Phytol exerts sedative-like effects and modulates the diazepam and flumazenil’s action, possibly through the GABAA receptor interaction pathway

Abstract

This study aimed at the evaluation of the sedative effect of phytol (PHY) with possible molecular mechanisms through in vivo and in silico studies. For this, adult male mice were randomly divided into six individual groups, namely control (vehicle), two standards (DZP: diazepam at 2 m/kg, FLU: flumazenil at 0.1 mg/kg), three test groups (PHY at 25, 50, and 75 mg/kg), and three combined groups with the DZP-2 and/or FLU-0.1 with PHY-75 mg/kg. After thirty minutes, each animal was treated with thiopental sodium (TS) at 40 mg/kg to produce sedation and observed for latency and duration of sleep up to 4 h. In silico studies were performed with the 6X3X protein of the GABA_A receptor α1 and β2 subunits. The results demonstrate that PHY dose-dependently enhanced sleep duration in animals. However, it produced an insignificant sleep duration compared to the control and standard groups. It also significantly (p < 0.05) decreased the latency and increased the duration of sleep with DZP-2, while reducing these parameters with FLU-0.1. In in silico studies, DZP and FLU exhibited binding affinities with 6X3X by −6.8 and −6.9 kcal/mol, respectively, while PHY exhibited −6.9 kcal/mol. Taken together, PHY may exert a sedative-like effect in TS-induced sleeping mice and modulate the effects of DZP and FLU, possibly through interacting with the 6X3X protein of the GABA_A receptor. PHY may be one of the good candidates for the management of sleep disturbances, such as insomnia.