Investigação das atividades antinociceptiva e anti-inflamatória do ácido 3-cumarino carboxílico

• Ano de defesa: 2022
• Autor(a) principal: Aragão Neto, Humberto de Carvalho
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal da Paraíba; Brasil; Farmacologia; Programa de Pós-Graduação em Desenvolvimento e Inovação Tecnológica em Medicamentos; UFPB
• Palavras-chave em Português: Cumarina; Docking; Cicloxigenase; Analgesia; Inflamação; Coumarin; Cyclooxygenase; Inflammation; CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA
• Link de acesso: https://repositorio.ufpb.br/jspui/handle/123456789/24464

Pain is an unpleasant sensory and emotional experience associated with actual or potential harm, or described in terms of such harm. Estimates suggest that 20% of adults suffer from some type of pain worldwide, such as orofacial pain. The treatment of orofacial pain disorders is difficult and controversial. The therapeutic use of nonsteroidal anti-inflammatory drugs as analgesics is associated with a wide spectrum of adverse effects, including gastrointestinal injuries, cardiovascular events, and renal toxicity. In this context, coumarins comprise an important class of phenolic compounds, exhibiting several pharmacological effects. Their therapeutic applications depend on the central chemical structure and the substitution patterns in the aromatic ring of these compounds. Simple coumarins represent the main subclass with anti-inflammatory properties. Studies demonstrate that the insertion of functional groups at carbon 3 of the coumarin basic skeleton results in pharmacological agents with potent antiinflammatory effects. At this juncture, coumarin-3-carboxylic acid (A3CC) is a substituted derivative of simple coumarins, whose effects on models of pain and inflammation have not yet been explored. The present study aimed to investigate for the first time the antinociceptive and anti-inflammatory effects of A3CC using in silico, in vitro and in vivo approaches. PASS, Molinspiration, Volsurf+, OSIRIS DataWarrior and Meta Site 6 software were used to establish data on spectrum of activity, bioavailability, toxicity, blood-brain permeability, druglikeness and metabolic profile. The effect on human erythrocytes was investigated through hemolysis and osmotic fragility assays. The antinociceptive activity was evaluated in the models of acetic acidinduced writhing test, orofacial nociception induced by glutamate and formalin, and the latter was used to investigate the participation of the opioid pathway and K+ATP channels. The anti-inflammatory activity was analyzed using the carrageenan-induced paw edema model and corroborated by molecular docking studies with the enzyme cyclooxygenase (COX). A3CC demonstrated viability in the bloodstream by showing a low percentage of hemolysis against human erythrocytes, in addition to being able to protect the erythrocyte membrane in the osmotic fragility test (p<0.001). It also exhibited analgesic properties, significantly inhibiting nociceptive behavior in the formalin (p<0.001) and glutamate (p<0.001) induced orofacial nociception tests, as well as in the acetic acid-induced writhing test (p<0.0001). A3CC has been shown to exert its effect peripherally, by exhibiting anti-inflammatory properties to reduce carrageenan-induced paw edema (p<0.05). It was found by molecular docking that this effect may be related to the inhibition of COX-2 by interactions with residues of Tyr385 and Ser530.