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 GABAA 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 GABAA receptor α1, α2, α3, α5, and γ2 subunits and 5HT1A 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 GABAA and 5HT1A 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.