Efeito antipsicótico de novos inibidores do transportador de prolina (SLC6A7)
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFG |
Texto Completo: | http://repositorio.bc.ufg.br/tede/handle/tede/12385 |
Resumo: | Schizophrenia is a serious psychiatric disorder that expresses a complex set of positive, negative and/or cognitive symptoms. Some hypotheses attempt to explain the cause of schizophrenia, one of which is the glutamatergic hypothesis based on pharmacological evidence and pathophysiological studies that point to a hypofunction of NMDA receptor signaling in the brain. Proline transporters (SLC6A7) are predominantly expressed in the central nervous system (CNS) and are associated with glutamatergic neurotransmission, however, their role in regulating neural function and pharmacological potential is little known. The objective of this work was to pharmacologically characterize new prototypes of proline transporter inhibitors (SLC6A7) and to test the effect of one of these in a ketamine-induced psychosis model. The results presented here demonstrate that the compounds LQFM 215, LQFM 216 and LQFM 217 have a low impact on the viability of LUHMES cells and in culture of peripheral neurons and are capable of reducing the uptake of intracellular proline in synaptosomes. The compound LQFM 215 had a greater impact on the viability of LUHMES cells as well as on peripheral neurons and a greater inhibitory effect on the uptake of proline. In the behavior of mice, the compound LQFM 215 reduced the mobility of the animals, without prejudice to the working memory in the highest tested dose of 10 mg/kg and was not able to induce anxious or depressive behaviors. In the marble burying test the compound LQFM 215 in all the tested doses of 2.5, 5 and 10 mg/kg was able to stimulate this behavior. By testing the compound LQFM 215 in the ketamine-induced psychosis model, he was able to reduce the animals' induced hyperlocomotion at the tested doses of 20 and 30 mg/kg. The set of these results indicates that the compound LQFM 215 is a neuroactive compound with an effect on the mobility of animals and with antipsychotic potential. This work demonstrates that PROT inhibitors can be targets for the development of new antipsychotics. |
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Pinto, Mauro Cunha Xavierhttp://lattes.cnpq.br/0868250984727943Pinto, Mauro Cunha XavierMenegatti, RicardoLeite, Jacqueline Alveshttp://lattes.cnpq.br/1650832043824574Carvalho, Gustavo Almeida de2022-10-21T12:36:20Z2022-10-21T12:36:20Z2020-05-29CARVALHO, G. A. Efeito antipsicótico de novos inibidores do transportador de prolina (SLC6A7). 2020. 67 f. Dissertação (Mestrado em Ciências Biológicas) - Universidade Federal de Goiás, Goiânia, 2020.http://repositorio.bc.ufg.br/tede/handle/tede/12385ark:/38995/0013000000szwSchizophrenia is a serious psychiatric disorder that expresses a complex set of positive, negative and/or cognitive symptoms. Some hypotheses attempt to explain the cause of schizophrenia, one of which is the glutamatergic hypothesis based on pharmacological evidence and pathophysiological studies that point to a hypofunction of NMDA receptor signaling in the brain. Proline transporters (SLC6A7) are predominantly expressed in the central nervous system (CNS) and are associated with glutamatergic neurotransmission, however, their role in regulating neural function and pharmacological potential is little known. The objective of this work was to pharmacologically characterize new prototypes of proline transporter inhibitors (SLC6A7) and to test the effect of one of these in a ketamine-induced psychosis model. The results presented here demonstrate that the compounds LQFM 215, LQFM 216 and LQFM 217 have a low impact on the viability of LUHMES cells and in culture of peripheral neurons and are capable of reducing the uptake of intracellular proline in synaptosomes. The compound LQFM 215 had a greater impact on the viability of LUHMES cells as well as on peripheral neurons and a greater inhibitory effect on the uptake of proline. In the behavior of mice, the compound LQFM 215 reduced the mobility of the animals, without prejudice to the working memory in the highest tested dose of 10 mg/kg and was not able to induce anxious or depressive behaviors. In the marble burying test the compound LQFM 215 in all the tested doses of 2.5, 5 and 10 mg/kg