Peripheral neuropathy induced by 2',3'-dideoxycytidine: A rabbit model of 2',3'-dideoxycytidine neurotoxicity

T. D. Anderson, A. Davidovich, R. Arceo, C. Brosnan, J. Arezzo, H. Schaumburg

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Abstract

The nucleoside analog 2',3'-dideoxycytidine (ddC) is a potent inhibitor of the reverse transcriptase of human immunodeficiency virus and a DNA chain terminator. In clinical trials in patients with acquired immunodeficiency syndrome, ddC treatment has been associated with a dose-limiting and dose- dependent, painful, sensorimotor peripheral neuropathy. In search of an animal model for ddC-induced neurotoxicity we studied 36 New Zealand White rabbits (3 males/3 females/group) given 0, 10, 50, 100, 150, or 250 mg/kg/day of ddC, by oral intubation, for 13 or 18 weeks. Rabbits in the 150 and 250 mg/kg/day groups were sacrificed at 13 weeks because of hematopoietic toxicity. After 16 weeks, rabbits in the 50 and 100 mg/kg/day groups showed hindlimb paresis and/or gait abnormalities. Nerve conduction velocities and amplitudes in the 100 mg/kg/day rabbits were reduced by 30 to 50%. The most prominent pathologic changes in peripheral nerve and ventral roots of ddC- treated rabbits were (a) myelin splitting and intramyelinic edema, (b) demyelination and remyelination of axons, and (c) axonal loss. Treatment- related histologic lesions were not observed in spinal cord, brain, or retina. The pathology in these ddC-treated rabbits is consistent with a peripheral myelinopathy and axonopathy. This represents the first clinical, electrophysiologic, and pathologic description of an animal model of a peripheral neuropathy induced by a nucleoside analog.

Original languageEnglish (US)
Pages (from-to)63-74
Number of pages12
JournalLaboratory Investigation
Volume66
Issue number1
StatePublished - Jan 1 1992

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Keywords

  • Axonopathy
  • Myelinopathy
  • Nucleoside

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

Anderson, T. D., Davidovich, A., Arceo, R., Brosnan, C., Arezzo, J., & Schaumburg, H. (1992). Peripheral neuropathy induced by 2',3'-dideoxycytidine: A rabbit model of 2',3'-dideoxycytidine neurotoxicity. Laboratory Investigation, 66(1), 63-74.