Metronidazole-induced neurotoxicity: Possible central serotonergic and noradrenergic system involvement

Abstract

Background: Metronidazole is a synthetic 5-nitroimidazole antibiotic. It remains a first-line therapy for anaerobic, parasitic, and bacterial infections in human and veterinary medicine. However, Metronidazole-induced neurotoxicity is a rising challenge. The mechanism of neurotoxicity induction is still unknown. Objective: To investigate a possible interference of metronidazole with central monoaminergic mechanisms using the Forced Swim Test. Methods: sixty adult rats were divided into 10 groups (n=10 for metronidazole and saline, n=5 for other groups). Group 1 = 5 ml/kg normal saline; Group 2 = 50 mg/kg metronidazole; group 3= 15 mg/kg imipramine; Group 4 =15 mg/kg imipramine + 50 mg/kg metronidazole. Group 5 = 5 mg/kg fluoxetine; Group 6 received 5 mg/kg fluoxetine + 50 mg/kg metronidazole; Group 7 = labetalol 10 mg/kg; Groups 8, 9 and 10 received labetalol 10 mg/kg + 50 mg/kg metronidazole, PCPA (p-chlorophenylalanine) 100 mg/kg and PCPA 100 mg/kg + 50 mg/kg metronidazole daily X 28 days. On day 28, FST was done 1h after the respective treatments. On day 29, blood samples were collected under halothane anesthesia for hematological assessment. Results: Immobility time increased (P<0.01) in the groups treated with metronidazole, labetalol, PCPA, labetalol + metronidazole, and PCPA+ metronidazole. Swimming was reduced by metronidazole, PCPA, metronidazole + PCPA and metronidazole + labetalol. Metronidazole + labetalol reduced climbing. These effects were not reduced by co-treatment with imipramine or fluoxetine. White blood cell count increased (p<0.01) in all treatment groups. Lymphocyte percent increased in the metronidazole-treated groups. Conclusion: Interference with postsynaptic central monoaminergic neurotransmission and immunomodulation may contribute to metronidazole-induced neurotoxicity.