Efeito modulatório in vitro da quetiapina não-metabolizada na citotoxicidade e ativação inflamatória de células brancas e na formação de armadilhas extracelulares de neutrófilos
Ano de defesa: | 2020 |
---|---|
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 da Saúde |
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Farmacologia
|
Departamento: |
Farmacologia
|
País: |
Brasil
|
Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://repositorio.ufsm.br/handle/1/24360 |
Resumo: | Quetiapine (QUE) is a highly complex drug that, due to its different forms of interaction with receptors, has great clinical applicability. Although widely used, QUE brings with it a range of side effects that include, in addition to disorders of the metabolic pathway, changes in levels of the immune system. Quickly metabolised by the liver, it is transformed into its main active metabolite, norquetiapine, being then the clearance of QUE only 5%. This percentage may increase in elderly people, with liver failure or through interaction with other drugs. Thus, non-metabolized quetiapine (nmQUE) may be responsible for inducing peripheral immune changes, especially low-grade chronic inflammation. Therefor, our objective was to evaluate in vitro the potential cytotoxicity and modulatory effect of nmQUE on inflammatory activation and in the formation of extracellular neutrophil traps (NETs). For this, cellular experiments were carried out, using a commercial macrophage cell line (RAW 264.7), in addition to leukocytes and neutrophils, obtained through blood collection from volunteers. The cells were cultured under ideal conditions according to standardisation until the concentration of 1x105 cells/mL was obtained. Then, macrophages, leukocytes and neutrophils were treated and activated, or not, with a mitogenic agent, phytohemagglutinin (PHA). After 24 hours, they were treated with different concentrations of QUE (25, 50, 100, 200 and 400 μg/L). Given at 24 hours of treatment, the cell viability and cytotoxicity of all cells were evaluated using the 3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium assay (MTT). With the result of these tests, the concentration of choice for QUE to be used in the following analyses was defined: 100 μg/L. Thus, after 72 hours of treatment, cell proliferation, oxidative molecules and gene and protein expression (via Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) of pro-inflammatory and anti-inflammatory cytokines in RAW 264.7 were evaluated. In addition, to assess the effect of nmQUE on the formation of NETs, neutrophils were previously activated, or not, by exposure to yeast cells for 2 hours, followed by exposure to QUE for an additional 2 hours, then fixed and stained, followed by images capture and evaluations consistent with the experiment.The results show the high capacity of nmQUE to interact with immune cells, not showing cytotoxicity, but modifying its inflammatory profile according to its initial state, thus corroborating it with a pro and anti-inflammatory pharmacological effect. In relation to the formation of NETs, neutrophils were surprisingly induced, with nmQUE being responsible for hyper-formation of NETs. With these results, it is concluded that nmQUE exerts an influence on the pathways of the immune system, being possibly responsible for the existence of morbidities and side effects, which represents the major problem of antipsychotic therapy. |
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2022-05-19T14:02:07Z2022-05-19T14:02:07Z2020-02-19http://repositorio.ufsm.br/handle/1/24360Quetiapine (QUE) is a highly complex drug that, due to its different forms of interaction with receptors, has great clinical applicability. Although widely used, QUE brings with it a range of side effects that include, in addition to disorders of the metabolic pathway, changes in levels of the immune system. Quickly metabolised by the liver, it is transformed into its main active metabolite, norquetiapine, being then the clearance of QUE only 5%. This percentage may increase in elderly people, with liver failure or through interaction with other drugs. Thus, non-metabolized quetiapine (nmQUE) may be responsible for inducing peripheral immune changes, especially low-grade chronic inflammation. Therefor, our objective was to evaluate in vitro the potential cytotoxicity and modulatory effect of nmQUE on inflammatory activation and in the formation of extracellular neutrophil traps (NETs). For this, cellular experiments were carried out, using a commercial macrophage cell line (RAW 264.7), in addition to leukocytes and