Envolvimento do receptor de potencial transitório anquirina 1 na analgesia induzida pela fração acetato de etila de Tabernaemontana catharinensis em camundongos
Ano de defesa: | 2018 |
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Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | , |
Tipo de documento: | Dissertação |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Universidade Federal de Santa Maria
Centro de Ciências Naturais e Exatas |
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica
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Departamento: |
Bioquímica
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País: |
Brasil
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Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://repositorio.ufsm.br/handle/1/20392 |
Resumo: | Pain is one condition that limits productivity and reduces the life quality of affected patients. Although exist an arsenal of effective analgesics, there is a great concern related to their safety and adverse effects making their clinical use problematic and motivating many people to choose treatments based on alternative medicine. Tabernaemontana catharinensis is a tree popularly known as cobrina. The diversity of biological actions found in the leaves of T. catharinensis ethyl acetate fraction (Eta) were attributed to the presence of majority compounds, among them the polyphenol gallic acid, known by its antagonist action of transient receptor potential ankyrin 1 (TRPA1). Until the moment, there are preclinical studies supporting the peripheral antinociceptive activity of this fraction. However, it is necessary to elucidate its action mechanism, and a likely Eta target could be the TRPA1 ion channel. The TRPA1 is essential for the detection and transmission of painful stimuli. This channel is activated by naturally occurring irritants and by endogenous oxidizing substances. Moreover, its activation is related to the development and maintenance of several painful conditions. In this context, we verified the involvement of the TRPA1 on Eta’s antinociceptive and anti-inflammatory effect in male Swiss mice (30-35 g). In order to elucidate the Eta’s action mechanism were performed calcium (Ca2+) influx and [3H]-resiniferatoxin specific binding assays. The effects of Eta’s oral treatment (0.01-100 mg/kg) or vehicle (10 ml/kg) were also evaluated by nociceptive (spontaneous nociception, mechanical and cold allodynia) and inflammatory parameters (edema measurement) following intraplantar administration of TRPA1 agonists hydrogen peroxide (H2O2), cinnamaldehyde or allyl isothiocyanate in mice. In addition, the effects of Eta were evaluated on complete Freund's adjuvant (CFA)-induced chronic inflammatory pain model, on postoperative pain model and on acute and chronic peripheral neuropathy induced by paclitaxel. Mice subjected to the CFA-induced chronic inflammatory pain model were used to analyze the fraction’s effect on oxidative parameters, such as tissue oxidation capacity and H2O2 levels. Eta inhibited the TRPA1 agonist-induced Ca2+ influx [Imax = 72.4±1.5%; IC50 = 0.023(0.004–0.135)μg/ml], but not vanilloid 1 (TRPV1) agonist-induced, such as Eta did not displace the [3H]-resiniferatoxin binding. Eta (0.1-100 mg/kg) inhibited the spontaneous nociception (ID50 = 0.043(0.002-0.723)mg/kg), mechanical (ID50 = 7.417(1.426-38.570)mg/kg) and cold allodynia, as well as edema development caused by TRPA1 agonists injections. Moreover, Eta (100 mg/kg) prevented and reversed the CFA-induced chronic inflammatory pain (Imax = 55.8±13.7%, Imax = 80.4±5.1%, respectively) and postoperative pain (Imax = 88.0±11.6%, Imax = 51.3±14.9%, respectively), been also effective in reversing the acute (Imax = 94.4±12.4%) and chronic (Imax = 86.8±8.6%) peripheral neuropathy induced by paclitaxel. These effects seem to occur by TRPA1 channels pathway, and independently of TRPV1 or oxidative mechanisms. Our results demonstrate that Eta-induced antinociception and anti-inflammatory effect occur by TRPA1 inhibition, enabling the use of this preparation as a potential therapeutic agent to treat pathological pains. |
