Efeito tipo-antidepressivo do derivado piperazínico 2,6-di-terc-butil-4-((4-(2-hidroxietil)piperazina-1-il)metil)fenol (LQFM212) e possíveis mecanismos de ação envolvidos
Autor(a) principal: | |
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Data de Publicação: | 2023 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFG |
Texto Completo: | http://repositorio.bc.ufg.br/tede/handle/tede/12734 |
Resumo: | Depressive disorders affect individuals worldwide and may also be associated with other mental disorders such as anxiety disorders. Despite advances to improve understanding of the neurobiology of depressive disorders, no single established mechanism per se can explain all facets of these disorders and the available drugs often show therapeutic delay for clinical effectiveness. A plethora of results show the effects of piperazine derivatives on the central nervous system and are indicators of its therapeutic potential for treating mental disorders. Previously, it was shown that the piperazine derivative 2,6-di-tert-butyl-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenol (LQFM212) has anxiolytic-like activity which involves serotonergic pathway, nicotinic receptors and BZD-site of GABAA receptor, without cognitive impairments. In this regard, since the same compound can have anxiolytic as well as antidepressant effects, the aim of this research was to evaluate the possible antidepressant-like activity of the compound LQFM212. Swiss albino male mice orally treated with LQFM212 (54 μmol/kg) showed behavioral effects related to antidepressant-like activity, in the forced swimming test (FST), after treatment with a single dose or with repeated doses for 15 consecutive days. Pretreatment with WAY-100635 (0.7 μmol/kg), p-chlorophenylalanine (500 μmol/kg), prazosin (2.6 μmol/kg), SCH-23390 (15 μg/kg), sulpiride (146 μmol/kg) ou α-methyl-p-tyrosine (512 μmol/kg) reversed the antidepressant-like effect of LQFM212 in the FST. Furthermore, repeated treatment with LQFM212 increased hippocampal brain-derived neurotrophic factor (BDNF) levels. Regarding the monitoring of body weight and the evaluation of possible biochemical changes the treatment with repeated doses with LQFM212 (54 μmol/kg) did not change: animals' body weight, liver glutathione (GSH) levels, and serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine. A possible action of the compound LQFM212 on inflammatory parameters, in mice, was evaluated by systemic inflammation by the lipopolysaccharide (LPS)-induced neuroinflammation model and by local inflammation by the carrageenan- or LPS-induced pleurisy model. In the LPS-induced neuroinflammation model, oral treatment with LQFM212 (54 μmol/kg) reversed the anxiety-like and depression-like behaviors, in the open field, forced swimming and tail suspension tests, the increase of pro-inflammatory cytokines (TNF-α and IL-1β) and the decrease of anti-inflammatory cytokines (IL-4 and IL-10), into animals’ serum, caused by intraperitoneal administration of LPS (1 mg/kg). In this same model, treatment with LQFM212 (54 μmol/kg) also attenuated oxidative stress-related changes, demonstrated by reduced nitrite levels and myeloperoxidase (MPO) activity, and increased glutathione levels in the prefrontal cortex and hippocampus, and also reduced cholinesterase activity in the whole brain, of animals that received intraperitoneal administration of LPS (1 mg/kg). On the other hand, oral treatment with LQFM212 (54 μmol/kg) failed to reduce the increase in cell migration and pro-inflammatory cytokines (TNF-α and IL-1β) in pleural exudate caused by intrapleural administration of 1% carrageenan or LPS (250 ng/mL) in the pleurisy model. In addition to the reduction in MPO activity seen in the LPS-induced neuroinflammation model, treatment with LQFM212 (54 μmol/kg) also reduced the activity of this enzyme in the pleural exudate of animals subjected to the carrageenan- or LPS-induced pleurisy model. Taken together, the results showed that treatment with LQFM212 promotes behavioral changes