Sappanone A mitigates cognitive impairment and oxidative stress through modulation of α7 nicotinic acetylcholine receptor in rats with trimethyltin-induced Alzheimer’s disease-like condition

• Cholinergic dysfunction and oxidative stress are strongly linked to cognitive decline in Alzheimer’s disease (AD). • The natural homoisoflavanone sappanone A (SAP) exhibits potent antioxidant properties, but its therapeutic potential in AD remains unexplored. • In the present study, administration of SAP significantly alleviated cognitive deficits in rats with trimethyltin (TMT)-induced AD-like condition. • SAP increased cholinergic neurotransmission by activating the α7 nicotinic acetylcholine receptor (α7nAR) and improving the antioxidant defense in the brain. • We suggest that SAP mitigates TMT-induced oxidative stress through α7nAR modulation, highlighting its potential as a therapeutic agent for AD. Sappanone A (SAP) is a homoisoflavone derived from the Traditional Chinese Medicine Sumu ( Lignum sappan ), the dry heartwood of Caesalpinia sappan L. (Leguminosae). Although SAP possesses strong antioxidant properties, its therapeutic potential in Alzheimer’s disease (AD) remains unexplored. We evaluated the ameliorative effects of SAP on AD-like pathology induced in rats by the neurotoxicant trimethyltin (TMT). Additionally, the involvement of the α7 nicotinic acetylcholine receptor (α7nAR) in the underlying effects of SAP was investigated. Seven days after TMT (8 mg/kg, i.p.) exposure, SAP (25 and 50 mg/kg, oral) was administered for two weeks, and cognitive abilities were screened by the Morris water maze test. The estimation of brain glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and malonaldehyde (MDA) contents was also conducted. Molecular docking studies were carried out to evaluate the binding affinity of SAP towards α7nAR. TMT-treated rats exhibited significant deficits in learning and memory performance. This was accompanied by decreased contents of GSH, CAT, and SOD, and elevated MDA levels in the brain. Administration of SAP significantly improved cognitive performance and restored oxidative stress markers. However, co-administration of α7nAR blocker methyllycaconitine attenuated these actions. Moreover, in-silico molecular docking analysis revealed SAP as a potent agonist of the α7nAR. SAP improved TMT-induced cognitive impairments, mainly due to its strong antioxidant effects in the brain, facilitated through α7nAR modulation. These findings suggest that SAP could serve as a promising candidate for treating cognitive dysfunction linked to oxidative stress.