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

Year: 2025

Type: article

Abstract: ABSTRACT 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.

Source: CNS Neuroscience & Therapeutics

DOI: 10.1111/cns.70350