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2021-03-10T10:35:35Z2021-03-10T10:35:35Z2018-03-09http://repositorio.ufsm.br/handle/1/20392Pain is one condition that limits productivity and reduces the life quality of affected patients. Although exist an arsenal of effective analgesics, there is a great concern related to their safety and adverse effects making their clinical use problematic and motivating many people to choose treatments based on alternative medicine. Tabernaemontana catharinensis is a tree popularly known as cobrina. The diversity of biological actions found in the leaves of T. catharinensis ethyl acetate fraction (Eta) were attributed to the presence of majority compounds, among them the polyphenol gallic acid, known by its antagonist action of transient receptor potential ankyrin 1 (TRPA1). Until the moment, there are preclinical studies supporting the peripheral antinociceptive activity of this fraction. However, it is necessary to elucidate its action mechanism, and a likely Eta target could be the TRPA1 ion channel. The TRPA1 is essential for the detection and transmission of painful stimuli. This channel is activated by naturally occurring irritants and by endogenous oxidizing substances. Moreover, its activation is related to the development and maintenance of several painful conditions. In this context, we verified the involvement of the TRPA1 on Eta’s antinociceptive and anti-inflammatory effect in male Swiss mice (30-35 g). In order to elucidate the Eta’s action mechanism were performed calcium (Ca2+) influx and [3H]-resiniferatoxin specific binding assays. The effects of Eta’s oral treatment (0.01-100 mg/kg) or vehicle (10 ml/kg) were also evaluated by nociceptive (spontaneous nociception, mechanical and cold allodynia) and inflammatory parameters (edema measurement) following intraplantar administration of TRPA1 agonists hydrogen peroxide (H2O2), cinnamaldehyde or allyl isothiocyanate in mice. In addition, the effects of Eta were evaluated on complete Freund's adjuvant (CFA)-induced chronic inflammatory pain model, on postoperative pain model and on acute and chronic peripheral neuropathy induced by paclitaxel. Mice subjected to the CFA-induced chronic inflammatory pain model were used to analyze the fraction’s effect on oxidative parameters, such as tissue oxidation capacity and H2O2 levels. Eta inhibited the TRPA1 agonist-induced Ca2+ influx [Imax = 72.4±1.5%; IC50 = 0.023(0.004–0.135)μg/ml], but not vanilloid 1 (TRPV1) agonist-induced, such as Eta did not displace the [3H]-resiniferatoxin binding. Eta (0.1-100 mg/kg) inhibited the spontaneous nociception (ID50 = 0.043(0.002-0.723)mg/kg), mechanical (ID50 = 7.417(1.426-38.570)mg/kg) and cold allodynia, as well as edema development caused by TRPA1 agonists injections. Moreover, Eta (100 mg/kg) prevented and reversed the CFA-induced chronic inflammatory pain (Imax = 55.8±13.7%, Imax = 80.4±5.1%, respectively) and postoperative pain (Imax = 88.0±11.6%, Imax = 51.3±14.9%, respectively), been also effective in reversing the acute (Imax = 94.4±12.4%) and chronic (Imax = 86.8±8.6%) peripheral neuropathy induced by paclitaxel. These effects seem to occur by TRPA1 channels pathway, and independently of TRPV1 or oxidative mechanisms. Our results demonstrate that Eta-induced antinociception and anti-inflammatory effect occur by TRPA1 inhibition, enabling the use of this preparation as a potential therapeutic agent to treat pathological pains.A dor é uma condição que limita a produtividade e diminui a qualidade de vida dos pacientes por ela acometidos. Embora exista um arsenal de analgésicos efetivos, há uma grande preocupação relacionada com sua segurança e efeitos adversos, tornando seu uso clínico problemático e fazendo com que muitas pessoas optem por tratamentos baseados na medicina alternativa. Tabernaemontana catharinensis é uma árvore popularmente conhecida como cobrina. A diversidade de ações biológicas encontradas na fração acetato de etila das folhas de T. catharinensis (Eta) foram atribuídas a presença de compostos majoritários, entre eles o polifenol ácido gálico, conhecido por sua ação antagonista do receptor de potencial