Melatonin Protects Against Titanium Oxide-Induced Neurotoxicity: Neurochemical, Neurobehavioral, and Histopathological Evidences.

titania (titanium dioxide, TiO) is known to induce neurotoxicity and CNS dysfunctions. Numerous studies have explored the neuroprotective effects of melatonin against neurotoxicity. This study evaluates the potential of melatonin to protect against titania-induced neurotoxicity and the role of the Keap1/Nrf2/ARE signaling pathway. One group of animals were treated with Titania (0.045 and 0.075 g/rat) alone while the other with added melatonin (1 mg/kg and 3 mg/kg) and behavioral alterations were assessed using OFT (open field test). Neurochemical and histopathological changes were also studied in the hippocampus by analyzing kelch ECH associating protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), and antioxidant response element (ARE). It was seen that the animals with added Melatonin had improved behavioral scores in the OFT, like anxiety and motor dysfunction triggered by TiO. Melatonin also reduced lipid peroxidation, ROS, GSSG, IL1β, TNFα, Bax, and Keap1 levels, but boosted GSH, GPx, GR, SOD,IL10,IL4, Bcl2, Nrf2, and ARE levels and improved quadruple mitochondrial enzyme complex activity in titania-treated animals. Histopathological examination showed melatonin induced cytoprotection against vacuolization and necrosis in granular cells of DG and pyramidal cells of CA1 area of the hippocampus. In our study, pretreatment with melatonin reduced titania-induced neurotoxicity in the hippocampus through a mechanism potentially mediated by the Keap-1/Nrf2/ARE pathway.