Therapeutic Potential of Quercetin in the Treatment of Alzheimer’s Disease: In Silico, In Vitro and In Vivo Approach

Background: The pathophysiology of Alzheimer’s disease (AD) is strongly linked to damage to the cholinergic systems of the central nervous system (CNS), mainly due to the formation of β-amyloid peptide plaques, which trigger intense inflammatory responses and are currently the main cause of the symptoms of the disease. Among the therapeutic strategies under investigation, classes of natural products with immunomodulatory properties, action on the CNS, and potent antioxidant activity, which contribute to neuroprotection, stand out. Methods: We aimed to evaluate the flavonoid quercetin using in silico, in vitro, and in vivo methods for the treatment of AD. Initially, the compounds were selected, and molecular dynamics simulations were performed. The in vitro assays included tests of antioxidant activity (DPPH), enzymatic inhibition of acetylcholinesterase (AChE), and prediction of oral toxicity. The in vivo studies investigated the effects on scopolamine-induced learning deficits and conducted histopathological analysis of the brain. Results: Quercetin showed structural stability in the complex with (AChE), with no significant alterations in the Root Mean Square Deviation (RMSD), SASA and radius of gyration (Rg) parameters. Through the same method it was possible to predict stability between the quercetin and inducible nitric oxide synthase (iNOS) complex, a possible mechanism for quercetin immunomodulation in the CNS. In the AChE inhibition test, the IC50 obtained for quercetin was 59.15 μg mL−1, while in the antioxidant test with DPPH, the concentration of 33.1 µM exhibited 50% of the scavenging of reactive oxygen species. This corroborates the perspective of quercetin having neuroprotective activity. This activity was also corroborated in vivo, in a zebrafish model, in which quercetin reduced the cognitive deficit induced by scopolamine. Histopathological analysis revealed its ability to prevent atrophy, caused by scopolamine, in the nervous tissue of animals, reinforcing the potential of quercetin as a neuroprotective agent. Conclusions: The results of the tests carried out with quercetin suggest that this molecule has antioxidant, AChE inhibitory, and neuroprotective activities, making it a good candidate for use in future clinical trials to ensure its efficacy and safety.