Imperatorin as an activator of Nrf2/ARE in mercury-induced brain damage based on rat model study, molecular docking, and molecular simulation approaches.

Mercury is a well-known toxicant and found to increase the production of reactive oxygen species (ROS) thereby leading to oxidative stress and cellular damage. The brain being the oxygen metabolizing organ is extremely sensitive to oxidative damage produced by mercury because of its relatively lower levels of antioxidant mechanisms resulting in brain damage/cerebrotoxicity. The increase in ROS levels may lead to increased oxidative stress, mitochondrial damage, and inflammatory responses resulting in aging, and neurodegenerative and neuropsychiatric diseases. Nrf2 is a key transcriptional factor that induces the expression of various antioxidants and detoxifying enzymes thereby protecting against oxidative stress. Imperatorin is an active natural furanocoumarin compound extracted from Qianghuo, and Angelica having many biological properties such as antioxidant, anti-inflammatory, and anticancer and acts as calcium channel blockers. This study explores the role of imperatorin against mercury-induced oxidative damage in the brain through the activation of the Nrf2-signaling pathway. Rat models were treated with mercury chloride and imperatorin, and the tissue morphology, lipid-peroxidation, antioxidant, acetylcholinesterase, and corticotropin releasing hormone levels were analyzed to confirm the treatment effects. The potential effects of imperatorin on Nrf2 signaling were analyzed through molecular docking studies using Fangchinoline and 1VV as controls in Autodock vina and visualized in Biovia Discovery studio, followed by ADME analysis in SwissADME. The results were validated using molecular dynamic simulation using GROMACS. The histopathology, antioxidant, and lipid peroxidation results showed its ability to activate the Nrf2 pathway and increase antioxidant levels in the mercury chloride-treated group evidenced by elevated antioxidant levels. The binding affinity score of Imperatorin (- 8.2) < Fangchinoline (- 9.1) < 1VV (- 10.9) indicates lesser binding affinity of Imperatorin; however, MM-PBSA showed Imperatorin had better binding energy compared to Fangchinoline. ADME results showed that imperatorin showed 0 Lipinski violation, the ability to cross the blood-brain barrier, and lower synthetic accessibility, serving as a potential drug of interest compared to the controls. The protective mechanism of imperatorin arises from its antioxidant, anti-inflammatory, and antiapoptotic properties.