Pizotifen

Syzygium cumini L. Skeels, commonly known as jamelão, is a fruit with high nutraceutical value and reported medicinal properties, including neuropharmacological potential. This study evaluated the anxiolytic effects and safety profile of S. cumini fruit ethanolic/methanolic extract (EMEScF) in adult zebrafish (Danio rerio), aZF, a well-established animal model for behavioral neuroscience due to its genetic and physiological similarities to mammals. No signs of toxicity or mortality at extract concentrations up to 1.0 mg/mL over 96 h in acute toxicity assays. Behavioral assessments using the Open Field Test and Light & Dark Test demonstrated that the extract induced anxiolytic-like effects without sedation, contrasting with diazepam's sedative profile. Further pharmacological analyses using serotonergic antagonists cyproheptadine, pizotifen, and granisetron attenuated the anxiolytic effects, implicating 5-HT_1B, 5-HT_2A/2C, and 5-HT_3A/3B receptors in the extract's mechanism of action. Additionally, flumazenil prevented anxiolytic-like effects, suggesting involvement of the GABA_A receptor. Molecular docking studies supported these findings, showing strong binding affinities of major anthocyanins, such as delphinidin, malvidin, and petunidin to serotonergic and GABAergic receptor models, with petunidin displaying the highest stability and affinity. In an alcohol withdrawal-induced anxiety-like model, EMEScF effectively reduced anxiety-like behaviors, comparable to diazepam. These results indicate that EMEScF exerts anxiolytic-like effects mediated by serotonergic and GABAergic systems, without motor impairment or toxicity, positioning it as a promising natural alternative for anxiety treatment.