Objective:The study was designed to assess the beneficial role of mangiferin (MGN) in lead (Pb)-induced neurological damages in the activation of Nrf2-goved enzymes,genes and proteins.Methods:A total of 96 weaned Wistar rats (48 males and 48 females,26-to 27-day-old),weighing 50-80 g were used.The experiment was performed in six groups:normal group (control,n =16),model group (chronic Pb exposed,n =16),Dimercaptosuccinic acid (DMSA)-treated group (positive control,Pb + DMSA,n =16),three MGN-treated groups with different doses (Pb + MGN,n =48).Normal group freely had access to purified water.DMSA-treated group was given DMSA,which was clinically used as the standard treatment for moderate Pb poisoning,at 50 mg/kg (2 mL suspension with purified water)by intragastric gavage (ig) 4 continual days a week for 4 weeks,MGN-treated groups were given MGN at 50,100,or 200 mg/kg (2 mL suspension with purified water) by ig daily for 4 weeks.At the end of the treatment,all rats were sacrificed and the brain samples were collected.The haematoxylin and eosin (H&E) staining was used for observation of histopathology.Commercial kit,real-time quantitative polymerase chain reaction (RT-qPCR),West-blot and immunohistochemistry (IHC) detection were used to detect the mRNA and protein expression.Results:Eight weeks exposure to Pb-containing water resulted in pathological alterations,anti-oxidative system disorder in the brain,all of which were blocked by MGN in a Nrf2-dependent manner.Nrf2 downstream enzymes such as HO-1,NQO1,y-GCS were activated.Nrf2,GCLC,GCLM,HO-1 mRNA and total Nrf2,Nuclear Nrf2,y-GCS,HO-1 protein expression were affected too.Conclusion:MGN ameliorated morphological damage in the hippocampus.Its neuroprotective effects were achieved by the activation of the Nrf2 downstream genes.The data from this in vitro study indicates that MGN targeting Nrf2 activation is a feasible approach to reduce adverse health effects associated with Pb exposure.Thus,MGN could be an effective candidate agent for the Pb-induced oxidative stress and neurotoxicity in the human body.