suggestive of antidepressant-like activity in mice, which probably involve the monoaminergic pathways, in addition to increased hippocampal levels of BDNF, suggesting changes in synaptic neuroplasticity possibly as a mechanism underlying the antidepressant-like effect of the compound. The effects found in the LPS-induced neuroinflammation model did not seem to be secondary to a peripheral anti-inflammatory action of LQFM212, since this compound failed to reduce the changes caused by carrageenan or LPS in the pleurisy model. On the other hand, treatment with LQFM212 reduced MPO enzyme activity in pleural exudate, prefrontal cortex, and hippocampus, and increased per se GSH levels in both brain regions mentioned above, thus suggesting a possible antioxidant activity in vivo that may contribute to the effects observed in the neuroinflammation and pleurisy model. |
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Costa, Elson Alveshttp://lattes.cnpq.br/2607893423583912Costa, Elson AlvesFajemiroye, James OluwagbamigbeGhedini, Paulo CésarRocha, Fábio Fagundes daCarvalho, Pablinny Moreira Galdino dehttp://lattes.cnpq.br/8708636914684725Moreira, Lorrane Kelle da Silva2023-04-05T11:09:36Z2023-04-05T11:09:36Z2023-02-27MOREIRA, L. K. S. Efeito tipo-antidepressivo do derivado piperazínico 2,6-di-terc-butil-4-((4-(2-hidroxietil)piperazina-1-il)metil)fenol (LQFM212) e possíveis mecanismos de ação envolvidos. 2023. 113 f. Tese (Doutorado em Ciências Biológicas) - Universidade Federal de Goiás, Goiânia, 2023.http://repositorio.bc.ufg.br/tede/handle/tede/12734ark:/38995/001300000drhvDepressive disorders affect individuals worldwide and may also be associated with other mental disorders such as anxiety disorders. Despite advances to improve understanding of the neurobiology of depressive disorders, no single established mechanism per se can explain all facets of these disorders and the available drugs often show therapeutic delay for clinical effectiveness. A plethora of results show the effects of piperazine derivatives on the central nervous system and are indicators of its therapeutic potential for treating mental disorders. Previously, it was shown that the piperazine derivative 2,6-di-tert-butyl-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenol (LQFM212) has anxiolytic-like activity which involves serotonergic pathway, nicotinic receptors and BZD-site of GABAA receptor, without cognitive impairments. In this regard, since the same compound can have anxiolytic as well as antidepressant effects, the aim of this research was to evaluate the possible antidepressant-like activity of the compound LQFM212. Swiss albino male mice orally treated with LQFM212 (54 μmol/kg) showed behavioral effects related to antidepressant-like activity, in the forced swimming test (FST), after treatment with a single dose or with repeated doses for 15 consecutive days. Pretreatment with WAY-100635 (0.7 μmol/kg), p-chlorophenylalanine (500 μmol/kg), prazosin (2.6 μmol/kg), SCH-23390 (15 μg/kg), sulpiride (146 μmol/kg) ou α-methyl-p-tyrosine (512 μmol/kg) reversed the antidepressant-like effect of LQFM212 in the FST. Furthermore, repeated treatment with LQFM212 increased hippocampal brain-derived neurotrophic factor (BDNF) levels. Regarding the monitoring of body weight and the evaluation of possible biochemical changes the treatment with repeated doses with LQFM212 (54 μmol/kg) did not change: animals' body weight, liver glutathione (GSH) levels, and serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine. A possible action of the compound LQFM212 on inflammatory parameters, in mice, was evaluated by systemic inflammation by the lipopolysaccharide (LPS)-induced neuroinflammation model and by local inflammation by the carrageenan- or LPS-induced pleurisy model. In the LPS-induced neuroinflammation model, oral treatment with LQFM212 (54 μmol/kg) reversed the anxiety-like and depression-like behaviors, in the open field, forced swimming and tail suspension tests, the increase of pro-inflammatory cytokines (TNF-α and