neutrophils, obtained through blood collection from volunteers. The cells were cultured under ideal conditions according to standardisation until the concentration of 1x105 cells/mL was obtained. Then, macrophages, leukocytes and neutrophils were treated and activated, or not, with a mitogenic agent, phytohemagglutinin (PHA). After 24 hours, they were treated with different concentrations of QUE (25, 50, 100, 200 and 400 μg/L). Given at 24 hours of treatment, the cell viability and cytotoxicity of all cells were evaluated using the 3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium assay (MTT). With the result of these tests, the concentration of choice for QUE to be used in the following analyses was defined: 100 μg/L. Thus, after 72 hours of treatment, cell proliferation, oxidative molecules and gene and protein expression (via Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) of pro-inflammatory and anti-inflammatory cytokines in RAW 264.7 were evaluated. In addition, to assess the effect of nmQUE on the formation of NETs, neutrophils were previously activated, or not, by exposure to yeast cells for 2 hours, followed by exposure to QUE for an additional 2 hours, then fixed and stained, followed by images capture and evaluations consistent with the experiment.The results show the high capacity of nmQUE to interact with immune cells, not showing cytotoxicity, but modifying its inflammatory profile according to its initial state, thus corroborating it with a pro and anti-inflammatory pharmacological effect. In relation to the formation of NETs, neutrophils were surprisingly induced, with nmQUE being responsible for hyper-formation of NETs. With these results, it is concluded that nmQUE exerts an influence on the pathways of the immune system, being possibly responsible for the existence of morbidities and side effects, which represents the major problem of antipsychotic therapy.A quetiapina (QUE) é um fármaco altamente complexo que por suas diferentes formas de interação com os receptores apresenta grande aplicabilidade clínica. Embora muito utilizada, a QUE traz consigo uma gama de efeitos colaterais que incluem além de distúrbios da via metabólica, alterações em nível de sistema imune. Rapidamente metabolizada pelo fígado ela é transformada em seu principal metabólito ativo, a norquetiapina, estando então, à depuração da QUE em apenas 5%. Este percentual pode aumentar em pessoas idosas, com isuficiência hepática ou através da interação com outros fármacos. Com isso, a quetiapina não metabolizada (nmQUE) pode ser responsável pela indução das alteraçãoes imunológicas periféricas, principalmente a inflamação crônica de baixo grau. Assim, nosso objetivo concentrou-se em avaliar in vitro o potencial efeito citotóxico e modulatório da nmQUE na ativação inflamatória e, na formação de armadilhas extracelulares de neutrófilos (NETs). Para isso, foram realizados experimentos celulares, utilizando a linhagem celular comercial de macrófagos (RAW 264.7), além de leucócitos e neutrófilos, obtidos através de coleta sanguínea de voluntários. As células foram cultivadas em condições ideais conforme a padronização até a obtenção da concentração de 1x105 cél/mL. Em seguida, os macrófagos, leucócitos e neutrófilos foram tratados e ativados ou não com agente mitogênico, a fitohemaglutinina (PHA). Após 24 horas, foram tratados com diferentes concentrações de QUE (25, 50, 100, 200 e 400 μg/L). Dada às 24 horas do tratamento, foi avaliada a viabilidade celular e citoxicidade de todas as células, através do ensaio espectrofotométrico do Brometo de 3-[4,5-dimetiltiazol-2-il]-2,5-difeniltetrazólio (MTT). Com o resultado destes testes, fora definida a concentração de escolha da QUE para ser utilizada nas análises seguintes: 100 μg/L. Com isso, após 72 horas de tratamento, avaliou-se a proliferação celular, moléculas oxidativas e a expressão proteica e gênica (via Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) de citocinas pró- inflamatórias e anti-inflamatória em RAW 264.7. Ainda, para avaliar o efeito da nmQUE na formação de NETs, os neutrófilos foram previamente ativados ou não pela exposição a células de leveduras por 2 horas, seguidos da exposição à QUE por mais 2 horas, estando posteriormente fixados e corados, seguidos pela captura de imagens e avaliação condizente. Os resultados mostram a alta capacidade de interação da nmQUE para com as células imunológicas, não demostrando citoxicidade, porém modificando seu perfil inflamatório conforme seu estado inicial, corroborando assim, para com um efeito farmacológico pró e anti- inflamatório. Já em relação a formação de NETs, os neutrófilos foram induzidos surpreendentemente, estando a nmQUE responsável por uma hiperformação das NETs. Com esses resultados, conclui-se que nmQUE exerce influência nas vias do sistema imune, sendo possivelmente responsável pela existência de morbidades e efeitos colaterais, o que representa o grande problema da terapia antipsicótica.