Efeito do resveratrol nas alterações comportamentais induzidas por flufenazina em ratos e sua interação com a enzima monoaminoxidase in silico e in vitro
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/18074 |
Resumo: | Typical antipsychotics, commonly used to schizophrenia treatment, cause tardive dyskinesia in humans and orofacial dyskinesia (OD) in rodents. In the present work, we investigated the effects of resveratrol, a polyphenol with neuroprotective properties mainly found in red fruits and wine, on the behavioral alterations induced by acute and chronic treatment with fluphenazine in rats. Furthermore, we evaluated the effects of resveratrol on the enzyme monoaminoxidade (MAO) in vitro, in silico and the participation of MAO in OD. Thus, the first aim of the present study was to investigate the action of resveratrol (using a low dose), in an acute model of vacuous chewing movements (VCMs) induced by the administration of fluphenazine in rats. In this study, we observed that resveratrol, at a dose of 1 mg/kg administered 3 times a week during 21 days, reduced the prevalence of VCMs, but not the intensity of OD, represented by number of VCMs. The treatment with fluphenazine reduced the locomotor and exploratory activity in open field and the co-treatment with resveratrol protected partially. As some studies suggest that MAO enzyme is a possible target of resveratrol, the second aim was to evaluate the effects of resveratrol on MAO activity in vitro and in silico. Resveratrol inhibits both isoforms of MAO, however with a potency approximately of 28 times higher to MAO-A than MAO-B. The data from analyse of kinetic of inhibition of MAO in the presence of resveratrol showed an alteration in Vmax without alter the Km, indicating a non competitive profile of inhibition to MAO-A as well as MAO-B. Furthermore, a profile partially reversible to MAOA and completely reversible to MAO-B was obtained. In in silico study using the human enzyme, both isoforms of resveratrol interacted with the active site of enzyme avoiding the entry of substrate, the cis-resveratrol to MAOA, and the trans-resveratrol to MAO-B. Hydroxyl groups from resveratrol in the H-bonds of the enzymes can be responsible for the affinity with them. The third aim of this work was to investigate the effects of resveratrol, administered in drinking water at a dose of 20 mg/kg, in a chronic model of OD (126 days) induced by fluphenazine in rats, as well as evaluate if alterations on MAO activity could be involved in the possible protective effect of resveratrol. Fluphenazine reduced the body weight gain and the locomotor and exploratory activity of the animals and the co-treatment with resveratrol did not alter these parameters. The chronic treatment with fluphenazine increased the number of VCMs and the co-treatment with resveratrol reduced the intensity of VCMs. With regard to MAO, only the striatal activity of MAO-B in the group treated with fluphenazine decreased in relation to resveratrol group. In general, the results suggest that the tested doses of resveratrol were efficacious in reduce OD in rats. Besides resveratrol had inhibited the activity os MAO in vitro, it is probable that its effects were not dependents of a direct action of resveratrol on the activity of this enzyme. |
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Efeito do resveratrol nas alterações comportamentais induzidas por flufenazina em ratos e sua interação com a enzima monoaminoxidase in silico e in vitroEffect of resveratrol in fluphenazine-induced changes in rats and its interaction with the enzyme monoaminoxidase in silico and in vitroDiscinesia tardiaSistema dopaminérgicoMMVAntipsicóticosMAOTardive dyskinesiaDopaminergic systemVCMAntipsychoticsCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIATypical antipsychotics, commonly used to schizophrenia treatment, cause tardive dyskinesia in humans and orofacial dyskinesia (OD) in rodents. In the present work, we investigated the effects of resveratrol, a polyphenol with neuroprotective properties mainly found in red fruits and wine, on the behavioral alterations induced by acute and chronic treatment with fluphenazine in rats. Furthermore, we evaluated the effects of resveratrol on the enzyme monoaminoxidade (MAO) in vitro, in silico and the participation of MAO in OD. Thus, the first aim of the present study was to