Anticonvulsant Potential of the Essential Oil of <i>Croton Heliotropiifolius</i> Kunth: In Vivo and In Silico Approach

Epilepsy is a chronic condition that significantly impacts the quality of life of many individuals, underscoring the urgent need for the identification of safe and effective anticonvulsant agents. In this context, medicinal plants have emerged as a promising source of bioactive compounds for treating epilepsy. This study involved an in vivo and in silico investigation of the anticonvulsant activity of the essential oil from the leaves of <i>Croton heliotropiifolius</i> Kunth (OCH). In vivo experiments revealed that the essential oil promoted a significant increase in seizure latency and survival rate in animals treated with OCH at a dose of 200 mg/kg, indicating an anticonvulsant effect. To understand the possible receptors and sites of action of the compounds in the oil, we performed a molecular docking study with GABA_A and NMDA receptors. Additionally, we calculated the electronic properties of the phytoconstituents at the B3LYP/6-311++G-(d,p)/SMD level. The results of the molecular docking studies revealed that the sesquiterpenes α-bulnesene, δ-cadinene, and β-bourbonene, which are present in OCH, have a high affinity for the GABA_A receptor, with binding energies ranging from -10.0 to -9.1 kcal/mol. These compounds primarily interact with the receptors through hydrophobic forces, highlighting the importance of interaction with Phe77 of the γ2^-(E) subunit of GABA_A. Docking analysis of NMDA revealed a higher affinity for the sesquiterpene guaiadiene, with a binding energy of -8.0 kcal/mol. Molecular dynamics simulations indicate that the α-bulnesene-GABA_A and guaiadiene-NMDA complexes remained stable over 100 ns. DFT analysis revealed that the most promising ligands are more stable and have moderate to strong electrophilicity. This research provides valuable insights for the identification of new molecules in the development of herbal medicines for the treatment of epilepsy, suggesting that the anticonvulsant effect of OCH may be related to the modulation of the GABA_A receptor or NMDA.