Santonin Attenuates Alzheimer’s-Like Pathology via Multitarget Modulation of the NLRP3 Inflammasome, BDNF Signaling, and Amyloidogenic Pathways: An Integrated Experimental and Computational Study

Alzheimer’s disease (AD) is a neurodegenerative disorder and the predominant cause of dementia, characterized by amyloid β (Aβ) plaques and tau tangles that disrupt neurons in memory-related brain regions. This study explores the therapeutic potential of santonin using integrated in silico, in vitro, and in vivo approaches. Molecular docking identified santonin as a promising acetylcholinesterase, NOD-like receptor family, pyrin domain-containing 3 (NLRP3), brain-derived neurotrophic factor (BDNF), and nuclear factor kappa B (NF-κB) ligand with significant binding affinities and supportive interaction scores supported by molecular dynamics simulations with significant multitarget therapeutic relevance. In vitro assays demonstrated that santonin has measurable inhibition of cholinesterase enzymes, showing significant effects on butyrylcholinesterase and acetylcholinesterase enzymes. Behavioral analysis revealed that santonin produced dose-dependent improvements in memory and exploratory behaviors, indicating significant neuroprotective effects against streptozotocin (STZ)-induced impairments. Histological analysis showed that santonin preserved neuronal architecture, enhanced neuronal density, and reduced Aβ deposition in STZ-treated brains using hematoxylin and eosin, Congo red, and Nissl analysis. These effects were evident in the cortical and hippocampal regions. Santonin exhibited strong antioxidant effects, mitigating induced enzyme depletion and oxidative marker elevation. Santonin effectively mitigated STZ-induced Aβ buildup and provided protective effects. Santonin modulated marker expression in STZ-treated brains by reducing the amyloid precursor protein, Tau, toll-like receptor 4, NLRP3, discs large MAGUK scaffold protein 4, and BDNF. Santonin reduces neuroinflammation and neurotrophic signaling in the early stages of AD, which suggests that it may be used as a treatment. However, more research is needed to confirm its effectiveness.