investigate the action of resveratrol (using a low dose), in an acute model of vacuous chewing movements (VCMs) induced by the administration of fluphenazine in rats. In this study, we observed that resveratrol, at a dose of 1 mg/kg administered 3 times a week during 21 days, reduced the prevalence of VCMs, but not the intensity of OD, represented by number of VCMs. The treatment with fluphenazine reduced the locomotor and exploratory activity in open field and the co-treatment with resveratrol protected partially. As some studies suggest that MAO enzyme is a possible target of resveratrol, the second aim was to evaluate the effects of resveratrol on MAO activity in vitro and in silico. Resveratrol inhibits both isoforms of MAO, however with a potency approximately of 28 times higher to MAO-A than MAO-B. The data from analyse of kinetic of inhibition of MAO in the presence of resveratrol showed an alteration in Vmax without alter the Km, indicating a non competitive profile of inhibition to MAO-A as well as MAO-B. Furthermore, a profile partially reversible to MAOA and completely reversible to MAO-B was obtained. In in silico study using the human enzyme, both isoforms of resveratrol interacted with the active site of enzyme avoiding the entry of substrate, the cis-resveratrol to MAOA, and the trans-resveratrol to MAO-B. Hydroxyl groups from resveratrol in the H-bonds of the enzymes can be responsible for the affinity with them. The third aim of this work was to investigate the effects of resveratrol, administered in drinking water at a dose of 20 mg/kg, in a chronic model of OD (126 days) induced by fluphenazine in rats, as well as evaluate if alterations on MAO activity could be involved in the possible protective effect of resveratrol. Fluphenazine reduced the body weight gain and the locomotor and exploratory activity of the animals and the co-treatment with resveratrol did not alter these parameters. The chronic treatment with fluphenazine increased the number of VCMs and the co-treatment with resveratrol reduced the intensity of VCMs. With regard to MAO, only the striatal activity of MAO-B in the group treated with fluphenazine decreased in relation to resveratrol group. In general, the results suggest that the tested doses of resveratrol were efficacious in reduce OD in rats. Besides resveratrol had inhibited the activity os MAO in vitro, it is probable that its effects were not dependents of a direct action of resveratrol on the activity of this enzyme.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESOs antipsicóticos típicos, comumente utilizados para o tratamento da esquizofrenia, causam discinesia tardia em humanos e discinesia orofacial (DO) em roedores. Neste trabalho, investigamos o efeito do resveratrol, um polifenol com propriedades neuroprotetoras encontrado principalmente em frutas vermelhas e no vinho tinto, sobre as alterações comportamentais induzidas por tratamento agudo e crônico com flufenazina em ratos. Além disso, avaliamos o efeito do resveratrol sobre a enzima monoaminoxidase (MAO) in vitro, in silico e a participação desta na DO. Com isto, o primeiro objetivo de nosso estudo foi investigar a ação do resveratrol (utilizando uma dose baixa), num modelo agudo de movimentos de mascar no vazio (MMV) induzido pela administração de flufenazina em ratos. Neste trabalho, observamos que o resveratrol, na dose de 1 mg/kg administrado 3 vezes na semana durante 21 dias, reduziu a prevalência dos MMV, mas não a intensidade da DO, representada pelo número de MMV. O tratamento com flufenazina reduziu a atividade locomotora e exploratória em campo aberto e o cotratamento com resveratrol protegeu parcialmente. Como alguns estudos sugerem que um dos possíveis alvos do resveratrol é a enzima MAO, o segundo objetivo foi avaliar o efeito do resveratrol sobre a atividade da MAO in vitro e in silico. O resveratrol inibiu ambas isoformas da MAO, porém com uma potência aproximadamente 28 vezes maior para a MAO-A do que para a MAO-B. Os dados da análise da cinética de inibição da MAO na presença do resveratrol demonstraram que houve alteração da Vmax sem alteração do Km, indicando um perfil de inibição do tipo não competitivo tanto para a MAO-A quanto para a MAO-B. Além disso, um perfil parcialmente reversível para MAO-A e completamente reversível para MAO-B foi obtido. No estudo in silico usando a enzima