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 GABA_A 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 GABA_A 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 GABA_A 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.

Trans-resveratrol, a polyphenolic phytoalexin found in various plant sources, has been the focus of increasing attention in recent years because of its role in the prevention of many human diseases, and particularly because of its antioxidant properties. However, the in vivo effect of trans-resveratrol after oral administration is negligible when compared to its efficacy in vitro, due to its low bioavailability. Moreover, it presents stability issues as it is an extremely photosensitive compound when exposed to light. This work aims to develop lipid-coated nanocrystals in order to improve the antioxidant activity and bioavailability of trans-resveratrol. Lipid-coated trans-resveratrol nanocrystals with sizes lower than 500 nm, spherical shapes and smooth surfaces were obtained via a milling method. They showed a faster dissolution rate than the coarse trans-resveratrol powder. The antioxidant properties of trans-resveratrol were not impaired by the milling process. The in vivo pharmacokinetics of lipid-coated trans-resveratrol nanocrystals were evaluated after oral administration to rats, with a commercial Phytosome^® formulation being used for comparison purposes. An increase in the trans-resveratrol area under the curve was observed and the lipid-coated nanocrystal formulation led to an enhancement in the oral bioavailability of the compound.