IL-1β) and the decrease of anti-inflammatory cytokines (IL-4 and IL-10), into animals’ serum, caused by intraperitoneal administration of LPS (1 mg/kg). In this same model, treatment with LQFM212 (54 μmol/kg) also attenuated oxidative stress-related changes, demonstrated by reduced nitrite levels and myeloperoxidase (MPO) activity, and increased glutathione levels in the prefrontal cortex and hippocampus, and also reduced cholinesterase activity in the whole brain, of animals that received intraperitoneal administration of LPS (1 mg/kg). On the other hand, oral treatment with LQFM212 (54 μmol/kg) failed to reduce the increase in cell migration and pro-inflammatory cytokines (TNF-α and IL-1β) in pleural exudate caused by intrapleural administration of 1% carrageenan or LPS (250 ng/mL) in the pleurisy model. In addition to the reduction in MPO activity seen in the LPS-induced neuroinflammation model, treatment with LQFM212 (54 μmol/kg) also reduced the activity of this enzyme in the pleural exudate of animals subjected to the carrageenan- or LPS-induced pleurisy model. Taken together, the results showed that treatment with LQFM212 promotes behavioral changes suggestive of antidepressant-like activity in mice, which probably involve the monoaminergic pathways, in addition to increased hippocampal levels of BDNF, suggesting changes in synaptic neuroplasticity possibly as a mechanism underlying the antidepressant-like effect of the compound. The effects found in the LPS-induced neuroinflammation model did not seem to be secondary to a peripheral anti-inflammatory action of LQFM212, since this compound failed to reduce the changes caused by carrageenan or LPS in the pleurisy model. On the other hand, treatment with LQFM212 reduced MPO enzyme activity in pleural exudate, prefrontal cortex, and hippocampus, and increased per se GSH levels in both brain regions mentioned above, thus suggesting a possible antioxidant activity in vivo that may contribute to the effects observed in the neuroinflammation and pleurisy model.Os transtornos depressivos atingem indivíduos em todo o mundo e podem se apresentar em comorbidade com outros distúrbios mentais, como os transtornos de ansiedade. Apesar dos avanços para melhorar a compreensão da neurobiologia dos transtornos depressivos, nenhum mecanismo já proposto per se pode explicar todas as facetas desses transtornos e os fármacos disponíveis mostram frequentemente um atraso terapêutico para a eficácia clínica. Uma variedade de resultados mostra os efeitos de derivados piperazínicos no sistema nervoso central, e são, dessa forma, indicadores do potencial terapêutico destes derivados para o tratamento de distúrbios mentais. Anteriormente, foi mostrado que o derivado piperazínico 2,6-di-terc-butil-4-((4-(2-hidroxietil)piperazin-1-il)metil)fenol (LQFM212) apresenta atividade-tipo ansiolítica em camundongos, envolvendo vias serotoninérgicas, receptores nicotínicos e sítio benzodiazepínico do receptor GABAA, sem levar a alterações na função cognitiva. Neste contexto, sabendo que um mesmo composto pode apresentar efeitos ansiolíticos bem como antidepressivos, o objetivo deste trabalho foi avaliar a possível atividade tipo-antidepressiva do composto LQFM212. Camundongos machos albinos Swiss tratados por via oral com LQFM212 (54 μmol/kg) mostraram efeitos comportamentais relacionados a atividade tipo-antidepressiva, no teste do nado forçado (TNF), após tratamento com dose única ou com doses repetidas por 15 dias consecutivos. O pré-tratamento com WAY-100635 (0,7 μmol/kg), p-clorofenilalanina (500 μmol/kg), prazosina (2,6 μmol/kg), SCH-23390 (15 μg/kg), sulpirida (146 μmol/kg) ou α-metil-p-tirosina (512 μmol/kg) reverteu o efeito tipo-antidepressivo de LQFM212 no TNF. Além disso, o tratamento com doses repetidas com LQFM212 aumentou os níveis hipocampais do fator neurotrófico derivado do cérebro (BDNF). Em relação ao monitoramento do peso corporal e a avaliação de possíveis alterações bioquímicas o tratamento com doses repetidas com LQFM212 (54 μmol/kg) não alterou: