ABSTRACT
Metronidazole, an old warhorse in treatment of anaerobic, parasitic as well as bacterial infections
in human and veterinary medicine has been observed to have neurotoxic adverse effects. Reports
of metronidazole-induced neurotoxicity are increasing on a daily basis but the mechanisms
involved are not clear. Increasing the knowledge on existing mechanisms and unravelling new
mechanisms responsible for metronidazole-induced neurotoxicity is necessary. This study was
aimed at determining the mechanism(s) of metronidazole-induced neurotoxicity in rats and SH
SY-5Y cells.
Depression-like effect of metronidazole was evaluated in adult rats grouped as follows: Group 1:
5 ml/kg of 0.5% Tween-80®; Group 2: 50 mg/kg of metronidazole; Group 3: 15 mg/kg of
imipramine; Group 4: 15 mg/kg of imipramine and 50 mg/kg of metronidazole; Group 5: 5 mg/kg
of fluoxetine; Group 6: 5 mg/kg of fluoxetine and 50 mg/kg of metronidazole; Group 7: 10 mg/kg
of labetalol; Group 8: 10 mg/kg of labetalol and 50 mg/kg of metronidazole; Group 9: 100 mg/kg
of para-chlorophenylalanine (PCPA); Group10: 100 mg/kg of PCPA and 50 mg/kg of
metronidazole. The effects of metronidazole on learning and memory were evaluated using the
following groups of rats: Group 1: 5 ml/kg of 0.5% Tween-80®; Group 2: 50 mg/kg of
metronidazole; Group 3: 1 mg/kg of risperidone; Group 4: 50 mg/kg of metronidazole + 1 mg/kg
of risperidone. For toxicological and antioxidant evaluations, rats were orally treated daily with
metronidazole (50 mg/kg) or 5 ml/kg of 0.5% Tween-80® for 14 or 28 days. SH-SY-5Y
neuroblastoma cells were treated with 1, 10, 25, 50, 100, 250 µM concentrations of metronidazole
and DMSO or culture media was used as control. Viability and effect of metronidazole on iron
uptake were evaluated in the treated cells.
Metronidazole increased the immobility time, reduced swimming and climbing activities in the
treated groups which were not reversed by co-treatment with either fluoxetine or imipramine
(P<0.01). Metronidazole impaired memory acquisition and learning, and reduced reference
memory index (RMI) on the hole board, increased the escape latency in the Moris water maze, and
reduced percentage alternation and spatial recognition memory in the Y-maze. Co-administration
of metronidazole with risperidone reversed all the memory and learning effects. White blood cell
counts and lymphocyte (%) were increased by metronidazole compared to control (P<0.05).
Histological distortions, hemorrhage in the granular layer, loss of Purkinje fibres and congestion
occurred in the Purkinje layer and over expression of neuron specific enolase was seen in the
xviiicerebellum of metronidazole treated rats. Reduced superoxide dismutase activity, increased
malondialdehyde (brain homogenate) and reduced serum brain derived neurotrophic factor
concentrations were recorded in metronidazole treated rats. Several histological distortions were
also seen in the liver and kidneys of treated rats. Metronidazole reduced viability and induced iron
overload in SH-SY-5Y cells. It is concluded that metronidazole induces depression-like behavior
and impairs cognitive function in rats. Increased oxidative stress, iron overload, reduced cell
viability and reduction in BDNF concentrations are contributing mechanisms of metronidazole
induced neurotoxicity
