Ultrastructural studies on the pathological effects of nitroimidazole compounds on peripheral nerve fibers
Description
Misonidazole (MIS) is a 2-nitroimidazole compound that is being evaluated clinically as a radiosensitizer of hypoxic tumor cells at radiotherapy centers throughout the world. However, therapeutic doses of the drug cause dose-related peripheral neuropathy, ototoxicity and convulsions. The purpose of this study was to study the pathology of MIS neuropathy experimentally, and to test other 2-nitroimidazoles for toxicity to peripheral nerve fibers Mice (C57BL/6J) were given daily IP injections (0.5 mg/g) of either MIS, desmethylmisonidazole (DMM), S-193, or saline. Routine electron microscopy of the plantar nerves indicated that no pathological changes were caused by either DMM or S-193 for up to 35 days. However, MIS caused degenerative changes in Schwann cells, disruption of myelin sheaths, and degeneration of myelinated as well as unmyelinated axons after 21 days of treatment. Approximately 5-8% of all myelin-forming Schwann cells contained large lamellar globular inclusions. Severe disruptions of myelin sheaths were observed in (TURN)10% of all nerve fibers. Approximately 5-8% of all myelinated axons showed degenerative changes. Degeneration of myelinated axons was indicated by the displacement of normal axoplasmic components by dense bodies, vacuoles, multivesicular bodies and myelin whorls. The frequency of MIS-induced unmyelinated fiber degeneration, as evidenced by extreme swelling and loss of organelles, was (TURN)2-4%. Concurrent administration of phenytoin (0.04 mg/g) prevented MIS-induced degeneration of peripheral nerve fibers In MIS-treated animals, acid phosphatase (APase) activity was localized in the axoplasm of unmyelinated nerve fibers. The presence of APase activity was observed prior to degenerative changes in the nerve fibers. APase activity was not associated with degenerating myelin sheaths Focal accumulations of axonal mitochondria were observed in the nerve fibers of MIS-treated animals. The volume density ratio (VDR) of mitochondria to axoplasm was determined by differential point counting. After 35 days of treatment, the VDR's in mice given either saline (2.74 (+OR-) 0.25), DMM (2.53 (+OR-) 0.22), S-193 (2.40 (+OR-) 0.12), MIS/phenytoin (2.39 (+OR-) 0.11) or phenytoin (2.54 (+OR-) 0.25) did not differ significantly (p > 0.50; analysis of variance). However, the VDR of mice given MIS for 35 days was 5.04 ((+OR-) 0.25) and significantly different from all other groups (p 0.05) The data from this study indicate that (1) misonidazole is directly toxic to Schwann cells and axons of peripheral nerves, but the occurrence of these changes is relatively infrequent, (2) the focal accumulation of axonal mitochondria may be an early symptom of axonal degeneration which can be quantitated, (3) acid phosphatase is associated with misonidazole-induced degeneration of unmyelinated axons in peripheral nerves, (4) concurrent phenytoin administration prevents misonidazole-induced pathological changes in peripheral nerve fibers, and (5) desmethyl-misonidazole and S-193 are 2-nitroimidazoles significantly less neurotoxic than misonidazole, and thus possibly more suitable for clinical use