NEUROTOXICITY OF MISONIDAZOLE IN RATS FOLLOWING INTRAVENOUS ADMINISTRATION

Misonidazole is a hypoxic cell radiosensitizer that induces a peripher al neuropathy in humans after exceeding a schedule-dependent cumulativ e threshold dose. Clinical studies of misonidazole have been conducted using oral administration, whereas most other radiosensitizers have b een administered intravenously. Since route of exposure can potentiall y influence the toxicity of xenobiotics, the objective of this study w as to assess the neurotoxicity of misonidazole in rats following intra venous dosing using a battery of routine clinical, neurofunctional, bi ochemical, and histopathologic screening methods. Male Sprague-Dawley rats were administered intravenous doses of misonidazole at 0 (vehicle control), 100, 200, 300, or 400 mg kg(-1) once per day, 5 days per we ek, for 2 weeks. Animals were evaluated for neurofunctional and pathol ogical changes following termination of treatment (Days 15-17) and at the end of a 4 week observation period (Days 43-45). During the dosing phase, hypoactivity, salivation, rhinorrhea, chromodacryorrhea, rough pelage and ataxia were observed at 400 mg kg(-1), and body weight gai n of the 300 and 400 mg kg(-1) groups was significantly decreased rela tive to the vehicle controls. by 24% and 49%, respectively. Correspond ing reductions in food consumption were 8% and 23%, respectively. Alth ough most 400 mg kg(-1) animals appeared normal on Day 15 prior to the neurofunctional evaluations, rotorod testing precipitated a number of clinical signs including: ataxia, impaired righting reflex, excessive rearing, tremors, vocalization, circling, head jerking, excessive sni ffing and hyperactivity. All of these animals recovered and appeared n ormal from Day 17 through study termination. There were no treatment-r elated effects on motor activity, acoustic startle response, rotorod p erformance, forelimb group strength, toe and tail pinch reflexes, tibi al nerve beta-glucuronidase activity or tail nerve conduction velocity . Although hindlimb grip strength of the 400 mg kg(-1) group was signi ficantly decreased by 17% relative to the vehicle controls on Day 15, this finding appeared related to the reduced food consumption and body weight gain in these animals. No microscopic changes were detected in peripheral nerves. Necrosis and proliferation of fibrillary astrocyte s (gliosis) were seen in the cerebellum and medulla of the 400 mg kg(- 1) animals on Day 16. Gliosis in these same brain regions was observed in the 300 and 400 mg kg(-1) groups on Day 44. The results show that intravenous administration of misonidazole to rats causes dose-limitin g central nervous system toxicity without effects on peripheral nervou s tissue. The lack of peripheral neurotoxicity was most likely due to a combination of several interrelated factors including route of admin istration, duration and intensity of the dosing regimen, and total cum ulative dose. (C) 1996 The Italian Pharmacological Society