Avaliação da toxicidade aguda, atividade antinociceptiva, antipirética, cognitiva e mecanismos de ação de um análogo da tinoridina
Autor(a) principal: | |
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Data de Publicação: | 2021 |
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/123456789/22072 |
Resumo: | RMD86 is a tinoridine analogue and thiophenic derivative which belongs to a class of compounds with diverse pharmacological activities such as antifungal, antitumor and antioxidant. The present work aimed to evaluate preclinical acute toxicity, antinociceptive and antipyretic potential and possible activity at NMDA receptors. Acute administration of RMD86 did not cause deaths at the evaluated doses (300 or 2000 mg/kg, via intraperitoneal i.p.), but an analgesic effect was observed in both doses. To see if RMD86 would be able to cause neuronal toxicity, the rota-rod test was performed, which showed that RMD86 was not able to cause alterations in the animals' motor coordination. In chemical nociception tests with acetic acid and formalin, RMD86 was able to promote an antinociceptive activity at doses of 25, 50 and 100 mg/kg. In the glutamate test, however, it showed an antinociceptive activity at doses of 50 and 100 mg/kg. In the thermal nociception test RMD86 (100 mg/kg) promoted a reduction in latency time in the first 30 minutes of the test. In evaluating the antipyretic activity, RMD86 was able to reduce pyrexia at times of 30, 60, 120 and 180 minutes at doses of 25, 50 and 100 mg/kg. In the study of mechanisms of action, the derivative did not show mechanisms involving the opioid, adenosinergic system or KATP channels. However, in in silico assays the product had a lower binding energy with enzymes such as COX-1/2, which suggests its possible mechanism of action. In in vitro tests on NMDA receptors an effect was observed at concentrations of 100 and 300 µM. The direct effect of RMD86 on NMDA receptors was confirmed with a use of the AMPA receptor antagonist NBQX. In LTP (Long term Potentiation), tests, it was observed that the product was able to promote increased stimulation in pyramidal cells in the CA1 region of the hippocampus. In in vivo assays, RMD86 promoted a reduction in freezing in the aversive conditioning test, to determine whether this result was related to impaired memory formation or increased animal movement, an open-field test was performed. As a result, an increase in anxiety was observed in animals treated in the open field test in which the animals spent more time in the periphery of the apparatus. From this, it can be inferred that the analyzed product presented a low acute toxicity, antinociceptive and antipyretic activity with a possible mechanism of action involving COX enzymes and presented an activation of NMDA receptors involved with cognitive processes. |
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Avaliação da toxicidade aguda, atividade antinociceptiva, antipirética, cognitiva e mecanismos de ação de um análogo da tinoridinaTiofenoNocicepçãoAntipiréticaReceptor NMDAThiopheneNociceptionAntipyreticNMDA receptorCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIARMD86 is a tinoridine analogue and thiophenic derivative which belongs to a class of compounds with diverse pharmacological activities such as antifungal, antitumor and antioxidant. The present work aimed to evaluate preclinical acute toxicity, antinociceptive and antipyretic potential and possible activity at NMDA receptors. Acute administration of RMD86 did not cause deaths at the evaluated doses (300 or 2000 mg/kg, via intraperitoneal i.p.), but an analgesic effect was observed in both doses. To see if RMD86 would be able to cause neuronal toxicity, the rota-rod test was performed, which showed that RMD86 was not able to cause alterations in the animals' motor coordination. In chemical nociception tests with acetic acid and formalin, RMD86 was able to promote an antinociceptive activity at doses of 25, 50 and 100 mg/kg. In the glutamate test, however, it showed an antinociceptive activity at doses of 50 and 100 mg/kg. In the thermal nociception test RMD86 (100 mg/kg) promoted a reduction in latency time in the first 30 minutes of the test. In evaluating the antipyretic activity, RMD86 was able to reduce pyrexia at times of 30, 60, 120 and 180 minutes at doses of 25, 50 and 100 mg/kg. In the study of mechanisms of action, the derivative did not show mechanisms involving the opioid, adenosinergic system or KATP channels. However, in in silico assays the product had a lower binding energy with enzymes such as COX-1/2, which suggests its possible mechanism of action. In in vitro tests on NMDA receptors an effect was observed at concentrations of 100 and 300 µM. The direct effect of RMD86 on NMDA receptors was confirmed with a use of the AMPA