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESporUniversidade Federal de Santa MariaCentro de Ciências da SaúdePrograma de Pós-Graduação em FarmacologiaUFSMBrasilFarmacologiaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessAntipsicóticosSistema ImuneMacrófagoLeucócitosAntipsychoticsImune systemMacrophageLeukocytesCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAEfeito modulatório in vitro da quetiapina não-metabolizada na citotoxicidade e ativação inflamatória de células brancas e na formação de armadilhas extracelulares de neutrófilosIn vitro modulatory effect of non-metabolized quetiapine on cytotoxicity and inflammatory activation of white cells and formation of neutrophile extracellular trapsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisBarbisan, Fernandahttp://lattes.cnpq.br/1428674947616182Cruz, Ivana Beatrice Mânica daPavanato, Maria AmáliaNogueira-Librelotto, Daniele Ruberthttp://lattes.cnpq.br/3529685763828545Turra, Bárbara Osmarin20100000000060060060060060060001a07e6d-51dc-4a6d-9730-97bd647aa96f1fb3fdcd-0fb9-4377-992b-f770c179978e0c52547c-372f-4eed-89c6-3ef315588e0dffd04c36-7494-45de-941b-897fca290f069d1c66f5-d109-465a-836c-664c39f70dd5reponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALDIS_PPGFARMACOLOGIA_2020_TURRA_BÁRBARA.pdfDIS_PPGFARMACOLOGIA_2020_TURRA_BÁRBARA.pdfDissertação de mestradoapplication/pdf2929968http://repositorio.ufsm.br/bitstream/1/24360/1/DIS_PPGFARMACOLOGIA_2020_TURRA_B%c3%81RBARA.pdff9547b442f3395ec8dc8f6fae53e22cbMD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Efeito modulatório in vitro da quetiapina não-metabolizada na citotoxicidade e ativação inflamatória de células brancas e na formação de armadilhas extracelulares de neutrófilos |
dc.title.alternative.eng.fl_str_mv |
In vitro modulatory effect of non-metabolized quetiapine on cytotoxicity and inflammatory activation of white cells and formation of neutrophile extracellular traps |
title |
Efeito modulatório in vitro da quetiapina não-metabolizada na citotoxicidade e ativação inflamatória de células brancas e na formação de armadilhas extracelulares de neutrófilos |
spellingShingle |
Efeito modulatório in vitro da quetiapina não-metabolizada na citotoxicidade e ativação inflamatória de células brancas e na formação de armadilhas extracelulares de neutrófilos Turra, Bárbara Osmarin Antipsicóticos Sistema Imune Macrófago Leucócitos Antipsychotics Imune system Macrophage Leukocytes CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Efeito modulatório in vitro da quetiapina não-metabolizada na citotoxicidade e ativação inflamatória de células brancas e na formação de armadilhas extracelulares de neutrófilos |
title_full |
Efeito modulatório in vitro da quetiapina não-metabolizada na citotoxicidade e ativação inflamatória de células brancas e na formação de armadilhas extracelulares de neutrófilos |
title_fullStr |
Efeito modulatório in vitro da quetiapina não-metabolizada na citotoxicidade e ativação inflamatória de células brancas e na formação de armadilhas extracelulares de neutrófilos |
title_full_unstemmed |
Efeito modulatório in vitro da quetiapina não-metabolizada na citotoxicidade e ativação inflamatória de células brancas e na formação de armadilhas extracelulares de neutrófilos |
title_sort |
Efeito modulatório in vitro da quetiapina não-metabolizada na citotoxicidade e ativação inflamatória de células brancas e na formação de armadilhas extracelulares de neutrófilos |
author |
Turra, Bárbara Osmarin |
author_facet |
Turra, Bárbara Osmarin |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Barbisan, Fernanda |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/1428674947616182 |
dc.contributor.advisor-co1.fl_str_mv |
Cruz, Ivana Beatrice Mânica da |
dc.contributor.referee1.fl_str_mv |
Pavanato, Maria Amália |
dc.contributor.referee2.fl_str_mv |
Nogueira-Librelotto, Daniele Rubert |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/3529685763828545 |
dc.contributor.author.fl_str_mv |
Turra, Bárbara Osmarin |
contributor_str_mv |
Barbisan, Fernanda Cruz, Ivana Beatrice Mânica da Pavanato, Maria Amália Nogueira-Librelotto, Daniele Rubert |
dc.subject.por.fl_str_mv |
Antipsicóticos Sistema Imune Macrófago Leucócitos |
topic |