humana, ambas isoformas do resveratrol interagiram com o sítio ativo da enzima evitando a entrada do substrato, o cis-resveratrol para a MAO-A, e o trans-resveratrol para a MAO-B. Os grupos hidroxila do resveratrol formando ligações de hidrogênio com a enzima podem ser os responsáveis pela afinidade entre eles. O terceiro objetivo deste trabalho foi investigar o efeito do resveratrol, administrado na água de beber, na dose de 20 mg/kg, em um modelo crônico de DO (126 dias) induzida por flufenazina em ratos, bem como avaliar se a alteração na atividade da MAO poderia estar envolvida no possível efeito protetor do resveratrol. A flufenazina reduziu o ganho de peso e a atividade locomotora e exploratória dos animais e o co-tratamento com resveratrol não alterou estes parâmetros. O tratamento crônico com flufenazina aumentou o número de MMV e o co-tratamento com resveratrol reduziu a intensidade dos MMV. No que se refere à atividade da MAO, apenas a atividade da MAO-B no estriado do grupo tratado com flufenazina foi menor em relação ao grupo resveratrol. No geral, os resultados sugerem que as doses de resveratrol testadas foram eficazes em reduzir a DO em ratos. Embora o resveratrol tenha inibido a atividade da MAO in vitro, é provável que seus efeitos na DO não sejam dependentes de uma ação direta sobre a atividade da enzima.Universidade Federal de Santa MariaBrasilFarmacologiaUFSMPrograma de Pós-Graduação em FarmacologiaCentro de Ciências da SaúdeFachinetto, Roseleihttp://lattes.cnpq.br/7203076675431306Barbosa, Nilda Berenice de Vargashttp://lattes.cnpq.br/5901511067144019Ávila, Daiana Silva dehttp://lattes.cnpq.br/4355211015887363Dalla Corte, Cristiane Lenzhttp://lattes.cnpq.br/5296284169605317Oliveira, Sara Marchesan dehttp://lattes.cnpq.br/6574555059806902Furian, Ana Fláviahttp://lattes.cnpq.br/0865191340133424Busanello, Alcindo2019-08-29T14:40:21Z2019-08-29T14:40:21Z2016-08-11info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/18074porAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSM2022-06-13T19:09:33Zoai:repositorio.ufsm.br:1/18074Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2022-06-13T19:09:33Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
Efeito do resveratrol nas alterações comportamentais induzidas por flufenazina em ratos e sua interação com a enzima monoaminoxidase in silico e in vitro Effect of resveratrol in fluphenazine-induced changes in rats and its interaction with the enzyme monoaminoxidase in silico and in vitro |
title |
Efeito do resveratrol nas alterações comportamentais induzidas por flufenazina em ratos e sua interação com a enzima monoaminoxidase in silico e in vitro |
spellingShingle |
Efeito do resveratrol nas alterações comportamentais induzidas por flufenazina em ratos e sua interação com a enzima monoaminoxidase in silico e in vitro Busanello, Alcindo Discinesia tardia Sistema dopaminérgico MMV Antipsicóticos MAO Tardive dyskinesia Dopaminergic system VCM Antipsychotics CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Efeito do resveratrol nas alterações comportamentais induzidas por flufenazina em ratos e sua interação com a enzima monoaminoxidase in silico e in vitro |
title_full |
Efeito do resveratrol nas alterações comportamentais induzidas por flufenazina em ratos e sua interação com a enzima monoaminoxidase in silico e in vitro |
title_fullStr |
Efeito do resveratrol nas alterações comportamentais induzidas por flufenazina em ratos e sua interação com a enzima monoaminoxidase in silico e in vitro |
title_full_unstemmed |
Efeito do resveratrol nas alterações comportamentais induzidas por flufenazina em ratos e sua interação com a enzima monoaminoxidase in silico e in vitro |
title_sort |
Efeito do resveratrol nas alterações comportamentais induzidas por flufenazina em ratos e sua interação com a enzima monoaminoxidase in silico e in vitro |
author |
Busanello, Alcindo |
author_facet |
Busanello, Alcindo |
author_role |
author |
dc.contributor.none.fl_str_mv |
Fachinetto, Roselei http://lattes.cnpq.br/7203076675431306 Barbosa, Nilda Berenice de Vargas http://lattes.cnpq.br/5901511067144019 Ávila, Daiana Silva de http://lattes.cnpq.br/4355211015887363 Dalla Corte, Cristiane Lenz http://lattes.cnpq.br/5296284169605317 Oliveira, Sara Marchesan de http://lattes.cnpq.br/6574555059806902 Furian, Ana Flávia http://lattes.cnpq.br/0865191340133424 |
dc.contributor.author.fl_str_mv |
