Anticonvulsant Effects of Citronellal, Daidzin, and Phytol, Possibly Through GABAA Receptor and Voltage-Gated Sodium Channel Interaction Pathways: In Vivo and In Silico Studies.

BACKGROUND

Natural compounds, such as citronellal (CTL), daidzin (DZN), and phytol (PHY), have demonstrated potential anticonvulsant properties, but their combined effects remain unexplored. This study aimed to evaluate the anticonvulsant efficacy of CTL, DZN, and PHY, individually and in combination, using in vivo and in silico approaches.

METHODS

In the in vivo study, pentylenetetrazole (PTZ)-induced seizures in chicks were used to assess seizure latency, frequency, and duration. CTL (250 mg/kg), DZN (20 mg/kg), and PHY (75 mg/kg) were administered oral (p.o.), alone and in combination. Carbamazepine (CAR, 80 mg/kg) and diazepam (DZP, 5 mg/kg) served as standard controls. In silico molecular docking was performed against γ-aminobutyric acid A (GABAA) and voltage-gated sodium channel (VGSC), whereas pharmacokinetics and toxicity predictions were evaluated.

RESULTS

Results showed that CTL, DZN, and PHY significantly increased seizure latency, reduced seizure frequency, and shortened seizure duration. The combination of CTL + DZN + PHY enhanced these effects by increasing latency and reducing seizure frequency and duration. When combined with DZP, the combination provided the highest protection (83.33%) and significantly reduced seizure duration. Docking studies revealed strong binding affinities (BAs) to GABAA (CTL: -7.0 kcal/mol, DZN: -8.4 kcal/mol, PHY: -5.4 kcal/mol) and VGSC (DZN: -8.9 kcal/mol). Pharmacokinetic analysis confirmed good absorption and blood-brain barrier (BBB) permeability, whereas toxicity profiling indicated a high safety margin.

CONCLUSION

These findings suggest that CTL, DZN, and PHY exert significant anticonvulsant effects via GABAergic and sodium channel modulation, warranting further clinical investigation.