This study reports the protective role of the aqueous extract of Syzygium aromaticum (ESA) against lead (Pb)-induced neurotoxicity in mice. Thirty male mice weighing between 18 g and 25 g were randomly divided into five groups. (1) Group 1 (control group), (2) group 2 (Pb-test group): was administered with a solution containing 0.1% (w/v) of lead acetate (PbAc), (3) group 3 (ESA + Pb100 group): was administered with 0.1% (w/v) of PbAc followed by 100 mg/kg of S. aromaticum extract by gavage, (4) group 4 (ESA + Pb200): was administered with 0.1% (w/v) of PbAc followed by 200 mg/kg of S. aromaticum extract, and (5) group 5 (ESA-group): was administered with 100 mg/kg of S. aromaticum. Level of lead was determined by atomic absorption spectroscopy. Cerebral cortex synaptosomes prepared from mice administered orally with lead-acetate shown a significantly increased (p < .05) in tyrosine hydroxylase and protein carbonyl level and significantly decreased (p < .05) superoxide dismutase, glutathione reductase, and glutathione transferase activities. Also, there was a significant increase in brain lead concentration level, however, it was observed that S. aromaticum significantly reduced (p < .05) the level of lead at all tested doses. S. aromaticum rescued cerebral cortex synaptosomes from lead-induced neurotoxicity by relieving oxidative stress and abating elevated tyrosine hydroxylase activity. Moreover, S. aromaticum at the different dose grade (100 mg and 200 mg) abrogated the loss of motor performance in mice groups induced with lead. Altogether, our findings showed that S. aromaticum possesses antioxidant and neuro-modulatory potential against lead-induced neuronal damage. PRACTICAL APPLICATIONS: Environmental pollution with heavy metals is a known public health concern and their incremental concentrations in soil and water have risen to an unprecedented degree. Lead is one of the top 10 contaminants on the WHO's list of substances of greatest public health concern that impact the brain. However, exogenous natural bioactive supplements molecules could be one of the remedies to reduce Pb-induced toxicity. Our findings indicate therefore that, S. aromaticum could be a good fit for lowering Pb neurotoxicity and could be suggested as a neuroprotective molecule against neurodegenerative diseases involving catecholaminergic dysfunction induced by metallic elements.

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