Antipsicóticos Sistema Imune Macrófago Leucócitos Antipsychotics Imune system Macrophage Leukocytes CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
dc.subject.eng.fl_str_mv |
Antipsychotics Imune system Macrophage Leukocytes |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
Quetiapine (QUE) is a highly complex drug that, due to its different forms of interaction with receptors, has great clinical applicability. Although widely used, QUE brings with it a range of side effects that include, in addition to disorders of the metabolic pathway, changes in levels of the immune system. Quickly metabolised by the liver, it is transformed into its main active metabolite, norquetiapine, being then the clearance of QUE only 5%. This percentage may increase in elderly people, with liver failure or through interaction with other drugs. Thus, non-metabolized quetiapine (nmQUE) may be responsible for inducing peripheral immune changes, especially low-grade chronic inflammation. Therefor, our objective was to evaluate in vitro the potential cytotoxicity and modulatory effect of nmQUE on inflammatory activation and in the formation of extracellular neutrophil traps (NETs). For this, cellular experiments were carried out, using a commercial macrophage cell line (RAW 264.7), in addition to leukocytes and neutrophils, obtained through blood collection from volunteers. The cells were cultured under ideal conditions according to standardisation until the concentration of 1x105 cells/mL was obtained. Then, macrophages, leukocytes and neutrophils were treated and activated, or not, with a mitogenic agent, phytohemagglutinin (PHA). After 24 hours, they were treated with different concentrations of QUE (25, 50, 100, 200 and 400 μg/L). Given at 24 hours of treatment, the cell viability and cytotoxicity of all cells were evaluated using the 3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium assay (MTT). With the result of these tests, the concentration of choice for QUE to be used in the following analyses was defined: 100 μg/L. Thus, after 72 hours of treatment, cell proliferation, oxidative molecules and gene and protein expression (via Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) of pro-inflammatory and anti-inflammatory cytokines in RAW 264.7 were evaluated. In addition, to assess the effect of nmQUE on the formation of NETs, neutrophils were previously activated, or not, by exposure to yeast cells for 2 hours, followed by exposure to QUE for an additional 2 hours, then fixed and stained, followed by images capture and evaluations consistent with the experiment.The results show the high capacity of nmQUE to interact with immune cells, not showing cytotoxicity, but modifying its inflammatory profile according to its initial state, thus corroborating it with a pro and anti-inflammatory pharmacological effect. In relation to the formation of NETs, neutrophils were surprisingly induced, with nmQUE being responsible for hyper-formation of NETs. With these results, it is concluded that nmQUE exerts an influence on the pathways of the immune system, being possibly responsible for the existence of morbidities and side effects, which represents the major problem of antipsychotic therapy. |
publishDate |
2020 |
dc.date.issued.fl_str_mv |
2020-02-19 |
dc.date.accessioned.fl_str_mv |
2022-05-19T14:02:07Z |
dc.date.available.fl_str_mv |
2022-05-19T14:02:07Z |
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info:eu-repo/semantics/masterThesis |
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masterThesis |
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dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/24360 |
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http://repositorio.ufsm.br/handle/1/24360 |
dc.language.iso.fl_str_mv |
por |
language |
por |
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201000000000 |
dc.relation.confidence.fl_str_mv |
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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 da Saúde |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Farmacologia |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Farmacologia |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria 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 |
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institution |
UFSM |
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collection |
Manancial - Repositório Digital da UFSM |
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bitstream.checksumAlgorithm.fl_str_mv |
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_ |
1794524322586427392 |