transitório anquirina 1 (TRPA1, do inglês transient receptor potential ankyrin 1). Até o momento, existem estudos pré-clínicos suportando a atividade antinociceptiva periférica desta fração. Entretanto, necessita-se elucidar seu mecanismo de ação, e um provável alvo da fração Eta poderia ser o canal iônico TRPA1. O TRPA1 é essencial para a detecção e transmissão de estímulos dolorosos. Este canal é ativado por substâncias irritantes de origem natural e por substâncias oxidantes endógenas. Além disso, sua ativação está relacionada ao desenvolvimento e manutenção de diversas condições dolorosas. Neste contexto, nós verificamos o envolvimento do TRPA1 no efeito antinociceptivo e anti-inflamatório da fração Eta em camundongos Swiss machos (30-35 g). A fim de elucidar o mecanismo de ação da Eta foram realizados ensaios de influxo de cálcio (Ca2+) e de união específica (deslocamento do radioligante [3H]-resiniferatoxina). Os efeitos do tratamento oral de Eta (0.01-100 mg/kg) ou veículo (10 ml/kg) foram avaliados por meio de parâmetros nociceptivos (nocicepção espontânea, alodínia mecânica e ao frio) e inflamatórios (medida de edema) seguido da administração intraplantar dos agonistas TRPA1 peróxido de hidrogênio (H2O2), cinamaldeído ou isotiocianato de alila em camundongos. Além disso, os efeitos de Eta foram avaliados sobre um modelo de dor inflamatória crônica induzido pelo adjuvante completo de Freund (CFA, do inglês complete Freund's adjuvant), sobre um modelo de dor pós-operatória e sobre a neuropatia periférica aguda e crônica induzida por paclitaxel. Parâmetros oxidativos como a capacidade de oxidação tecidual e níveis de H2O2 foram avaliados em amostras teciduais de camundongos submetidos ao modelo de dor inflamatória crônica induzido por CFA. Eta inibiu o influxo de Ca2+ induzido por um agonista TRPA1 [Imáx = 72,4±1,5%; CI50 = 0,023(0,004–0,135)μg/ml], mas não por um agonista vaniloide 1 (TRPV1), assim como não deslocou o radioligante [3H]-resiniferatoxina. Eta (0.1-100 mg/kg) inibiu a nocicepção espontânea (DI50 = 0,043(0,002-0,723)mg/kg), alodínia mecânica (DI50 = 7,417(1,426-38,570)mg/kg) e ao frio, assim como o desenvolvimento de edema causado pela injeção de diferentes agonistas TRPA1. Além disso, Eta (100 mg/kg) preveniu e reverteu a dor inflamatória crônica induzida por CFA (Imáx = 55,8±13,7%, Imáx = 80,4±5,1%, respectivamente) e a dor pós-operatória (Imáx = 88,0±11,6%, Imáx = 51,3±14,9%, respectivamente), sendo também efetiva em reverter a neuropatia periférica aguda (Imáx = 94,4±12,4%) e crônica (Imáx = 86,8±8,6%) induzida pelo paclitaxel. Estes efeitos parecem ocorrer via canal TRPA1, e independentemente do TRPV1 ou de mecanismos oxidativos. Nossos resultados demonstram que Eta exerce sua atividade antinociceptiva e anti-inflamatória por meio da inibição do canal TRPA1, possibilitando o uso desta preparação como um agente terapêutico potencial para tratar dores patológicas.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESporUniversidade Federal de Santa MariaCentro de Ciências Naturais e ExatasPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaUFSMBrasilBioquímicaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessCobrinaAntinocicepçãoDor inflamatória crônicaDor pós-operatóriaPaclitaxelInfluxo de cálcioAntinociceptionChronic inflammatory painPostoperative painPaclitaxelCalcium influxCNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICAEnvolvimento do receptor de potencial transitório anquirina 1 na analgesia induzida pela fração acetato de etila de Tabernaemontana catharinensis em camundongosTransient receptor potential ankyrin 1 involviment in analgesia induced by Tabernaemontana catharinensis ethyl acetate fraction in miceinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisOliveira, Sara Marchesan dehttp://lattes.cnpq.br/6574555059806902Bochi, Guilherme Vargashttp://lattes.cnpq.br/4191221572795869Torres, Iraci Lucena da Silvahttp://lattes.cnpq.br/3765572633415830http://lattes.cnpq.br/7964782400647822Brum, Evelyne da Silva2008000000026002f2fa82b-4312-45cb-99e1-777746963f4beb7b45e8-8665-485f-b659-5d128835a0456e2ef066-1dbd-42a0-9cf7-367e79b50354b9804fb9-2412-4de8-9e13-003a2a52f378reponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALDIS_PPGBT_2018_BRUM_EVELYNE.pdfDIS_PPGBT_2018_BRUM_EVELYNE.pdfDissertação de Mestradoapplication/pdf5810578http://repositorio.ufsm.br/bitstream/1/20392/1/DIS_PPGBT_2018_BRUM_EVELYNE.pdf15a27f134dbed94a85a92c6bc9952862MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Envolvimento do receptor de potencial transitório anquirina 1 na analgesia induzida pela fração acetato de etila de Tabernaemontana catharinensis em camundongos |