receptor antagonist NBQX. In LTP (Long term Potentiation), tests, it was observed that the product was able to promote increased stimulation in pyramidal cells in the CA1 region of the hippocampus. In in vivo assays, RMD86 promoted a reduction in freezing in the aversive conditioning test, to determine whether this result was related to impaired memory formation or increased animal movement, an open-field test was performed. As a result, an increase in anxiety was observed in animals treated in the open field test in which the animals spent more time in the periphery of the apparatus. From this, it can be inferred that the analyzed product presented a low acute toxicity, antinociceptive and antipyretic activity with a possible mechanism of action involving COX enzymes and presented an activation of NMDA receptors involved with cognitive processes.Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqCoordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESRMD86 é um análogo da tinoridina e derivado tiofênico o qual pertence a uma classe de compostos com diversas atividades farmacológicas como antifúngica, antitumoral e antioxidante. O presente trabalho teve como objetivo avaliar a toxicidade aguda pré-clínica, o potencial antinociceptivo e antipirético e possível atividade em receptores NMDA. A administração aguda de RMD86 não provocou mortes nas doses avaliadas (300 ou 2000 mg/kg, via intraperitoneal i.p.), porém foi observado um efeito analgésico nas duas doses. Para constatar se RMD86 seria capaz de provocar uma toxicidade neuronal foi realizado o teste do rota-rod o qual demonstrou que RMD86 não foi capaz de causar alterações na coordenação motora dos animais. Nos testes da nocicepção química com ácido acético e formalina RMD86 foi capaz de promover uma atividade antinociceptiva nas doses de 25, 50 e 100 mg/kg. Já no teste do glutamato ele apresentou uma atividade antinociceptiva nas doses de 50 e 100 mg/kg. No teste de nocicepção térmica RMD86 (100 mg/kg) promoveu uma redução no tempo de latência nos primeiros 30 minutos do teste. Na avaliação da atividade antipirética RMD86 foi capaz de reduzir a pirexia nos tempos de 30, 60, 120 e 180 minutos nas doses de 25, 50 e 100 mg/kg. No estudo dos mecanismos de ação, o derivado não apresentou mecanismos envolvendo o sistema opioide, adenosinérgico e nem canais de KATP. No entanto, em ensaios in silico o produto teve uma menor energia de ligação com enzimas como a COX-1/2, o que sugere o seu possível mecanismo de ação. Nos testes in vitro em receptores NMDA foi observado um efeito nas concentrações de 100 e 300 µM. O efeito direto de RMD86 em receptores NMDA foi confirmado com um uso do antagonista do receptor AMPA o NBQX. Em testes de LTP (Long-term Potentiation), observou-se que o produto foi capaz de promover o aumento do estímulo em células piramidais da região CA1 do hipocampo. Em ensaios in vivo, RMD86 promoveu uma redução do congelamento no teste do condicionamento aversivo, para determinar se esse resultado tinha relação com a deficiência da formação da memória ou com o aumento da movimentação do animal foi realizado um teste do campo aberto. Como resultado, observou-se um aumento da ansiedade nos animais tratados no teste do campo aberto no qual os animais passaram mais tempo na periferia do aparato. A partir disso, pode-se inferir que o produto analisado apresentou uma baixa toxicidade aguda, atividade antinociceptiva e antitérmica com possível mecanismo de ação envolvendo enzimas COX e apresentou uma ativação de receptores NMDA envolvidos com processos cognitivos.Universidade Federal da ParaíbaBrasilFarmacologiaPrograma de Pós-Graduação em Produtos Naturais e Sintéticos BioativosUFPBAlmeida, Reinaldo Nóbrega dehttp://lattes.cnpq.br/5034028656386134Cruz, Ryldene Marques Duarte da2022-02-14T21:00:37Z2021-10-142022-02-14T21:00:37Z2021-09-17info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesishttps://repositorio.ufpb.br/jspui/handle/123456789/22072porAttribution-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:UFPB2022-04-28T17:18:18Zoai:repositorio.ufpb.br:123456789/22072Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufpb.br/PUBhttp://tede.biblioteca.ufpb.br:8080/oai/requestdiretoria@ufpb.br|| diretoria@ufpb.bropendoar:2022-04-28T17:18:18Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)false |
dc.title.none.fl_str_mv |
Avaliação da toxicidade aguda, atividade antinociceptiva, antipirética, cognitiva e mecanismos de ação de um análogo da tinoridina |
title |
Avaliação da toxicidade aguda, atividade antinociceptiva, antipirética, cognitiva e mecanismos de ação de um análogo da tinoridina |
spellingShingle |
