Possible GABAkine-Mediated Sedative-Like Antidepressant Effects of Phytol: Molecular Interventions Through In Vitro, In Vivo and In Silico Approaches

Background

A previous report suggests that phytol (PHY) may exert its antidepressant effects in mice, possibly through GABA_A receptor interaction pathways.

Aim

We aimed to check its antidepressant effect with possible molecular mechanisms through behavioral and in silico studies.

Methods

For this, adult mice were randomly divided into different groups (n = 6), namely control (vehicle), standards (DZP: diazepam at 2 mg/kg, FLU: flumazenil at 0.1 mg/kg, FLUX: fluoxetine at 20 mg/kg), PHY (25, 50, and 75 mg/kg), and combined groups (PHY-75 with DZP-2 and/or FLU-0.1, and FLUX-20). Thirty minutes after treatment, each animal was subjected to tail suspension and forced swimming tests, and their immobility time (IMT) was counted for 5 min. In silico studies were performed with the GABA_A receptor α1, α2, α3, α5, and γ2 subunits and 5HT_1A to investigate possible molecular mechanisms. Additionally, in vitro GABA activity of PHY and/or reference drugs was also performed by using the colorimetric method.

Results

The results demonstrated that PHY and/or DZP significantly (p < 0.05) and concentration-dependently inhibited GABA, while FLU alone or its combination with PHY reversed it. In mice, PHY dose-dependently reduced the IMT in both protocols, while FLUX-20 showed lower IMT compared to the control and DZP, indicating elevated locomotion in mice. It showed a reduced IMT value in male animals than in female animals. In both sexes, PHY at 75 mg/kg significantly (p < 0.05) increased the IMT values with DZP-2, while reducing this parameter with FLU-0.1. In silico studies demonstrated that PHY exhibited higher binding affinities with the α2 and α3 subunits of the GABA_A and 5HT_1A receptors by −6.5, −7.2 and 6.7 kcal/mol, respectively.

Conclusion

Taken together, PHY exerted sedative-like antidepressant effects in mice and modulated the effects of GABAergic drugs DZP and FLU and serotonergic drug FLUX. PHY may be a potential candidate for the management of depression.