Investigação das atividades antinociceptiva e anti-inflamatória do ácido 3-cumarino carboxílico
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da UFPB |
Texto Completo: | https://repositorio.ufpb.br/jspui/handle/123456789/24464 |
Resumo: | 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. |
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Investigação das atividades antinociceptiva e anti-inflamatória do ácido 3-cumarino carboxílicoCumarinaDockingCicloxigenaseAnalgesiaInflamaçãoCoumarinCyclooxygenaseInflammationCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAPain 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.NenhumaA dor é uma experiência sensorial e emocional desagradável associada a dano real ou potencial, ou descrita em termos de tal dano. Estimativas sugerem que 20% dos adultos sofrem de algum tipo de dor em todo o mundo, como por exemplo a dor orofacial. O tratamento de distúrbios da dor orofacial é difícil e controverso. O uso terapêutico de anti-inflamatórios não esteroidais como analgésicos está associado a um amplo espectro de efeitos adversos, incluindo lesões gastrointestinais, eventos cardiovasculares e toxicidade renal. Nesse contexto, as cumarinas compreendem uma importante classe de compostos fenólicos, exibindo diversos efeitos farmacológicos. Suas aplicações terapêuticas dependem da estrutura química central e dos padrões de substituição no anel aromático destes compostos. As cumarinas simples representam a principal subclasse com propriedades anti-inflamatórias. Estudos demonstram que a inserção de grupos funcionais no carbono 3 do esqueleto básico cumarínico resulta em agentes farmacológicos com potente efeito antiinflamatório. Nessa conjuntura, o ácido 3-cumarino carboxílico (A3CC) é um derivado substituído das cumarinas simples, cujos efeitos em modelos de dor e inflamação ainda não foram explorados. O presente estudo se propôs a investigar pela primeira vez os efeitos antinociceptivo e anti-inflamatório do A3CC utilizando abordagens in silico, in vitro e in vivo. Os softwares PASS, Molinspiration, Volsurf+, OSIRIS DataWarrior e Meta Site 6 foram utilizados para estabelecer dados sobre espectro de atividade, biodisponibilidade, toxicidade, permeabilidade hematoencefálica, druglikeness e perfil metabólico. O efeito sob eritrocitos humanos foi investigado através de ensaios de hemolise e fragilidade osmótica. A atividade antinociceptiva foi avaliada nos modelos de contorções abdominais induzidas por ácido acético, nocicepção orofacial induzida por glutamato e formalina, e este último foi utilizado na investigação da participação da via opioide e de canais K*ATP. A atividade antiinflamatória foi analisada através do modelo de edema de pata induzido por carragenina e corroborada por estudos de docking molecular com a enzima cicloxigenase (COX). O A3CC demonstrou possuir viabilidade na circulação sanguínea ao exibir baixo percentual de hemolise frente a eritrocitos humanos, além de ser capaz de proteger a membrana eritrocitária no teste de fragilidade osmótica (p<0,001). Ele também exibiu propriedades analgésicas, inibindo significativamente o comportamento nociceptivo nos testes de nocicepção orofacial induzida por formalina (p<0,001) e glutamato (p<0,001), bem como no teste de contorções abdominais induzidas por ácido acético (p<0,0001). O A3CC demonstrou exercer seu efeito perifericamente, ao exibir propriedades anti-inflamatórias de redução do edema de pata induzido por carragenina (p<0,05). Foi constatado por docking molecular que este efeito pode estar relacionado com a inibição da COX-2 por interações com os resíduos de Tyr385 e Ser530.Universidade Federal da ParaíbaBrasilFarmacologiaPrograma de Pós-Graduação em Desenvolvimento e Inovação Tecnológica em MedicamentosUFPBAlmeida, Reinaldo Nóbrega dehttp://lattes.cnpq.br/5034028656386134Oliveira Filho, Abrahão Alves dehttp://lattes.cnpq.br/7440461731944347Aragão Neto, Humberto de