Laboratory investigation; a journal of technical methods and pathology
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Comparative Study
Mitochondrial schwannopathy and peripheral myelinopathy in a rabbit model of dideoxycytidine neurotoxicity.
The reverse transcriptase inhibitor, 2',3'-dideoxycytidine (ddC), causes a dose-limiting peripheral neuropathy in humans, the mechanism of which is unknown. Rabbits given ddC develop peripheral myelinopathy and axonopathy, but it has not been determined if either the myelin or axonal changes are primary or if they occur concurrently. ⋯ The peripheral neuropathy caused by ddC in rabbits is characterized as a myelinopathy of the proximal portion of the nerve fibers and as an axonopathy involving both proximal and distal fibers. The myelinopathy was associated with enlarged and abnormally shaped mitochondria in Schwann cells and is consistent with an effect of ddC on structure and function of Schwann cell mitochondria. Altered Schwann cell metabolism was evident by reduced levels of P0 messenger RNA, loss of homophilic myelin adhesion at the intraperiod line, and subsequent intramyelinic edema. Because axonal degeneration occurred concurrently with the myelin changes, it could not be determined if axonal changes were secondary to serve myelinic edema or if they represented a primary effect of ddC on neurons.