Metronidazole-Induced Sensorimotor Deficits in Rats Are Associated With Cerebral Cortex-Related Thiamine Dysmetabolism and Ameliorated by High-Dose Thiamine

Background: Metronidazole neurotoxicity is a well-known phenomenon, but the underlying mechanisms remain poorly understood and may be linked to disrupted thiamine metabolism. This study aimed to establish a rat model of metronidazole-induced neuropathology, characterize the associated physiological parameters, including the thiamine status in blood and cerebral cortex, and assess whether thiamine supplementation can correct the impairments. Methods: Dose-response relationships were estimated using oral metronidazole (200 or 400 mg/kg, n = 9 in each group) or saline (n = 10) for 29 days. Other rats were given oral metronidazole (400 mg/kg, n = 16) or saline (n = 16) for 39 days; half of each group additionally received intraperitoneal thiamine (100 mg/kg, n = 8) or saline (n = 8) from day 30 to 39. Sensorimotor function was assessed with the beam walking test, rotarod, and open field; electrocardiogram variability parameters were used for the assessment of autonomic nervous system functions. Thiamine diphosphate (ThDP) in whole blood was measured enzymatically, and thiamine derivatives in the cortex were quantified a week after discontinuation of metronidazole and/or thiamine fluorometrically. Results: Metronidazole at 400 mg/kg increased forelimb errors in the beam walking test on days 17/18 (p = 0.03), also increasing the number of defecation acts in the open field test (p = 0.03), whereas rotarod performance was unchanged. A dose-dependent elevation of blood ThDP levels was observed (p < 0.0001), while the levels of cerebral phosphorylated thiamine derivatives decreased (p < 0.01). Thiamine co-treatment reduced forelimb beam walking errors by 51% in metronidazole-treated rats (p < 0.01), also reducing errors by 43% in controls (p = 0.04). However, thiamine supplementation was ineffective in preventing the long-term blood and cerebral cortex alterations of thiamine pools induced by metronidazole. Conclusions: Metronidazole administration induces sensorimotor deficit and causes a stable reduction in cerebral cortex thiamine phosphates despite elevated blood ThDP. The latter indicates that the neurotoxicity was accompanied by thiamine deficiency in the cerebral cortex, but not in whole blood. High-dose thiamine mitigates the neurological signs, with no long-term effect on the alterations in thiamine pools.