peso corporal dos animais, níveis de glutationa (GSH) no fígado, níveis séricos de aspartato aminotransferase (AST), alanina aminotransferase (ALT), ureia e creatinina. Uma possível ação do composto LQFM212 sob parâmetros inflamatórios, em camundongos, foi avaliada por inflamação sistêmica pelo modelo de neuroinflamação induzida por lipopolissacarídeo (LPS) e por inflamação local pelo modelo de pleurisia induzida por carragenina ou LPS. No modelo de neuroinflamação induzida por LPS, o tratamento oral com LQFM212 (54 μmol/kg) reverteu as alterações comportamentais nos testes de campo aberto, nado forçado e suspensão pela cauda, o aumento sérico de citocinas pró-inflamatórias (TNF-α e IL-1β) e a redução sérica de citocinas anti-inflamatórias (IL-4 e IL-10) causados pela administração intraperitoneal de LPS (1 mg/kg). Neste mesmo modelo, o tratamento com LQFM212 (54 μmol/kg) também atenuou as alterações relacionadas ao estresse oxidativo, demonstrado pela redução dos níveis de nitritos e da atividade da mieloperoxidase (MPO), e aumento dos níveis de GSH no córtex pré-frontal e hipocampo, além disso também reduziu a atividade da colinesterase no cérebro total, dos animais que receberam administração intraperitoneal de LPS (1 mg/kg). Por outro lado, o tratamento oral com LQFM212 (54 μmol/kg) não conseguiu reduzir o aumento da migração celular e das citocinas pró-inflamatórias (TNF-α e IL-1β) no exsudato pleural causados pela administração intrapleural de carragenina a 1% ou LPS (250 ng/mL) no modelo de pleurisia. Além da redução da atividade da MPO vista no modelo de neuroinflamação induzida por LPS, o tratamento com LQFM212 (54 μmol/kg) também reduziu a atividade desta enzima no exsudato pleural de animais submetidos ao modelo de pleurisia induzida por carragenina ou LPS. Em conjunto, os resultados mostraram que o tratamento com LQFM212 promove alterações comportamentais sugestivas de atividade tipo-antidepressiva em camundongos, que provavelmente envolvem as vias monoaminérgicas, além de aumento dos níveis hipocampais de BDNF, sugerindo mudanças na neuroplasticidade sináptica possivelmente como um mecanismo subjacente ao efeito tipo-antidepressivo do composto. Os efeitos encontrados no modelo de neuroinflamação induzida por LPS não parecem ser secundários a uma ação anti-inflamatória periférica de LQFM212, visto que este composto não conseguiu reduzir as alterações causadas pela carragenina ou LPS no modelo de pleurisia. Por outro lado, o tratamento com LQFM212 reduziu a atividade da enzima MPO no exsudato pleural, córtex pré-frontal e hipocampo, além de aumentar per se os níveis de GSH em ambas as regiões cerebrais mencionadas acima, sugerindo dessa forma uma possível atividade antioxidante in vivo que pode, portanto, contribuir para os efeitos observados no modelo de neuroinflamação e de pleurisia.Submitted by Leandro Machado (leandromachado@ufg.br) on 2023-03-27T16:27:43Z No. of bitstreams: 2 Tese - Lorrane Kelle da Silva Moreira - 2023.pdf: 6408708 bytes, checksum: 7b5f76631aca34a60b84690ba162a6a6 (MD5) license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5)Rejected by Luciana Ferreira (lucgeral@gmail.com), reason: Veja com a Cláudia se realmente pode ser depositada essa tese devido ao seguinte: ANEXO II - Comprovante de aprovação da patente de LQFM212 on 2023-04-03T13:31:33Z (GMT)Submitted by Leandro Machado (leandromachado@ufg.br) on 2023-04-04T17:07:37Z No. of bitstreams: 2 Tese - Lorrane Kelle da Silva Moreira - 2023.pdf: 6408708 bytes, checksum: 7b5f76631aca34a60b84690ba162a6a6 (MD5) license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5)Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2023-04-05T11:09:34Z (GMT) No. of bitstreams: 2 Tese - Lorrane Kelle da Silva Moreira - 2023.pdf: 6408708 bytes, checksum: 7b5f76631aca34a60b84690ba162a6a6 (MD5) license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5)Made available in DSpace on 2023-04-05T11:09:36Z (GMT). No. of bitstreams: 2 Tese - Lorrane Kelle da Silva Moreira - 2023.pdf: 6408708 bytes, checksum: 