Mitochondrial schwannopathy and peripheral myelinopathy in a rabbit model of dideoxycytidine neurotoxicity.
BACKGROUND
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.


METHODS
To characterize sequential development of the ddC-induced neuropathy, 40 rabbits were given either vehicle or ddC by oral intubation at a dose of 35 mg/kg per day for 24 weeks. Electrophysiologic studies, pathologic examination of peripheral and central nervous system and skeletal muscle, and biochemical analysis of the sciatic nerve were performed at baseline (electrophysiology only) and after 8, 12, 16, 20, and 24 weeks of treatment.


RESULTS
Neuropathologic changes in peripheral nerves were first evident at 16 weeks and were more pronounced at 20 and 24 weeks; onset of paresis occurred at week 20, whereas clear electrophysiologic deficits were seen only at week 24. Electrophysiologic changes were prolonged F-waves (measure of proximal motor conduction) and minor changes in distal conduction measurements. Pathologic changes included myelin splitting, intramyelinic edema, demyelination, and remyelination of the largest diameter nerve fibers in the ventral root and sciatic nerve. Axonal degeneration and reduction in axonal diameter were seen. Enlarged mitochondria with abnormal ultrastructure were present in Schwann cells of those animals with a myelinopathy. Mitochondrial abnormalities or other signs of degeneration were not seen in neurons of the dorsal root ganglia or in skeletal muscle. Significant changes were not present in myelin protein composition, myelin lipid composition, or activity of the myelin-specific enzyme 2',3'-cyclic nucleotide 3'-phosphohydrolase. Major reductions in levels of protein zero (P0, the homophilic adhesion protein of myelin) were not seen; however, the turnover rate of P0 was reduced as P0 messenger RNA expression in ddC-treated sciatic nerves decreased to 30 to 50% of control values.


CONCLUSIONS
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.
Anderson
T D
TD
Department of Toxicology and Pathology, Hoffmann-La Roche Inc., Nutley, New Jersey.
Davidovich
A
A
Feldman
D
D
Sprinkle
T J
TJ
Arezzo
J
J
Brosnan
C
C
Calderon
R O
RO
Fossom
L H
LH
DeVries
J T
JT
DeVries
G H
GH
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D004594:Electrophysiology; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018993:Myelin P0 Protein; D009185:Myelin Proteins / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D009412:Nerve Fibers / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D009431:Neural Conduction; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010543:Peroneal Nerve / Q000187:drug effects / Q000503:physiopathology; D010743:Phospholipids / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D012016:Reference Values; D012583:Schwann Cells / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D013997:Time Factors; D016047:Zalcitabine / Q000633:toxicity*
D018993:Myelin P0 Protein; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; D010743:Phospholipids; D012333:RNA, Messenger; D016047:Zalcitabine