In silico molecular modeling, neuro-behavioral profile, and toxicity assessment of the essential oil of Ferula gummosa Boiss. as an anti-seizure agent.

Abstract

Ferula gummosa Boiss., known in Persian as "Baridje," belongs to the Apiaceae family. All parts of this plant, especially the root, contain galbanum. Galbanum, the oleo-gum resin of F. gummosa, is one of the essential traditional herbal medicines in Iran, which is used as a tonic for epilepsy and chorea, memory enhancement, gastrointestinal diseases, and wound healing. We investigated the toxicity, anticonvulsant effects, and molecular modeling of the essential oil (EO) distilled from the oleo-gum resin of F. gummosa. Gas chromatography-mass spectrometry was used to identify the EO components. The cytotoxicity of EO on HepG2 cell lines was assessed by the MTT method. Male mice were arranged as follows: negative control groups (sunflower oil (10ml/kg, i.p.) or saline (10ml/kg, p.o.)), EO groups (0.5, 1, 1.5, and 2.5ml/kg, p.o.), and positive control groups (ethosuximide (150mg/kg, p.o.) or diazepam (1.0 or 2mg/kg, i.p.)). The motor coordination and neurotoxicity of EO were studied using the rota-rod test. Open-field, novel object recognition, and passive avoidance learning tests were used to investigate the effect of EO on locomotor activity and memory function. An acute pentylenetetrazole-induced seizure model was utilized to evaluate the anticonvulsant properties of the EO. The interaction of the EO main components with the GABAA receptor was investigated by coarse-grained molecular dynamics simulations. β-pinene, sabinene, α-pinene, and ρ-cymene were the main components of EO. The IC50 of the EO at 24, 48, and 72h was found to be 59.90, 12.96, and 3.93μl/ml, respectively. No adverse effects were observed in memory, motor coordination, and locomotor activity in mice treated with EO. Administration of EO (1, 1.5, and 2.5ml/kg) improved survival rates in mice receiving pentylenetetrazole (PTZ; to induce an epileptic seizure). Sabinene was able to bind to the binding site of benzodiazepines at the GABAA receptor. Acute treatment with the EO of F. gummosa caused antiepileptic effects and could effectively increase the survival rate in PTZ-treated mice with no significant toxicity.