Potencial anticonvulsivante do óleo essencial da Croton heliotropiifolius Kunth: abordagem in vivo e in silico

Abstract

Epilepsy is a chronic disease that affects the quality of life of thousands of individuals, highlighting the need to identify safe and effective anticonvulsant agents. In this context, medicinal plants emerge as a promising source of bioactive compounds for the treatment of epilepsy. In this study, we conducted an in vivo and in silico investigation of the anticonvulsant activity of the essential oil extracted from the leaves of Croton heliotropiifolius Kunth (OCH). The results obtained from in vivo experiments revealed that the essential oil exhibited anticonvulsant effects by significantly increasing the latency to the first seizure and the survival rate of animals treated with OCH at a dose of 200 mg/kg. To understand the potential receptors and sites of action of the compounds present in the oil, a molecular docking study was carried out focusing on the GABAA and NMDA receptors. Additionally, the electronic properties of the phytoconstituents were calculated at the B3LYP/6-311++G(d,p)/SMD level. Molecular docking results indicated that the sesquiterpenes α-bulnesene, δ-cadinene, guaiadiene and β-bourboneno —present in the OCH—exhibit high affinity for the GABAA receptor, particularly at the α1+(D)/γ2-(E) (site 1) benzodiazepine binding site, with binding energies ranging from −10.0 to −9.1 kcal/mol. This affinity is primarily maintained through hydrophobic interactions, especially involving the Phe77 residue of the γ2-(E) subunit of the GABAA receptor. Regarding the NMDA receptor, the same ligands δ-cadinene, guaiadiene, and α-bulnesene also exhibited favorable binding energies of −9.4, −8.7 and −8.4 kcal/mol, respectively, surpassing that of ketamine (−7.4 kcal/mol). These interactions were also predominantly driven by hydrophobic contacts. Moreover, the bicyclic structure of the sesquiterpenes proved crucial for fitting within the binding regions. The DFT analysis revealed that the most promising ligands showed higher stability and moderate electrophilic character. This research provides valuable insights into the identification of new molecules for the development of phytotherapeutics for epilepsy, suggesting that the sesquiterpenes from OCH may exert anticonvulsant activity through modulation of the GABAA receptor and/or NMDA receptor blockade.