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Numerous previous studies reported that ferulic acid exerts anxiolytic activity. However, the mechanisms have yet to be elucidated. The current study aimed to investigate the anxiolytic effect of trans-ferulic acid (TFA), a stereoisomer of ferulic acid, and evaluated its underlying mechanism using in vivo and computational studies. For this, different experimental doses of TFA (25, 50, and 75 mg/kg) were administered orally to Swiss albino mice, and various behavioral methods of open field, hole board, swing box, and light–dark tests were carried out. Diazepam (DZP), a positive allosteric modulator of the GABAA receptor, was employed as a positive control at a dose of 2 mg/kg, and distilled water served as a vehicle. Additionally, molecular docking was performed to estimate the binding affinities of the TFA and DZP toward the GABAA receptor subunits of α2 and α3, which are associated with the anxiolytic effect; visualizations of the ligand-receptor interaction were carried out using various computational tools. Our findings indicate that TFA dose-dependently reduces the locomotor activity of the animals in comparison with the controls, calming their behaviors. In addition, TFA exerted the highest binding affinity (−5.8 kcal/mol) to the α2 subunit of the GABAA receptor by forming several hydrogen and hydrophobic bonds. Taken together, our findings suggest that TFA exerts a similar effect to DZP, and the compound exerts moderate anxiolytic activity through the GABAergic interaction pathway. We suggest further clinical studies to develop TFA as a reliable anxiolytic agent. [ABSTRACT FROM AUTHOR]

trans -Ferulic acid (TFA), a bioactive compound found in many plants, has been recognized for its diverse pharmacological activities, including potential neurological benefits. Previous studies suggest that TFA exerts anxiolytic effects via GABAergic pathways. This study aimed to investigate the sedative effects of TFA and its possible molecular mechanisms through in vivo and in silico approaches. Adult Swiss mice were randomly divided into six groups (n = 7): control (vehicle), standard (DZP: Diazepam at 3 mg/kg, p.o.), three test groups (TFA at 25, 50, and 75 mg/kg, p.o.), and a combination group (TFA: 50 mg/kg with DZP: 3 mg/kg, p.o.). Thirty minutes post-treatment, thiopental sodium (TS) at 40 mg/kg was administered to induce sedation, and latency as well as duration of sleep, were observed for up to 4 h. In silico studies were conducted with GABA A receptor subunits (α1 and β2) to elucidate the possible molecular interactions. The results demonstrated that TFA significantly reduced latency and extended sleep duration in a dose-dependent manner compared to the control. Additionally, TFA combined with DZP further significantly (p < 0.001) enhanced these effects. In silico analysis revealed that TFA and DZP exhibited strong binding affinities with the GABA A receptor subunits (α1 and β2) in the identical binding sites, with binding energies of −6.8 and − 8.7 kcal/mol, respectively. Collectively, TFA exerted a mild sedative effect in TS-induced sleeping mice and modulated the activity of DZP, likely through interactions with GABA A receptors. TFA showed promising activity as a potential candidate for managing sleep disorders such as insomnia. • trans -Ferulic acid exerted significant sedative activity on mice. • trans -Ferulic acid decreased the sedative activity of diazepam. • trans -Ferulic acid showed partial agonistic effects with diazepam on GABAergic pathway. • trans -Ferulic acid manifested drug-likeness properties with better pharmacokinetics. [ABSTRACT FROM AUTHOR]