Evaluation of the Sedative Activity of Naringenin: In Vivo Study with Pharmacokinetics and Molecular Docking Insights.

Abstract

This research is designed to investigate the sedative effects of naringenin (NAR) and diazepam against thiopental sodium-induced sleeping mice. NAR (5 and 10 mg kg), diazepam (DZP) (2 mg kg), flumazenil (FLN) (0.1 mg kg), and their combinations are administered intraperitoneally to mice. After 30 min, sleep is induced with intraperitoneal thiopental sodium (20 mg kg), and sleep latency and duration are measured. In silico analysis investigates the role of GABA receptors. NAR significantly reduces sleep latency and prolongs sleep duration in a dose-dependent manner, with the combination of NAR-10 and DZP-2 showing a synergistic effect. The combination of the antagonist (FLN) (NAR-10 and FLN-0.1) indicates that latency increases and sleep duration decreases compared to NAR-10 alone. Furthermore, in silico docking studies corroborates these results, demonstrating a significant binding affinity of NAR (-8.3 kcal mol), which is comparable to the standard ligand DZP (-8.7 kcal mol) and FLN (-7.0 kcal mol) for the GABA_A (6X3X) receptor, indicating a GABAergic mechanism. Pharmacokinetics and toxicity evaluations confirm NAR's potential as a safe therapeutic agent, with a high LD50 (2000 mg kg) and minimal toxicity. These findings highlight NAR's potential as a GABAergic sedative agent, requiring further research before being used clinically to treat sleep disorders.