Banca de DEFESA: FRANCISCO JUNIO DIAS
Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.STUDENT : FRANCISCO JUNIO DIAS
DATE: 25/02/2025
TIME: 14:00
LOCAL: FAMED
TITLE:
VASORELAXANT EFFECT OF EUGENOL IN HUMAN UMBILICAL ARTERIES WITH PREECLAMPSIA: EVALUATION OF 5-HT2A RECEPTOR INVOLVEMENT EX VIVO AND IN SILICO
KEY WORDS:
Eugenol; human umbilical artery; preeclampsia; 5-HT2A receptor.
PAGES: 85
BIG AREA: Ciências Biológicas
AREA: Bioquímica
SUMMARY:
Introduction: Preeclampsia (PE) is a multisystem disease exclusive to pregnancy characterized by arterial hypertension and often proteinuria that appears after the 20th week of gestation. Its manifestations may develop or evolve into more serious complications with high maternal and perinatal morbidity and mortality, such as HELLP syndrome and eclampsia. The exact etiology of PE is unknown, although its pathophysiology is associated with poor maternal adaptation to pregnancy resulting in placental ischemia, which can lead to fetal growth restriction and other exacerbated maternal responses such as systemic vascular resistance, proteinuria, and liver damage. Treatment of PE involves controlling blood pressure levels and protecting organs, although the use of drugs is limited due to the gestational period or has little efficacy. Resolution of labor is the only cure for PE, which leads to premature births and perinatal morbidity. That said, it is of great importance to explore vasodilator substances with the potential to normalize fetoplacental circulation in order to avoid fetal damage. Secondary metabolites present great chemical-structural diversity and biological activities. Among these, eugenol (EUG), from the phenylpropanoid family, presents low toxicity and great vasodilatory potential with reports in animal vessels: cerebral, thoracic, pulmonary, mesenteric artery, aorta and more recently in normotensive human umbilical artery (HUA). Objectives: Therefore, the present study sought to evaluate the vasorelaxant effect of EUG in HUAs affected by PE using the organ bath technique. Methodology: For this purpose, the study was previously submitted and approved by an ethics committee (nº 3.832.881). After umbilical cord collection, the AUHs were dissected, cut into 3-5 mm rings and mounted between thermostated organ bath rods (37°C) with 10 mL cuvettes of Krebs Henseleit nutrient solution, under aeration (95% O2 and 5% CO2) and pH 7.4. Before each experiment, the AUHs underwent 90-minute stabilization followed by verification of tissue viability with KCl. The effect of EUG (1-1200 µM) on spontaneous basal tone was evaluated in the presence of electromechanical (KCl 60 mM) and pharmacomechanical (5-HT 10 µM) agonists and in the presence of blockers (4-AP, GLI, TEA). In addition, the affinity of EUG with the 5-HT2A receptor was evaluated by computational simulation. For molecular docking, 13 structures were used. The docking parameters were defined through the redocking process and the calculations performed using the AutoDock 4.2.6 software. Results: EUG (1-1200 µM) caused a reduction in basal tone (statistically significant concentrations from 20 µM). At 1000 µM it relaxed 100% the contractions induced by KCl and 5-HT with EC50 of 266.74 ± 4.90 µM and 153.20 ± 4.73 µM, respectively, being, therefore, more potent in the pharmacomechanical pathway. In the presence of K+ channel blockers, 100% relaxation was obtained in the presence of 4-AP and GLI and 94.81% in the presence of TEA (1 mM), with a slight change in EC50 compared to the 5-HT pathway, which suggests little or no participation of K+ channels in the vasorelaxant effect of EUG in AUH with PE. In its interaction with the 13 structures of the 5-HT2A receptor, EUG occupied a binding site formed by 11 to 15 residues, demonstrating binding energy between -5.7 and -7.4 Kcal/mol-1, therefore within the standard deviation (2.0 Kcal/mol-1). Conclusion: The results indicate an important vasorelaxant effect of EUG on the basal tone and contraction pathways of AUH-PE, with the in-silico study suggesting a potential action on the 5-HT2A receptor. Therefore, we can suggest that EUG is promising for the treatment of fetal-placental circulation disorders; however, future investigations into its molecular mechanisms are necessary.
COMMITTEE MEMBERS:
Externo à Instituição - LUÍS PEREIRA DE MORAIS - URCA
Presidente - CLAUDENER SOUZA TEIXEIRA
Interno - IRI SANDRO PAMPOLHA LIMA
Externa à Instituição - RENATA EVARISTO RODRIGUES DUARTE - UPE