Unraveling therapeutic potential of curcuminoids in anxiety, seizure, and cognitive impairment in a zebrafish model

Abstract Curcuminoid derivatives have emerged as promising scaffolds for the development of neuroactive compounds, and in this study their safety and neurobehavioral effects were investigated through complementary in vitro, in vivo, and in silico approaches. Cytotoxicity was assessed in PC12 cells, while acute toxicity and neurobehavioral outcomes were evaluated in adult zebrafish, with selected derivatives further examined in behavioral models of anxiety, PTZ-induced seizures, and ethanol-induced memory impairment; flumazenil was used to probe GABAergic involvement, and molecular docking was performed. Curcuminoids bearing dimethylamino and methoxy groups showed no cytotoxicity at tested concentrations, no mortality occurred in zebrafish during 96 h of exposure, all compounds exhibited anxiolytic-like effects, and notably the effects of derivatives with ethoxy, thiophene, and dimethylammonium substituents were attenuated by flumazenil, suggesting participation of a flumazenil-sensitive GABA A related pathway; the thiophene-bearing curcuminoid delayed PTZ-induced seizure behaviors, while ethoxy and dimethylammonium derivatives attenuated ethanol-induced memory impairment. Docking studies indicated favorable interactions with benzodiazepine-binding regions of the GABA A receptor, altogether providing preliminary evidence that selected curcuminoid derivatives possess neuroactive properties and supporting further investigation into their pharmacological safety and therapeutic potential.