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NETWORK PHARMACOLOGY OF ANNONA CRASSIFLORA ALKALOIDAL FRACTION ON ALZHEIMER’S AND ITS EFFECT ON DROSOPHILA MELANOGASTER MODEL

NETWORK PHARMACOLOGY OF ANNONA CRASSIFLORA ALKALOIDAL FRACTION ON ALZHEIMER’S AND ITS EFFECT ON DROSOPHILA MELANOGASTER MODEL

Heitor Cappato Guerra Silva, Serena Mares Malta, Alice Norberto de Carvalho, Luiz Gabriel Alves Santos, Natieli Saito, Carlos Ueira-Vieira and Foued Salmen Espindola

From an alkaloid fraction already identified in a semi-purification of Annona crassiflora previously, a specific enzymatic inhibition was shown. And to harness the full potential of the alkaloid fraction, a network approach was then used. Thus, this work aims to search possible human targets for these alkaloids, and from the targets found evaluate the effect of the alkaloid fraction on the Alzheimer model and predict its pathways of action. Swisstargetprediction and targetnet platforms were used for predicting targets. After the interaction between these targets was predicted with STRING 11.0, the analysis of the interactions to elucidate potential diseases that may be affected was done with DAVID 6.8 platform. All network preparation was done with Cytoscape 3.8.0 software. One of the predicted diseases was Alzheimer’s and as cholinesterase inhibitors are currently the main treatment for Alzheimer’s, and cholinesterase was a predicted target, I first confirmed that the alkaloid fraction had this activity in an in vitro enzyme assay. With this confirmed, I used the genotype Drosophila melanogaster, which expresses human APP and BACE, generating beta-amyloid, to test the alkaloid fraction by evaluating its motor function intervention with behavioral tests and acetylcholinesterase activity in vivo as well. I observed an improvement in motor behavior and a decrease in acetylcholinesterase activity in vivo and in vitro. After that, we evaluated which other pathways could be affected in drosophila and the impact on Alzheimer’s, we made a network with drosophila targets using the DRSC prediction tool – Integrative Ortholog, and with these new networks, we showed other pathways related to Alzheimer’s, such as inflammation and oxidative stress. To conclude, these results confirmed acetylcholinesterase as a target and showed a perspective of a potential fraction that can participate in distinct pathways, and then be used for further studies for Alzheimer’s.