7b5f76631aca34a60b84690ba162a6a6 (MD5) license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5) Previous issue date: 2023-02-27Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESporUniversidade Federal de GoiásPrograma de Pós-graduação em Ciências Biológicas (ICB)UFGBrasilInstituto de Ciências Biológicas - ICB (RMG)Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessDepressãoPiperazinaMonoaminasFatores neurotróficosLipopolissacarídeoCitocinasDepressionPiperazineMonoaminesNeurotrophic factorsLipopolysaccharideCytokinesOUTROSEfeito tipo-antidepressivo do derivado piperazínico 2,6-di-terc-butil-4-((4-(2-hidroxietil)piperazina-1-il)metil)fenol (LQFM212) e possíveis mecanismos de ação envolvidosAntidepressant-like effect of the piperazine derivative 2,6-di-tert-butyl-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenol (LQFM212) and possible mechanisms of action involvedinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesis15500500500500239521reponame:Repositório Institucional da UFGinstname:Universidade Federal de Goiás (UFG)instacron:UFGCC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8805http://repositorio.bc.ufg.br/tede/bitstreams/a65612d3-f539-41a6-b112-92dfeb2eb541/download4460e5956bc1d1639be9ae6146a50347MD52ORIGINALTese - Lorrane Kelle da Silva Moreira - 2023.pdfTese - Lorrane Kelle da Silva Moreira - 2023.pdfapplication/pdf6408708http://repositorio.bc.ufg.br/tede/bitstreams/89c2e8c8-e89e-4789-9e13-4de37ae8b9a7/download7b5f76631aca34a60b84690ba162a6a6MD53LICENSElicense.txtlicense.txttext/plain; charset=utf-81748http://repositorio.bc.ufg.br/tede/bitstreams/416ae58b-30e8-46db-b5ce-f080e893f504/download8a4605be74aa9ea9d79846c1fba20a33MD54tede/127342023-04-05 08:09:43.825http://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 Internationalopen.accessoai:repositorio.bc.ufg.br:tede/12734http://repositorio.bc.ufg.br/tedeRepositório InstitucionalPUBhttp://repositorio.bc.ufg.br/oai/requesttasesdissertacoes.bc@ufg.bropendoar:2023-04-05T11:09:43Repositório Institucional da UFG - Universidade Federal de Goiás (UFG)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 |
dc.title.pt_BR.fl_str_mv |
Efeito tipo-antidepressivo do derivado piperazínico 2,6-di-terc-butil-4-((4-(2-hidroxietil)piperazina-1-il)metil)fenol (LQFM212) e possíveis mecanismos de ação envolvidos |
dc.title.alternative.eng.fl_str_mv |
Antidepressant-like effect of the piperazine derivative 2,6-di-tert-butyl-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenol (LQFM212) and possible mechanisms of action involved |
title |
Efeito tipo-antidepressivo do derivado piperazínico 2,6-di-terc-butil-4-((4-(2-hidroxietil)piperazina-1-il)metil)fenol (LQFM212) e possíveis mecanismos de ação envolvidos |
spellingShingle |
Efeito tipo-antidepressivo do derivado piperazínico 2,6-di-terc-butil-4-((4-(2-hidroxietil)piperazina-1-il)metil)fenol (LQFM212) e possíveis mecanismos de ação envolvidos Moreira, Lorrane Kelle da Silva Depressão Piperazina Monoaminas Fatores neurotróficos Lipopolissacarídeo Citocinas Depression Piperazine Monoamines Neurotrophic factors Lipopolysaccharide Cytokines OUTROS |
title_short |
Efeito tipo-antidepressivo do derivado piperazínico 2,6-di-terc-butil-4-((4-(2-hidroxietil)piperazina-1-il)metil)fenol (LQFM212) e possíveis mecanismos de ação envolvidos |
title_full |
Efeito tipo-antidepressivo do derivado piperazínico 2,6-di-terc-butil-4-((4-(2-hidroxietil)piperazina-1-il)metil)fenol (LQFM212) e possíveis mecanismos de ação envolvidos |
title_fullStr |
Efeito tipo-antidepressivo do derivado piperazínico 2,6-di-terc-butil-4-((4-(2-hidroxietil)piperazina-1-il)metil)fenol (LQFM212) e possíveis mecanismos de ação envolvidos |
title_full_unstemmed |
Efeito tipo-antidepressivo do derivado piperazínico 2,6-di-terc-butil-4-((4-(2-hidroxietil)piperazina-1-il)metil)fenol (LQFM212) e possíveis mecanismos de ação envolvidos |
title_sort |
Efeito tipo-antidepressivo do derivado piperazínico 2,6-di-terc-butil-4-((4-(2-hidroxietil)piperazina-1-il)metil)fenol (LQFM212) e possíveis mecanismos de ação envolvidos |
