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dc.contributor.authorGonçalves, Gabriela Mastrangelo
dc.date.accessioned2023-12-22T01:52:19Z-
dc.date.available2023-12-22T01:52:19Z-
dc.date.issued2016-02-23
dc.identifier.citationGONÇALVES, Gabriela Mastrangelo. Avaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto (±)-4-cloro-6-(naftaleno-1-il)-tetrahidro-2h-pirano-2-il-metanol. 2016. 63 f. Dissertação (Mestrado em Ciências Fisiológicas) - Instituto de Ciências Biológicas e da Saúde, Universidade Federal Rural do Rio de Janeiro, Seropédica - RJ, 2016.por
dc.identifier.urihttps://rima.ufrrj.br/jspui/handle/20.500.14407/11405-
dc.description.abstractDiversos fármacos de uso corrente foram descobertos durante ensaios experimentais e mediante a observação em animais. Quando um novo composto parece promissor, geralmente este sofre alterações em sua estrutura química a fim de aperfeiçoar a sua seletividade, potência e eficácia terapêutica. O objetivo deste estudo foi avaliar as atividades antinociceptiva e anti-inflamatória de um novo composto sintético (±)-4-cloro-6-(naftaleno-1-il)-tetrahidro-2h-pirano-2-il-metanol (CTHP) preparado a partir de um protótipo anterior, ácido (±)-cis-(6-etil-tetrahidropirano-2-il) fórmico. O composto CTHP foi avaliado em ensaios de indução de dor aguda. A administração oral do composto foi capaz de induzir atividade antinociceptiva nos modelos de contorções abdominais induzidas por ácido acético, formalina (em ambas as fases) e retirada da cauda. Para elucidação do mecanismo de ação do composto, o modelo de retirada de cauda foi utilizado. Neste modelo foi realizada a administração prévia de naloxona (antagonista opioide não-seletivo), em que foi observada a inibição do efeito produzido pelo composto. Assim, foi então avaliada a participação seletiva de receptores opioides (μ, δ e κ), através de administração prévia de metilnaltrexona, naltrindol e nor-binaltorfimina, respectivamente, onde somente a nor-binaltorfimina foi capaz de reduzir o efeito antinociceptivo do composto. Para avaliar a possível participação da via NO/GMPc/KATP, os animais foram pré-tratados com N-nitro-arginina-L-metil éster (L-NAME), 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalina-1-ona (ODQ) (inibidor da guanilato ciclase sensível ao óxido nítrico) e glibenclamida (bloqueador de canais de potássio regulados por ATP), foi observado redução do efeito antinociceptivo com a administração prévia de todos estes. No teste de indução de tolerância, tanto a morfina quanto o composto desenvolveram tolerância, porém o composto de forma mais lenta e houve desenvolvimento de tolerância cruzada com a morfina. Para avaliar o envolvimento da via serotoninérgica na atividade do composto, foi realizada a administração diária por 3 dias de 4-cloro-DL-fenilalanina (inibidor da enzima triptofano hidroxilase). Nenhuma alteração no efeito antinociceptivo do composto foi observado, no que diz respeito ao envolvimento da via serotoninérgica. Já o modelo de campo aberto foi utilizado para avaliar a possibilidade de interferência da performance motora sobre o efeito antinociceptivo, foi demonstrada ausência desta interferência. Quanto à atividade anti-inflamatória, o resultado no teste de edema de pata indica efeito antiedematogênico do composto. Houve uma diminuição na quantidade de leucócitos totais, indicando que o composto foi capaz de reduzir a migração leucocitária na inflamação existente na bolsa de ar subcutâneo. O composto também demonstrou atividade inibitória sobre a produção de TNF-α e inibição seletiva da enzima COX-2. Esses resultados indicam atividade antinociceptiva significativa do composto, sem evidências de comprometimento motor. O composto CTHP demonstrou efeito antinociceptivo central, tendo este último contribuição dos sistemas opioide (seletivo para receptores do tipo κ) e nitrérgico em seu mecanismo de ação. E ainda, atividade anti-inflamatória, com inibição da migração leucocitária, de TNF-α e atividade inibitória seletiva sobre COX-2.por
dc.description.sponsorshipFAPERJ - Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiropor
dc.formatapplication/pdf*
dc.languageporpor
dc.publisherUniversidade Federal Rural do Rio de Janeiropor
dc.rightsAcesso Abertopor
dc.subjectopioid system,, .eng
