina and the presence of lipid droplets and/or myelin figures within endoneurial fibroblasts and macrophages. The results of this study indicate that ddC induces a myelinopathy in rabbits characterized by myelin splitting and intramyelinic edema and an axonopathy that may be secondary to the myelin changes.
Feldman
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Department of Toxicology and Pathology, Hoffmann-La Roche Inc., Nutley, New Jersey.
Brosnan
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C
Anderson
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TD
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D008854:Microscopy, Electron; D009185:Myelin Proteins / Q000187:drug effects; D009186:Myelin Sheath / Q000187:drug effects / Q000648:ultrastructure; D010525:Peripheral Nerves / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D011817:Rabbits; D012583:Schwann Cells / Q000187:drug effects / Q000648:ultrastructure; D016047:Zalcitabine / Q000009:adverse effects* / Q000494:pharmacology
D009185:Myelin Proteins; D016047:Zalcitabine