Mercury-induced neurotoxicity in rat: in vivo and in silico studies of thymoquinone modulatory effect via oxidative stress and inflammation, HO-1/NRF/Trx/Trx-R trajectories

Mercury exposure has been associated with the onset of neurodegenerative disorders via mechanisms that include oxidative stress, inflammation, and apoptosis. Thymoquinone (TQ) has been documented to possess antioxidant, anti-inflammatory, and apoptotic modulatory effects. We assessed TQ's neuroprotective potential against mercuric chloride (HgCl₂) induced neurotoxicity in rats. Experimental groups included: Control; HgCl₂ alone (20 µg/mL); TQ alone (5 mg/kg); and co-administration of HgCl₂ with TQ at doses of 2.5 or 5 mg/kg over a period of 28 days. Behavioural changes were evaluated on days 27 and 28 using the open field, negative geotaxis, and forelimb grip tests. Subsequently, oxidative stress, lipid peroxidation, inflammation, and apoptosis were measured in the cerebral and cerebellar cortices; histology and histomorphometry were also performed. Alone, HgCl₂ reduced locomotor and exploratory activity and induced anxiety-like behaviour. Co-treatment with TQ significantly (p < 0.05) improved these behaviours. HgCl₂ decreased (p < 0.05) cerebral and cerebellar antioxidant levels while increasing (p < 0.05) oxidative/nitrosative stress. TQ co-treatment increased antioxidant activities and dose-dependently reduced (p < 0.05) pro-oxidant levels. TQ co-treatment reversed (p < 0.05) the HgCl₂-induced changes in inflammatory, pro-apoptotic, and anti-inflammatory biomarkers. Histomorphometry revealed that TQ reduced (p < 0.05) HgCl₂-induced neuronal pyknosis and loss of pyramidal and Purkinje cells. TQ interacts with PPAR-γ (Molecular docking Score: 1.65 × 10⁻⁵ M), enhances Nrf-2/HO-1 antioxidant signalling and downregulates NF-κB inflammatory pathways. TQ protects against HgCl₂-induced neuronal toxicity by boosting antioxidant defences, reducing oxidative and inflammatory stress through Nrf-2/HO-1 and NF-κB pathways, and involving PPAR-γ signalling.