Tangeretin enhances sedative activity of diazepam in Swiss mice through GABAA receptor interaction: In vivo and in silico approaches

Abstract

The citrus peel flavonoid tangeretin (TAN) has diverse biological activities, including antioxidant, anti-inflammatory, antitumor, hepatoprotective, and neuroprotective effects. This study investigates the sedative effects of TAN, in Swiss albino mice using in vivo and in silico approaches. TAN (10 and 20 mg/kg, i.p.) was administered alone and in combination with diazepam (DZP, 2 mg/kg, i.p.) and flumazenil (FLU, 0.1 mg/kg, i.p.) to evaluate its impact on thiopental sodium (TS)-induced sleep, locomotor activity, and dark-light behavior. Results demonstrated that TAN at 10 mg/kg significantly (p < 0.05) reduced sleep onset latency and increased sleep duration, with a synergistic effect observed when combined with DZP. In locomotor activity tests, TAN dose-dependently decreased the distance traveled, while the combination with DZP further enhanced this effect. Dark-light tests revealed that TAN increased dark residence time, indicating potential anxiolytic properties. Molecular docking studies showed that TAN binds to the GABA_A receptor (α1 and β2 subunits) with a binding affinity of -6.6 kcal/mol, suggesting its interaction with GABAergic pathways. Pharmacokinetic analysis indicated high intestinal absorption and compliance with Lipinski's rule of five, with a favorable safety profile (LD₅₀ = 5000 mg/kg). Overall, TAN enhances the sedative effects of DZP through GABA_A receptor modulation, highlighting its potential as a natural sedative agent. Further research should explore the long-term effects, bioavailability, blood-brain barrier permeability, and synergistic interactions of TAN, with comprehensive in vitro studies and clinical trials needed to validate its potential as a natural sedative.

Keywords: Citrus flavonoid; GABAkine interaction pathway; Neuroprotective; Sedative effect; Tangeretin.