Misonidazole neurotoxicity in the mouse: evaluation of functional, pharmacokinetic, electrophysiologic and morphologic parameters

Journal Article · Sun Jul 01 04:00:00 EDT 1979 · Int. J. Radiat. Oncol., Biol. Phys.; (United States)

DOI:https://doi.org/10.1016/0360-3016(79)90604-7· OSTI ID:6882572

Conroy, P J; Von Burg, R; Passalacqua, W; Penney, D P; Sutherland, R M

The neurotoxic effects of chronic administration of misonidazole (0.3 mg/g/day, 5 times weekly) were investigated in Balb/cKa mice over 12 weeks; a variety of measurements were used, including functional and clinical performance, morphologic, electrophysiologic and pharmacokinetic parameters. The half life of drug for a single dose was greater in brain (3 hrs) compared to serum (1.2 hrs); these values decreased to 1.9 hrs and 1.0 hrs respectively after 3 weeks. Misonidazole induced a peripheral lesion after three weeks with a total administered dose of 13.5 g/m/sup 2/ or exposure dose of 57 to 75 mM X hrs, which is similar to the doses that cause neuropathy in humans. There was some suggestion of a central neurological deficit related to locomotor control and balance; however, no gross morphological damage was found in the brain. The sequence of effects demonstrated began at 3 to 4 weeks and included: 1) morphologic damage to peripheral nerves; 2) hyperactivity and listlessness; 3) a decrease in rotarod retention time which reached a value 50% of that of saline injected control mice at 8 to 10 weeks; 4) walking on tip-toes with a slightly hunched back (4 to 6 weeks); and 5) an increase in hind foot splay (6 to 7 weeks). The morphologic damage primarily involved the more distal portions of the nerves supplying the interosseous muscles and footpads of the hind limbs. The damage was more severe and progressed more rapidly with time in these distal areas compared to the more proximal regions of the nerves. No marked changes were found in nerve conduction velocity although neuropathy produced by acrylamide produced significant decreases. The changes in neurological parameters reported here may be useful in the further evaluation of hypoxic cell radiosensitizers.

• Research Organization: Univ. of Rochester, NY
• OSTI ID: 6882572
• Journal Information: Int. J. Radiat. Oncol., Biol. Phys.; (United States), Journal Name: Int. J. Radiat. Oncol., Biol. Phys.; (United States) Vol. 5:7; ISSN IOBPD
• Country of Publication: United States
• Language: English

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550603* -- Medicine-- External Radiation in Therapy-- (1980-)
560152 -- Radiation Effects on Animals-- Animals
62 RADIOLOGY AND NUCLEAR MEDICINE
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
ANOXIA
ANTIBIOTICS
AZOLES
BODY
BRAIN
CENTRAL NERVOUS SYSTEM
DOSE-RESPONSE RELATIONSHIPS
DOSES
DRUGS
HETEROCYCLIC COMPOUNDS
IMIDAZOLES
MAMMALS
MEDICINE
MICE
MORPHOLOGICAL CHANGES
NERVES
NERVOUS SYSTEM
NEUROLOGY
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PHARMACOLOGY
RADIOSENSITIVITY EFFECTS
REFLEXES
RODENTS
SENSITIVITY
TOXICITY
VERTEBRATES