Carvalho2022-09-16T14:17:53Z2022-07-242022-09-16T14:17:53Z2022-07-15info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesishttps://repositorio.ufpb.br/jspui/handle/123456789/24464porAttribution-NoDerivs 3.0 Brazilhttp://creativecommons.org/licenses/by-nd/3.0/br/info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFPBinstname:Universidade Federal da Paraíba (UFPB)instacron:UFPB2022-10-25T13:10:55Zoai:repositorio.ufpb.br:123456789/24464Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufpb.br/PUBhttp://tede.biblioteca.ufpb.br:8080/oai/requestdiretoria@ufpb.br|| diretoria@ufpb.bropendoar:2022-10-25T13:10:55Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)false |
dc.title.none.fl_str_mv |
Investigação das atividades antinociceptiva e anti-inflamatória do ácido 3-cumarino carboxílico |
title |
Investigação das atividades antinociceptiva e anti-inflamatória do ácido 3-cumarino carboxílico |
spellingShingle |
Investigação das atividades antinociceptiva e anti-inflamatória do ácido 3-cumarino carboxílico Aragão Neto, Humberto de Carvalho Cumarina Docking Cicloxigenase Analgesia Inflamação Coumarin Cyclooxygenase Inflammation CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Investigação das atividades antinociceptiva e anti-inflamatória do ácido 3-cumarino carboxílico |
title_full |
Investigação das atividades antinociceptiva e anti-inflamatória do ácido 3-cumarino carboxílico |
title_fullStr |
Investigação das atividades antinociceptiva e anti-inflamatória do ácido 3-cumarino carboxílico |
title_full_unstemmed |
Investigação das atividades antinociceptiva e anti-inflamatória do ácido 3-cumarino carboxílico |
title_sort |
Investigação das atividades antinociceptiva e anti-inflamatória do ácido 3-cumarino carboxílico |
author |
Aragão Neto, Humberto de Carvalho |
author_facet |
Aragão Neto, Humberto de Carvalho |
author_role |
author |
dc.contributor.none.fl_str_mv |
Almeida, Reinaldo Nóbrega de http://lattes.cnpq.br/5034028656386134 Oliveira Filho, Abrahão Alves de http://lattes.cnpq.br/7440461731944347 |
dc.contributor.author.fl_str_mv |
Aragão Neto, Humberto de Carvalho |
dc.subject.por.fl_str_mv |
Cumarina Docking Cicloxigenase Analgesia Inflamação Coumarin Cyclooxygenase Inflammation CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Cumarina Docking Cicloxigenase Analgesia Inflamação Coumarin Cyclooxygenase Inflammation CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
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. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-09-16T14:17:53Z 2022-07-24 2022-09-16T14:17:53Z 2022-07-15 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufpb.br/jspui/handle/123456789/24464 |
url |
https://repositorio.ufpb.br/jspui/handle/123456789/24464 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
Attribution-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nd/3.0/br/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nd/3.0/br/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal da Paraíba Brasil Farmacologia Programa de Pós-Graduação em Desenvolvimento e Inovação Tecnológica em Medicamentos UFPB |
publisher.none.fl_str_mv |
Universidade Federal da Paraíba Brasil Farmacologia Programa de Pós-Graduação em Desenvolvimento e Inovação Tecnológica em Medicamentos UFPB |
dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações da UFPB instname:Universidade Federal da Paraíba (UFPB) instacron:UFPB |
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Universidade Federal da Paraíba (UFPB) |
instacron_str |
UFPB |
institution |
UFPB |
reponame_str |
Biblioteca Digital de Teses e Dissertações da UFPB |
collection |
Biblioteca Digital de Teses e Dissertações da UFPB |
repository.name.fl_str_mv |
Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB) |
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diretoria@ufpb.br|| diretoria@ufpb.br |
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1801842999690264576 |