author |
Moreira, Lorrane Kelle da Silva |
author_facet |
Moreira, Lorrane Kelle da Silva |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Costa, Elson Alves |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/2607893423583912 |
dc.contributor.referee1.fl_str_mv |
Costa, Elson Alves |
dc.contributor.referee2.fl_str_mv |
Fajemiroye, James Oluwagbamigbe |
dc.contributor.referee3.fl_str_mv |
Ghedini, Paulo César |
dc.contributor.referee4.fl_str_mv |
Rocha, Fábio Fagundes da |
dc.contributor.referee5.fl_str_mv |
Carvalho, Pablinny Moreira Galdino de |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/8708636914684725 |
dc.contributor.author.fl_str_mv |
Moreira, Lorrane Kelle da Silva |
contributor_str_mv |
Costa, Elson Alves Costa, Elson Alves Fajemiroye, James Oluwagbamigbe Ghedini, Paulo César Rocha, Fábio Fagundes da Carvalho, Pablinny Moreira Galdino de |
dc.subject.por.fl_str_mv |
Depressão Piperazina Monoaminas Fatores neurotróficos Lipopolissacarídeo Citocinas |
topic |
Depressão Piperazina Monoaminas Fatores neurotróficos Lipopolissacarídeo Citocinas Depression Piperazine Monoamines Neurotrophic factors Lipopolysaccharide Cytokines OUTROS |
dc.subject.eng.fl_str_mv |
Depression Piperazine Monoamines Neurotrophic factors Lipopolysaccharide Cytokines |
dc.subject.cnpq.fl_str_mv |
OUTROS |
description |
Depressive disorders affect individuals worldwide and may also be associated with other mental disorders such as anxiety disorders. Despite advances to improve understanding of the neurobiology of depressive disorders, no single established mechanism per se can explain all facets of these disorders and the available drugs often show therapeutic delay for clinical effectiveness. A plethora of results show the effects of piperazine derivatives on the central nervous system and are indicators of its therapeutic potential for treating mental disorders. Previously, it was shown that the piperazine derivative 2,6-di-tert-butyl-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenol (LQFM212) has anxiolytic-like activity which involves serotonergic pathway, nicotinic receptors and BZD-site of GABAA receptor, without cognitive impairments. In this regard, since the same compound can have anxiolytic as well as antidepressant effects, the aim of this research was to evaluate the possible antidepressant-like activity of the compound LQFM212. Swiss albino male mice orally treated with LQFM212 (54 μmol/kg) showed behavioral effects related to antidepressant-like activity, in the forced swimming test (FST), after treatment with a single dose or with repeated doses for 15 consecutive days. Pretreatment with WAY-100635 (0.7 μmol/kg), p-chlorophenylalanine (500 μmol/kg), prazosin (2.6 μmol/kg), SCH-23390 (15 μg/kg), sulpiride (146 μmol/kg) ou α-methyl-p-tyrosine (512 μmol/kg) reversed the antidepressant-like effect of LQFM212 in the FST. Furthermore, repeated treatment with LQFM212 increased hippocampal brain-derived neurotrophic factor (BDNF) levels. Regarding the monitoring of body weight and the evaluation of possible biochemical changes the treatment with repeated doses with LQFM212 (54 μmol/kg) did not change: animals' body weight, liver glutathione (GSH) levels, and serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine. A possible action of the compound LQFM212 on inflammatory parameters, in mice, was evaluated by systemic inflammation by the lipopolysaccharide (LPS)-induced neuroinflammation model and by local inflammation by the carrageenan- or LPS-induced pleurisy model. In the LPS-induced neuroinflammation model, oral treatment with LQFM212 (54 μmol/kg) reversed the anxiety-like and depression-like behaviors, in the open field, forced swimming and tail suspension tests, the increase of pro-inflammatory cytokines (TNF-α and IL-1β) and the decrease of anti-inflammatory cytokines (IL-4 and IL-10), into animals’ serum, caused by intraperitoneal administration of LPS (1 mg/kg). In this same model, treatment with LQFM212 (54 μmol/kg) also attenuated oxidative stress-related