Avaliação da fração alcaloidal de Annona crassiflora no modelo beta-amiloide de Drosophila melanogaster e investigação de seu mecanismo com base na farmacologia em rede

Abstract

Studies from Annona crassiflora has shown the potential of its metabolites and therapeutic use. One of these metabolites were alkaloids, which have been identified in the A. crassiflora fruit peel and were known for its role in the therapeutics of several neuronal diseases, therefore we aim to investigate these alkaloids using a Drosophila melanogaster model of Alzeheimer disease and an approach of pharmacology in sílico network to harness the full potential of the alkaloid fraction of A. crassiflora. Thus, this work aims to search possible human targets for these alkaloids, and from the found targets, evaluate the effect of the alkaloid fraction treatment on an Alzheimer model using D. melanogaster and predict its mechanism of action. Swisstargetprediction and targetnet platforms were used for predicting targets. After the interaction between these targets, we use STRING 11.0, to predicted the interactions. The elucidation of potential diseases that may be affected was done with DAVID 6.8 platform. One of the predicted diseases was Alzheimer's. Cholinesterase inhibitors are currently the main treatment for Alzheimer's, and AChE was a predicted target for the alkaloidal fraction and, confirmed in vivo an in vitro inhibition of its activity. A genotype of D. melanogaster, which expresses human APP and BACE, leading to the amyloidal pathway, was used to test the alkaloidal fraction by evaluating its motor function intervention with behavioral tests and acetylcholinesterase activity in vivo as well. We observed an improvement in motor behavior and a decrease in acetylcholinesterase activity. After that, we evaluated which mechanism affected D. melanogaster and to access the impact on Alzheimer's, we analyze a network with D. melanogaster ortholog targets using the DRSC prediction tool. Using Integrative Ortholog, and this network, we showed other pathways related to Alzheimer's, such as inflammation, oxidative stress, and cognitive function. These results suggested acetylcholinesterase as a target and showed a prospect of a potential of the A. crassiflora alkaloidal fraction that could participate in distinct pathways, and then used for future studies on Alzheimer's disease.