Bioassay-Guided Fractionation of Annona macroprophyllata Seeds to Evaluate Their Anxiolytic and Toxicological Effects.

The genus Annona is scarcely investigated for its neuropharmacological and toxicological activities, especially regarding its seeds. To explore the effects on the central nervous system (CNS) and the acute toxicity (LD50) of the polar extracts and fractions obtained from the A. macroprophyllata seeds, their potential as a possible source of anxiolytic drugs was evaluated. After determining LD50, one or two doses were selected to evaluate the neuronal activity using electrocorticographic (ECoG) recordings, and the anxiolytic-like behavior in mice treated with the crude extracts or some of their fractions was assessed in the experimental models of anxiety, such as the open-field, hole-board, and plus-maze tests. Phytochemical analysis was carried out to identify the most abundant constituents, whose possible mechanism of action was also evaluated by in silico analysis. Results showed CNS depressant activity associated with an anxiolytic-like behavior, in which cherimolacyclopeptide D and squamins C and D were identified. According to a docking analysis, the inhibitory receptors GABAA and 5-HT1A of serotonin are possible mechanisms of action involved in the anxiolytic-like effects of these cyclopeptides, which, in conclusion, might be potential molecules for anxiety therapy.