Anxiolytic-Like Effects of Citronellal and Phytol, Possibly Through the GABAergic Interaction Pathway: In Vivo with...

Citronellal (CTL), a natural monoterpenoid aldehyde, and phytol (PHY), a chlorophyll-derived diterpenoid, have been reported to exert neuropharmacological activities with possible GABAergic involvement. This study investigated their anxiolytic-like effects in Swiss albino mice, supported by molecular docking and pharmacokinetic evaluations. Animals received CTL (62.5, 125, and 250 mg/kg, per orally (p.o.)) or PHY (25, 50, and 75 mg/kg, p.o.) either alone or in combination with the gamma-aminobutyric acid (GABA) agonist diazepam (DZP, 2 mg/kg, p.o.) or the GABA antagonist flumazenil (FLU, 0.1 mg/kg, intraperitoneally (i.p.)). Behavioral analyses (open-field, hole-cross, swing, and light-dark tests) revealed that CTL significantly and dose-dependently reduced locomotor activity, while PHY produced variable responses, with higher doses enhancing exploratory behavior. Both compounds potentiated DZP-induced anxiolytic effects and counteracted FLU, suggesting GABAergic modulation. Molecular docking demonstrated stronger binding affinities of PHY (-4.9 and -4.2 kcal/mol) than CTL (-4.7 and -4.0 kcal/mol) at the α2 and α3 subunits of the GABA_A receptor, with PHY forming hydrogen bonds (HBs) indicative of stable interactions. Pharmacokinetics and toxicity predictions confirmed favorable drug-likeness and higher LD₅₀ values for CTL and PHY compared to DZP and FLU, with no major toxic liabilities. Collectively, these findings highlight that CTL may exert sedative-type anxiolytic-like effects, whereas PHY may show antidepressant-like anxiolytic properties, both mediated via the GABAergic pathway. These results support further investigation of CTL and PHY as potential natural anxiolytic candidates.