Sedative Effects of Daidzin, Possibly Through the GABAA Receptor Interaction Pathway: In Vivo Approach with Molecular Dynamic Simulations

Abstract

The soy isoflavone daidzin (DZN) has been considered a hopeful bioactive compound having diverse biological activities, including anxiolytic, memory-enhancing, and antiepileptic effects, in experimental animals. However, its sedative and hypnotic effects are yet to be discovered. This study aimed to evaluate its sedative/hypnotic effect on Swiss mice. Additionally, in silico studies were also performed to see the possible molecular mechanisms behind the tested neurological effect. For this, male Swiss albino mice were treated with DZN (5, 10, or 20 mg/kg) intraperitoneally (i.p.) with or without the standard GABAergic medication diazepam (DZP) and/or flumazenil (FLU) and checked for the onset and duration of sleeping time using thiopental sodium-induced as well as DZP-induced sleeping tests. A molecular docking study was also performed to check its interaction capacity with the α1 and β2 subunits of the GABA_A receptor. Findings suggest that DZN dose-dependently and significantly reduced the latency while increasing the duration of sleep in animals. In combination therapy, DZN shows synergistic effects with the DZP-2 and DZP-2 + FLU-0.01 groups, resulting in significantly (p < 0.05) reduced latency and increased sleep duration. Further, molecular docking studies demonstrate that DZN has a strong binding affinity of − 7.2 kcal/mol, which is closer to the standard ligand DZP (− 8.3 kcal/mol) against the GABA_A (6X3X) receptor. Molecular dynamic simulations indicated stability and similar binding locations for DZP and DZN with 6X3X. In conclusion, DZN shows sedative effects on Swiss mice, possibly through the GABA_A receptor interaction pathway.