dc.subjectleukocyte migrationeng
dc.subjectnociceptioneng
dc.subjectsistema opioidepor
dc.subjectmigração leucocitáriapor
dc.subjectnocicepçãopor
dc.titleAvaliação farmacológica das atividades antinociceptiva e anti-inflamatória do composto (±)-4-cloro-6-(naftaleno-1-il)-tetrahidro-2h-pirano-2-il-metanolpor
dc.title.alternativeAntinociceptive and anti-inflammatory profile of (±)-4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl-methanoleng
dc.typeDissertaçãopor
dc.description.abstractOtherSeveral drugs in current use were discovered during experimental tests and by observing animals. When a new compound looks promising, it usually undergoes changes in its chemical structure in order to perfect its selectivity, potency and therapeutic efficacy. The aim of this study was to evaluate the antinociceptive and anti-inflammatory activities of a new synthetic hybrid compound (±)-4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl-methanol (CTHP) prepared from a previous prototype acid, (±) - cis- (6-ethyl-tetrahydropyran-2-yl) Formic. The compound CTHP was evaluated in acute pain induction assays. Oral administration of the compound was able to induce antinociceptive activity in models of writhing induced by acetic acid, formalin (both stages) and tail flick. To elucidate the mechanism of action of the compound, the tail flick model was used. This model was perform by prior administration of naloxone (opioid antagonist non-selective), where we observed the inhibition of the effect produced by the compound. The selective involvement of opioid receptors (μ, δ and κ) was then evaluated by prior administration of methylnaltrexone, naltrindol, and nor-binaltorphimine, respectively, where only nor-binaltorphimine was able to reduce the analgesic effect of the compound. To evaluate the possible role of the NO/cGMP/KATP, animals were pretreated with N-nitro-L-arginine methyl ester (L-NAME), 1H- [1,2,4 ] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) (inhibitor of guanylate cyclase sensitive to nitric oxide), and glibenclamide (blocker of the ATP-regulated potassium channels), where reduction was observed with the administration of analgesic effect prior to all of these. In the tolerance induction test, both morphine and compound developed tolerance, however the compound perform at a slower rate and developed cross-tolerance with morphine. To assess the involvement of serotonin pathway in the activity of the compound, daily administration for 3 days of 4-chloro-DL-phenylalanine (inhibitor of the enzyme tryptophan hydroxylase) was performed. No changes in the analgesic effect of the compound was noted, with regard to the involvement of serotonin pathway. The open field model was used to assess the possibility of interference from motor performance on the analgesic effect, which demonstrated absence of this interference. As for anti-inflammatory activity results in paw edema test indicate anti-oedematogenic effect of compound. There was a decrease in the number of total leukocytes, indicating that the compound was able to reduce existing inflammation in leukocyte migration in the air pouch model. The compound also demonstrated an inhibitory activity on TNF-α production and selective inhibition of COX-2 enzyme. These results indicate significant antinociceptive activity of the compound without evidence of motor impairment. The compound CTHP showed central analgesic effect, which has contribution of opioid systems (selective for the κ-like receptors) and nitrergic in its mechanism of action. It has also showed an anti-inflammatory activity, with inhibition of leukocyte migration, TNF-α production and selective inhibitory activity on COX-2.eng
dc.contributor.advisor1Marinho, Bruno Guimarães
dc.contributor.advisor1ID077.077.277-38por
dc.contributor.advisor1Latteshttp://lattes.cnpq.br/2685794388394484por
dc.contributor.referee1Cortes, Wellington da Silva
dc.contributor.referee2Matheus, Maria Eline
dc.creator.ID384.158.588-41por
dc.creator.Latteshttp://lattes.cnpq.br/0300079148359674por
dc.publisher.countryBrasilpor
dc.publisher.departmentInstituto de Ciências Biológicas e da Saúdepor
dc.publisher.initialsUFRRJpor
dc.publisher.programPrograma de Pós-Graduação em Ciências Fisiológicaspor
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