dc.title.alternative.eng.fl_str_mv |
Transient receptor potential ankyrin 1 involviment in analgesia induced by Tabernaemontana catharinensis ethyl acetate fraction in mice |
title |
Envolvimento do receptor de potencial transitório anquirina 1 na analgesia induzida pela fração acetato de etila de Tabernaemontana catharinensis em camundongos |
spellingShingle |
Envolvimento do receptor de potencial transitório anquirina 1 na analgesia induzida pela fração acetato de etila de Tabernaemontana catharinensis em camundongos Brum, Evelyne da Silva Cobrina Antinocicepção Dor inflamatória crônica Dor pós-operatória Paclitaxel Influxo de cálcio Antinociception Chronic inflammatory pain Postoperative pain Paclitaxel Calcium influx CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
title_short |
Envolvimento do receptor de potencial transitório anquirina 1 na analgesia induzida pela fração acetato de etila de Tabernaemontana catharinensis em camundongos |
title_full |
Envolvimento do receptor de potencial transitório anquirina 1 na analgesia induzida pela fração acetato de etila de Tabernaemontana catharinensis em camundongos |
title_fullStr |
Envolvimento do receptor de potencial transitório anquirina 1 na analgesia induzida pela fração acetato de etila de Tabernaemontana catharinensis em camundongos |
title_full_unstemmed |
Envolvimento do receptor de potencial transitório anquirina 1 na analgesia induzida pela fração acetato de etila de Tabernaemontana catharinensis em camundongos |
title_sort |
Envolvimento do receptor de potencial transitório anquirina 1 na analgesia induzida pela fração acetato de etila de Tabernaemontana catharinensis em camundongos |
author |
Brum, Evelyne da Silva |
author_facet |
Brum, Evelyne da Silva |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Oliveira, Sara Marchesan de |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/6574555059806902 |
dc.contributor.referee1.fl_str_mv |
Bochi, Guilherme Vargas |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/4191221572795869 |
dc.contributor.referee2.fl_str_mv |
Torres, Iraci Lucena da Silva |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/3765572633415830 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/7964782400647822 |
dc.contributor.author.fl_str_mv |
Brum, Evelyne da Silva |
contributor_str_mv |
Oliveira, Sara Marchesan de Bochi, Guilherme Vargas Torres, Iraci Lucena da Silva |
dc.subject.por.fl_str_mv |
Cobrina Antinocicepção Dor inflamatória crônica Dor pós-operatória Paclitaxel Influxo de cálcio |
topic |
Cobrina Antinocicepção Dor inflamatória crônica Dor pós-operatória Paclitaxel Influxo de cálcio Antinociception Chronic inflammatory pain Postoperative pain Paclitaxel Calcium influx CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
dc.subject.eng.fl_str_mv |
Antinociception Chronic inflammatory pain Postoperative pain Paclitaxel Calcium influx |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
description |
Pain is one condition that limits productivity and reduces the life quality of affected patients. Although exist an arsenal of effective analgesics, there is a great concern related to their safety and adverse effects making their clinical use problematic and motivating many people to choose treatments based on alternative medicine. Tabernaemontana catharinensis is a tree popularly known as cobrina. The diversity of biological actions found in the leaves of T. catharinensis ethyl acetate fraction (Eta) were attributed to the presence of majority compounds, among them the polyphenol gallic acid, known by its antagonist action of transient receptor potential ankyrin 1 (TRPA1). Until the