Investigação da toxicidade e atividade antidepressiva-símile do o-Eugenol em camundongos fêmeas

Abstract

Major depressive disorder (MDD) is a common and debilitating mental disorder, with women almost twice as likely to develop the disease as men. Conventional treatment options have side effects and questionable efficacy, requiring the search for new, more effective and safer drugs. The present study investigated pharmacokinetic parameters and in silico toxicity, acute and subacute toxicity in vivo, and the antidepressant-like activity of o-eugenol administered in repeated doses, in a behavioral animal model of depression induced by repeated administra-tion of dexamethasone in female mice. In the in silico study, pkCSM and SwissADME virtual platforms were used. In the in vivo studies, acute and repeated-dose oral toxicity were per-formed following the protocols of the Organization of Economic Cooperation and Develop-ment (OECD), through the observation of behavioral, weight, feeding, anatomopathological, and hematological and biochemical parameters in the subacute part. In the investigation of the antidepressant-like activity of o-eugenol, orally, behavioral tests of forced swimming (FST), tail suspension (TST) and sucrose preference (SPT) were performed, in addition to the rota-rod to evaluate motor coordination. The effect of o-eugenol on the seizure threshold and its synergism with imipramine were studied, oxidative stress parameters, IL-1β levels and metabolomic study by nuclear magnetic resonance technique were evaluated. As in silico re-sults, o-eugenol showed good oral absorption, permeability to the blood-brain barrier and the central nervous system, was not a substrate for other products and did not show toxic respons-es in predictive models. In vivo studies, in acute and repeated dose toxicity, o-eugenol did not promote significant changes in most of the parameters investigated. The estimated acute lethal dose (LD50) was 1000 mg/kg. From the pharmacological screening, the three doses of o-eugenol (25, 50 and 100 mg/kg) used in the study were determined. The o-eugenol did not alter the motor coordination of the animals in the rota-rod test (p>0,05). In the FST and TST tests, dexamethasone increased the immobility time and decreased the latency to immobility of the mice in relation to the control, while o-eugenol and imipramine decreased the immo-bility time and increased the latency to immobility in relation to dexamethasone (p<0,05). In the SPT, dexamethasone decreased sucrose preference of the animals, while o-eugenol and imipramine reversed the behavior (p<0,05). The o-eugenol reduced lipid peroxidation and increased the levels of the antioxidant glutathione in brain structures, and decreased serum levels of IL-1β (p<0.05). In the metabolomic study performed in the hippocampus, there were no significant differences between the groups according to PCA analysis. Pretreatment with o-eugenol did not decrease the latency to the first seizure in animals that received a subconvul-sive dose of 35 mg/kg of pentylenetetrazol (p<0.05) and a synergistic interaction between imipramine and o-eugenol was suggested (p<0.05). Thus, the findings demonstrated that o-eugenol presented relatively low toxicity, showed an effect similar to the antidepressant imi-pramine with a decrease in oxidative stress in brain structures, a decrease in serum levels of IL-1β, and also had a synergistic effect with imipramine, but was devoid of proconvulsant adverse effects.