changes, demonstrated by reduced nitrite levels and myeloperoxidase (MPO) activity, and increased glutathione levels in the prefrontal cortex and hippocampus, and also reduced cholinesterase activity in the whole brain, of animals that received intraperitoneal administration of LPS (1 mg/kg). On the other hand, oral treatment with LQFM212 (54 μmol/kg) failed to reduce the increase in cell migration and pro-inflammatory cytokines (TNF-α and IL-1β) in pleural exudate caused by intrapleural administration of 1% carrageenan or LPS (250 ng/mL) in the pleurisy model. In addition to the reduction in MPO activity seen in the LPS-induced neuroinflammation model, treatment with LQFM212 (54 μmol/kg) also reduced the activity of this enzyme in the pleural exudate of animals subjected to the carrageenan- or LPS-induced pleurisy model. Taken together, the results showed that treatment with LQFM212 promotes behavioral changes suggestive of antidepressant-like activity in mice, which probably involve the monoaminergic pathways, in addition to increased hippocampal levels of BDNF, suggesting changes in synaptic neuroplasticity possibly as a mechanism underlying the antidepressant-like effect of the compound. The effects found in the LPS-induced neuroinflammation model did not seem to be secondary to a peripheral anti-inflammatory action of LQFM212, since this compound failed to reduce the changes caused by carrageenan or LPS in the pleurisy model. On the other hand, treatment with LQFM212 reduced MPO enzyme activity in pleural exudate, prefrontal cortex, and hippocampus, and increased per se GSH levels in both brain regions mentioned above, thus suggesting a possible antioxidant activity in vivo that may contribute to the effects observed in the neuroinflammation and pleurisy model. |
publishDate |
2023 |
dc.date.accessioned.fl_str_mv |
2023-04-05T11:09:36Z |
dc.date.available.fl_str_mv |
2023-04-05T11:09:36Z |
dc.date.issued.fl_str_mv |
2023-02-27 |
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.citation.fl_str_mv |
MOREIRA, L. K. S. Efeito tipo-antidepressivo do derivado piperazínico 2,6-di-terc-butil-4-((4-(2-hidroxietil)piperazina-1-il)metil)fenol (LQFM212) e possíveis mecanismos de ação envolvidos. 2023. 113 f. Tese (Doutorado em Ciências Biológicas) - Universidade Federal de Goiás, Goiânia, 2023. |
dc.identifier.uri.fl_str_mv |
http://repositorio.bc.ufg.br/tede/handle/tede/12734 |
dc.identifier.dark.fl_str_mv |
ark:/38995/001300000drhv |
identifier_str_mv |
MOREIRA, L. K. S. Efeito tipo-antidepressivo do derivado piperazínico 2,6-di-terc-butil-4-((4-(2-hidroxietil)piperazina-1-il)metil)fenol (LQFM212) e possíveis mecanismos de ação envolvidos. 2023. 113 f. Tese (Doutorado em Ciências Biológicas) - Universidade Federal de Goiás, Goiânia, 2023. ark:/38995/001300000drhv |
url |
http://repositorio.bc.ufg.br/tede/handle/tede/12734 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.program.fl_str_mv |
15 |
dc.relation.confidence.fl_str_mv |
500 500 500 500 |
dc.relation.department.fl_str_mv |
23 |
dc.relation.cnpq.fl_str_mv |
952 |
dc.relation.sponsorship.fl_str_mv |
1 |
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 Goiás |
dc.publisher.program.fl_str_mv |
Programa de Pós-graduação em Ciências Biológicas (ICB) |
dc.publisher.initials.fl_str_mv |
UFG |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Instituto de Ciências Biológicas - ICB (RMG) |
publisher.none.fl_str_mv |
Universidade Federal de Goiás |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFG instname:Universidade Federal de Goiás (UFG) instacron:UFG |
instname_str |
Universidade Federal de Goiás (UFG) |
instacron_str |
UFG |
institution |
UFG |
reponame_str |
Repositório Institucional da UFG |
collection |
Repositório Institucional da UFG |
bitstream.url.fl_str_mv |
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Repositório Institucional da UFG - Universidade Federal de Goiás (UFG) |
repository.mail.fl_str_mv |
tasesdissertacoes.bc@ufg.br |
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1811721525076688896 |