Avaliação da toxicidade aguda, atividade antinociceptiva, antipirética, cognitiva e mecanismos de ação de um análogo da tinoridina Cruz, Ryldene Marques Duarte da Tiofeno Nocicepção Antipirética Receptor NMDA Thiophene Nociception Antipyretic NMDA receptor CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Avaliação da toxicidade aguda, atividade antinociceptiva, antipirética, cognitiva e mecanismos de ação de um análogo da tinoridina |
title_full |
Avaliação da toxicidade aguda, atividade antinociceptiva, antipirética, cognitiva e mecanismos de ação de um análogo da tinoridina |
title_fullStr |
Avaliação da toxicidade aguda, atividade antinociceptiva, antipirética, cognitiva e mecanismos de ação de um análogo da tinoridina |
title_full_unstemmed |
Avaliação da toxicidade aguda, atividade antinociceptiva, antipirética, cognitiva e mecanismos de ação de um análogo da tinoridina |
title_sort |
Avaliação da toxicidade aguda, atividade antinociceptiva, antipirética, cognitiva e mecanismos de ação de um análogo da tinoridina |
author |
Cruz, Ryldene Marques Duarte da |
author_facet |
Cruz, Ryldene Marques Duarte da |
author_role |
author |
dc.contributor.none.fl_str_mv |
Almeida, Reinaldo Nóbrega de http://lattes.cnpq.br/5034028656386134 |
dc.contributor.author.fl_str_mv |
Cruz, Ryldene Marques Duarte da |
dc.subject.por.fl_str_mv |
Tiofeno Nocicepção Antipirética Receptor NMDA Thiophene Nociception Antipyretic NMDA receptor CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Tiofeno Nocicepção Antipirética Receptor NMDA Thiophene Nociception Antipyretic NMDA receptor CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
RMD86 is a tinoridine analogue and thiophenic derivative which belongs to a class of compounds with diverse pharmacological activities such as antifungal, antitumor and antioxidant. The present work aimed to evaluate preclinical acute toxicity, antinociceptive and antipyretic potential and possible activity at NMDA receptors. Acute administration of RMD86 did not cause deaths at the evaluated doses (300 or 2000 mg/kg, via intraperitoneal i.p.), but an analgesic effect was observed in both doses. To see if RMD86 would be able to cause neuronal toxicity, the rota-rod test was performed, which showed that RMD86 was not able to cause alterations in the animals' motor coordination. In chemical nociception tests with acetic acid and formalin, RMD86 was able to promote an antinociceptive activity at doses of 25, 50 and 100 mg/kg. In the glutamate test, however, it showed an antinociceptive activity at doses of 50 and 100 mg/kg. In the thermal nociception test RMD86 (100 mg/kg) promoted a reduction in latency time in the first 30 minutes of the test. In evaluating the antipyretic activity, RMD86 was able to reduce pyrexia at times of 30, 60, 120 and 180 minutes at doses of 25, 50 and 100 mg/kg. In the study of mechanisms of action, the derivative did not show mechanisms involving the opioid, adenosinergic system or KATP channels. However, in in silico assays the product had a lower binding energy with enzymes such as COX-1/2, which suggests its possible mechanism of action. In in vitro tests on NMDA receptors an effect was observed at concentrations of 100 and 300 µM. The direct effect of RMD86 on NMDA receptors was confirmed with a use of the AMPA receptor antagonist NBQX. In LTP (Long term Potentiation), tests, it was observed that the product was able to promote increased stimulation in pyramidal cells in the CA1 region of the hippocampus. In in vivo assays, RMD86 promoted a reduction in freezing in the aversive conditioning test, to determine whether this result was related to impaired memory formation or increased animal movement, an open-field test was performed. As a result, an increase in anxiety was observed in animals treated in the open field test in which the animals spent more time in the periphery of the apparatus. From this, it can be inferred that the analyzed product presented a low acute toxicity, antinociceptive and antipyretic activity with a possible mechanism of action involving COX enzymes and presented an activation of NMDA receptors involved with cognitive processes. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-10-14 2021-09-17 2022-02-14T21:00:37Z 2022-02-14T21:00:37Z |
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/123456789/22072 |
url |
https://repositorio.ufpb.br/jspui/handle/123456789/22072 |
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 Produtos Naturais e Sintéticos Bioativos UFPB |
publisher.none.fl_str_mv |
Universidade Federal da Paraíba Brasil Farmacologia Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos UFPB |
dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações da UFPB instname:Universidade Federal da Paraíba (UFPB) instacron:UFPB |
instname_str |
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) |
repository.mail.fl_str_mv |
diretoria@ufpb.br|| diretoria@ufpb.br |
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1801842988248203264 |