Busanello, Alcindo |
dc.subject.por.fl_str_mv |
Discinesia tardia Sistema dopaminérgico MMV Antipsicóticos MAO Tardive dyskinesia Dopaminergic system VCM Antipsychotics CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Discinesia tardia Sistema dopaminérgico MMV Antipsicóticos MAO Tardive dyskinesia Dopaminergic system VCM Antipsychotics CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
Typical antipsychotics, commonly used to schizophrenia treatment, cause tardive dyskinesia in humans and orofacial dyskinesia (OD) in rodents. In the present work, we investigated the effects of resveratrol, a polyphenol with neuroprotective properties mainly found in red fruits and wine, on the behavioral alterations induced by acute and chronic treatment with fluphenazine in rats. Furthermore, we evaluated the effects of resveratrol on the enzyme monoaminoxidade (MAO) in vitro, in silico and the participation of MAO in OD. Thus, the first aim of the present study was to investigate the action of resveratrol (using a low dose), in an acute model of vacuous chewing movements (VCMs) induced by the administration of fluphenazine in rats. In this study, we observed that resveratrol, at a dose of 1 mg/kg administered 3 times a week during 21 days, reduced the prevalence of VCMs, but not the intensity of OD, represented by number of VCMs. The treatment with fluphenazine reduced the locomotor and exploratory activity in open field and the co-treatment with resveratrol protected partially. As some studies suggest that MAO enzyme is a possible target of resveratrol, the second aim was to evaluate the effects of resveratrol on MAO activity in vitro and in silico. Resveratrol inhibits both isoforms of MAO, however with a potency approximately of 28 times higher to MAO-A than MAO-B. The data from analyse of kinetic of inhibition of MAO in the presence of resveratrol showed an alteration in Vmax without alter the Km, indicating a non competitive profile of inhibition to MAO-A as well as MAO-B. Furthermore, a profile partially reversible to MAOA and completely reversible to MAO-B was obtained. In in silico study using the human enzyme, both isoforms of resveratrol interacted with the active site of enzyme avoiding the entry of substrate, the cis-resveratrol to MAOA, and the trans-resveratrol to MAO-B. Hydroxyl groups from resveratrol in the H-bonds of the enzymes can be responsible for the affinity with them. The third aim of this work was to investigate the effects of resveratrol, administered in drinking water at a dose of 20 mg/kg, in a chronic model of OD (126 days) induced by fluphenazine in rats, as well as evaluate if alterations on MAO activity could be involved in the possible protective effect of resveratrol. Fluphenazine reduced the body weight gain and the locomotor and exploratory activity of the animals and the co-treatment with resveratrol did not alter these parameters. The chronic treatment with fluphenazine increased the number of VCMs and the co-treatment with resveratrol reduced the intensity of VCMs. With regard to MAO, only the striatal activity of MAO-B in the group treated with fluphenazine decreased in relation to resveratrol group. In general, the results suggest that the tested doses of resveratrol were efficacious in reduce OD in rats. Besides resveratrol had inhibited the activity os MAO in vitro, it is probable that its effects were not dependents of a direct action of resveratrol on the activity of this enzyme. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-08-11 2019-08-29T14:40:21Z 2019-08-29T14:40:21Z |
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 |
http://repositorio.ufsm.br/handle/1/18074 |
url |
http://repositorio.ufsm.br/handle/1/18074 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Farmacologia UFSM Programa de Pós-Graduação em Farmacologia Centro de Ciências da Saúde |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Farmacologia UFSM Programa de Pós-Graduação em Farmacologia Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Manancial - Repositório Digital da UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
collection |
Manancial - Repositório Digital da UFSM |
repository.name.fl_str_mv |
Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
atendimento.sib@ufsm.br||tedebc@gmail.com |
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1805922111103959040 |