Avaliação in vitro dos efeitos anticolinesterásico e neuroprotetor de compostos isolados de Annona Muricata

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease with a major socioeconomicimpact,mainly affecting the elderly population. Available drugs have many adverse reactionsandhigh treatment costs. The study of bioactive natural products favors the discoveryofcompounds used as drug matrices, with the Annonaceae family being promisingduetoitschemical composition and distribution in the national territory. This work was dividedintotwo chapters. The first chapter reviews the literature on species and phytocompounds oftheAnnonaceae family that act on the central nervous system, with the aimof identifyingthemain species and their bioactive compounds. Knowledge of these activities contributestotheexploration of the pharmacological potential of this family. The second chapter aimedtoevaluate in vitro and in silico the anticholinesterase activity and neuroprotectionofcompounds isolated from the species Annona muricata. The structural determinationof thesenatural products was performed by analyzing the spectra obtained by mass spectrometry(ESI-MS) and one- and two-dimensional Nuclear Magnetic Resonance (1Dand 2DNMR),allowing the elucidation of the structure of 22,23-dihydropolyprenol-10 (1) and its esterifiedderivative (2). In vitro assays evaluated polyprenols 1 and 2 against the inhibitionofacetylcholinesterase and butyrylcholinesterase, cytotoxicity in PC12 cells andtheneuroprotective effect in an inflammatory damage model with Escherichiacolilipopolysaccharide (LPS, 5 μg/mL) in differentiated PC12 cells. Polyprenol 1 showedlowactivity (36%) for acetylcholinesterase, while 2 showed high selectivity for the inhibitionofthis enzyme (82%). The results obtained with the cell viability test demonstratedthatpolyprenol 1 was not toxic to PC12 cells at any of the concentrations tested (0.3 to200μM)and polyprenol 2 was toxic at concentrations higher than 10 μM. At lowconcentrations(0.3μM), both compounds attenuated the effects of LPS exposure on differentiated PC12cells.The interaction of polyprenols with the acetylcholinesterase enzyme was evaluatedbymolecular docking assay and polyprenol 2 showed important in silico interactions withtheenzyme. This work allowed the structural elucidation of two new 22,23-dihydroprenolsandprovided evidence of anticholinesterase activity and protection against LPS-induceddamagein PC12 cells