Anticonvulsant effect of (±) citronellal possibly through the GABAergic and voltage-gated sodium channel receptor interaction pathways: In vivo and in silico studies

This study aimed to investigate the anticonvulsant effects of citronellal (CIT) and possible underlying mechanisms through an isoniazid (INH)-induced seizure (convulsion) via in vivo and in silico studies. For this, convulsions were induced by the oral administration of INH (300 mg/kg) to the mice. The animals were treated orally with different doses of CIT (50, 100, and 200 mg/kg). Vehicle served as a negative control (NC), while diazepam (DZP) (2 mg/kg) and carbamazepine (CAR) (80 mg/kg) were provided (p.o.) as positive controls (PC). A combination therapy of CIT (middle dose) with DZP and CAR was also given to two separate groups of animals to estimate the synergistic or antagonistic effects. Molecular docking and visualization of ligand-receptor interactions are also estimated through different computational tools. The results of the in vivo study showed that CIT dose-dependently significantly (p < 0.05) exhibited a higher onset of seizures while reducing the frequency and duration of seizures in mice compared to the NC group. Besides these, in combination therapy, CIT significantly antagonized the activity of CAR and DZP, leading to a reduction in the onset of seizures and an increase in their frequency and duration compared to treatment with CAR and DZP alone. Additionally, molecular docking revealed that the CIT exhibited a moderate binding affinity (-5.8 kcal/mol) towards the GABA_A receptor and a relative binding affinity (-5.3 kcal/mol) towards the voltage-gated sodium channel receptor by forming several bonds. In conclusion, CIT showed moderate anticonvulsant activity in INH-induced convulsion animals, possibly by enhancing GABA_A receptor activity and inhibiting the voltage-gated sodium channel receptor.