moment, there are preclinical studies supporting the peripheral antinociceptive activity of this fraction. However, it is necessary to elucidate its action mechanism, and a likely Eta target could be the TRPA1 ion channel. The TRPA1 is essential for the detection and transmission of painful stimuli. This channel is activated by naturally occurring irritants and by endogenous oxidizing substances. Moreover, its activation is related to the development and maintenance of several painful conditions. In this context, we verified the involvement of the TRPA1 on Eta’s antinociceptive and anti-inflammatory effect in male Swiss mice (30-35 g). In order to elucidate the Eta’s action mechanism were performed calcium (Ca2+) influx and [3H]-resiniferatoxin specific binding assays. The effects of Eta’s oral treatment (0.01-100 mg/kg) or vehicle (10 ml/kg) were also evaluated by nociceptive (spontaneous nociception, mechanical and cold allodynia) and inflammatory parameters (edema measurement) following intraplantar administration of TRPA1 agonists hydrogen peroxide (H2O2), cinnamaldehyde or allyl isothiocyanate in mice. In addition, the effects of Eta were evaluated on complete Freund's adjuvant (CFA)-induced chronic inflammatory pain model, on postoperative pain model and on acute and chronic peripheral neuropathy induced by paclitaxel. Mice subjected to the CFA-induced chronic inflammatory pain model were used to analyze the fraction’s effect on oxidative parameters, such as tissue oxidation capacity and H2O2 levels. Eta inhibited the TRPA1 agonist-induced Ca2+ influx [Imax = 72.4±1.5%; IC50 = 0.023(0.004–0.135)μg/ml], but not vanilloid 1 (TRPV1) agonist-induced, such as Eta did not displace the [3H]-resiniferatoxin binding. Eta (0.1-100 mg/kg) inhibited the spontaneous nociception (ID50 = 0.043(0.002-0.723)mg/kg), mechanical (ID50 = 7.417(1.426-38.570)mg/kg) and cold allodynia, as well as edema development caused by TRPA1 agonists injections. Moreover, Eta (100 mg/kg) prevented and reversed the CFA-induced chronic inflammatory pain (Imax = 55.8±13.7%, Imax = 80.4±5.1%, respectively) and postoperative pain (Imax = 88.0±11.6%, Imax = 51.3±14.9%, respectively), been also effective in reversing the acute (Imax = 94.4±12.4%) and chronic (Imax = 86.8±8.6%) peripheral neuropathy induced by paclitaxel. These effects seem to occur by TRPA1 channels pathway, and independently of TRPV1 or oxidative mechanisms. Our results demonstrate that Eta-induced antinociception and anti-inflammatory effect occur by TRPA1 inhibition, enabling the use of this preparation as a potential therapeutic agent to treat pathological pains. |
publishDate |
2018 |
dc.date.issued.fl_str_mv |
2018-03-09 |
dc.date.accessioned.fl_str_mv |
2021-03-10T10:35:35Z |
dc.date.available.fl_str_mv |
2021-03-10T10:35:35Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/20392 |
url |
http://repositorio.ufsm.br/handle/1/20392 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
200800000002 |
dc.relation.confidence.fl_str_mv |
600 |
dc.relation.authority.fl_str_mv |
2f2fa82b-4312-45cb-99e1-777746963f4b eb7b45e8-8665-485f-b659-5d128835a045 6e2ef066-1dbd-42a0-9cf7-367e79b50354 b9804fb9-2412-4de8-9e13-003a2a52f378 |
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.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências Naturais e Exatas |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Bioquímica |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências Naturais e Exatas |
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 |
bitstream.url.fl_str_mv |
http://repositorio.ufsm.br/bitstream/1/20392/1/DIS_PPGBT_2018_BRUM_EVELYNE.pdf http://repositorio.ufsm.br/bitstream/1/20392/2/license_rdf http://repositorio.ufsm.br/bitstream/1/20392/3/license.txt http://repositorio.ufsm.br/bitstream/1/20392/4/DIS_PPGBT_2018_BRUM_EVELYNE.pdf.txt http://repositorio.ufsm.br/bitstream/1/20392/5/DIS_PPGBT_2018_BRUM_EVELYNE.pdf.jpg |
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bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 MD5 MD5 |
repository.name.fl_str_mv |
Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
|
_version_ |
1794524407688855552 |