A biochemical neurotoxicity study relating the neurotoxic potential of metronidazole and nitrofurantoin with misonidazole

Abstract

The neurotoxic potential of metronidazole and nitrofurantoin was studied using a biochemical approach which involved the fluoriimetric measurement of β-glucuronidase and β-galactosidase in homogenates of rat nervous tissue e.g. (distal and proximal sections of sciatic/ posterior tibial nerve (SPTN) and trigeminal ganglia (TG)). An increase in the activity of these enzymes was taken as indicative of degenerative changes. Groups of 5–8 Wistar rats were dosed on 7 consecutive clays as follows[pthree groups received metronidazole 400 and 800 mg/kg or misonidazole 400 mg/kg i.p. and were analyzed for biochemical evidence of nerve damage 4 weeks after the start of dosing. Eight groups which received nitrofurantoin 100 or 200 mg/kg i.p. were analyzed 2, 3, 4 and 6 weeks after the start of dosing. Four further groups (vehicle control) which received 2 ml/kg dimethylsulphoxide were examined at each of the 4 analysis times. Metronidazole 400 and 800 mg/kg produced significant enzyme increases in the distal section of the SPTN (124–148% of control values). No significant enzyme changes were found in the SPTN proximal section. Significant enzyme increases were found in the TG of rats administered 7 × 800 mg/kg metronidazole. Eighteen of the 20 rats which received 7 x 200 mg/kg nitrofurantoin died, whereas no deaths occurred in the 7 × 100 mg/kg dose group. In the 7 × 100 mg/kg nitrofurantoin dose group, maximum enzyme increases in the SPTN occurred at weeks 3 and 4 (122–157% of control values), the highest increases being in the distal section of the nerve. Significant enzyme increases (130% of control values) were found in the TG from these rats. Misonidazole 7 × 400 mg/kg produced similar enzyme increases in the distal SPTN (<150% of control values) to those previously reported. It may, therefore, be concluded that both metronidazole and nitrofurantoin produce biochemical changes that are similar in magnitude to those produced by misonidazole and are consistent with mild peripheral nerve damage.