BACKGROUND: Memory loss and cognitive decline are prominent symptoms of various neurodegenerative diseases, impacting daily activities and posing a significant burden on healthcare systems. The study aimed to explore the effect of barbigerone against LPS-induced memory impairment in rats and may offer novel therapeutics for neurodegenerative diseases. METHODS: A total of 30 male Wistar rats were utilized and subsequently divided into five distinct experimental groups: group I received saline water as a control, group II- received LPS, group III - received LPS, and barbigerone (10 mg/kg/p.o.), group IV- received LPS and a higher dose of barbigerone (20 mg/kg/p.o.), and group V -barbigerone alone (20 mg/kg/p.o.). Behavioural test was performed through the Morris water maze and Y-maze test. Biochemical markers such as oxidative, proinflammatory, apoptotic, and further molecular docking and simulations elucidate the mechanisms of barbigerone effects. RESULTS: Barbigerone significantly improved the learning capacity of rats in both the MWM and Ymaze tests, indicating enhanced memory and reduced latency times. Furthermore, barbigerone exhibited beneficial effects on oxidative stress and inflammation markers, suggesting its potential to protect against neuronal damage and promote cognitive function. Based on molecular docking, barbigerone showed a greater binding affinity with different intermolecular interactions
among them, NF-KB (ISVC) had the most potent interaction. Molecular dynamics simulations were performed to assess the stability and convergence of complexes formed by Barbigerone with 1NME_ Barbigerone, 1SVC_Barbigerone, and 4AQ3 4AQ3_Barbigerone. CONCLUSION: These findings demonstrate that barbigerone possesses neuronal protective effects against LPS-induced memory deficits in rats by restoring endogenous antioxidant and pro-inflammatory cytokines.