was able to stimulate this behavior. By testing the compound LQFM 215 in the ketamine-induced psychosis model, he was able to reduce the animals' induced hyperlocomotion at the tested doses of 20 and 30 mg/kg. The set of these results indicates that the compound LQFM 215 is a neuroactive compound with an effect on the mobility of animals and with antipsychotic potential. This work demonstrates that PROT inhibitors can be targets for the development of new antipsychotics.A esquizofrenia é uma desordem psiquiátrica grave que expressa um conjunto complexo de sintomas positivos, negativos e/ou cognitivos. Algumas hipóteses tentam explicar a causa da esquizofrenia, uma delas a hipótese glutamatérgica é baseada em evidências farmacológicas e estudos fisiopatológicos que apontam para uma hipofunção da sinalização de receptores NMDA no cérebro. Os transportadores de prolina (SLC6A7) são expressos predominantemente no sistema nervoso central (SNC) e estão associados à neurotransmissão glutamatérgica, no entanto, seu papel na regulação da função neural e do seu potencial farmacológico é pouco conhecido. O objetivo deste trabalho foi caracterizar farmacologicamente novos protótipos de inibidores dos transportadores de prolina (SLC6A7) e testar o efeito de um destes em modelo de psicose induzido por cetamina. Os resultados aqui apresentados demonstram que os compostos LQFM 215, LQFM 216 e LQFM 217 apresentam baixo impacto na viabilidade de células LUHMES e em cultura de neurônios periféricos e são capazes de reduzir a captação de prolina intracelular em sinaptossomas. O composto LQFM 215 apresentou maior impacto na viabilidade das células LUHMES como também em neurônios periféricos e maior efeito inibitório na captação de prolina. No comportamento de camundongos o composto LQFM 215 reduziu a mobilidade dos animais, sem prejuízo da memória de trabalho na maior dose testada de 10 mg/kg e não foi capaz de induzir comportamentos do tipo ansioso ou do tipo depressivo. No teste de enterrar bolinhas o composto LQFM 215 em todas as doses testadas de 2,5, 5 e 10 mg/kg foi capaz de estimular esse comportamento. Ao testar o composto LQFM 215 no modelo de psicose induzido por cetamina foi capaz de reduzir a hiperlocomoção induzida dos animais nas doses testadas de 20 e 30 mg/kg. O conjunto destes resultados indica que o composto LQFM 215 é um composto neuroativo com efeito na mobilidade dos animais e com potencial antipsicótico. Este trabalho demonstra que os inibidores de PROT podem ser alvos para o desenvolvimento de novos antipsicóticos.Submitted by Marlene Santos (marlene.bc.ufg@gmail.com) on 2022-10-20T19:46:05Z No. of bitstreams: 2 Dissertação - Gustavo Almeida de Carvalho - 2020.pdf: 3386190 bytes, checksum: 23598dc48f42033e003b5814caa1d4bd (MD5) license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5)Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2022-10-21T12:36:19Z (GMT) No. of bitstreams: 2 Dissertação - Gustavo Almeida de Carvalho - 2020.pdf: 3386190 bytes, checksum: 23598dc48f42033e003b5814caa1d4bd (MD5) license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5)Made available in DSpace on 2022-10-21T12:36:20Z (GMT). No. of bitstreams: 2 Dissertação - Gustavo Almeida de Carvalho - 2020.pdf: 3386190 bytes, checksum: 23598dc48f42033e003b5814caa1d4bd (MD5) license_rdf: 805 bytes, checksum: 4460e5956bc1d1639be9ae6146a50347 (MD5) Previous issue date: 2020-05-29Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESporUniversidade Federal de GoiásPrograma de Pós-graduação em Ciências Biológicas (ICB)UFGBrasilInstituto de Ciências Biológicas - ICB (RG)Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessTransportador de prolinaSLC6A7EsquizofreniaAntipsicóticosProline transportersSchizophreniaAntipsychoticsCIENCIAS BIOLOGICAS::FARMACOLOGIAEfeito antipsicótico de novos inibidores do transportador de prolina (SLC6A7)Antipsychotic effect of new proline transporter inhibitors (SLC6A7)info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesis15500500500500231641reponame:Repositório Institucional da UFGinstname:Universidade Federal de Goiás (UFG)instacron:UFGLICENSElicense.txtlicense.txttext/plain; charset=utf-81748http://repositorio.bc.ufg.br/tede/bitstreams/d459261f-74ff-49be-adf9-4431ce086b33/download8a4605be74aa9ea9d79846c1fba20a33MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8805http://repositorio.bc.ufg.br/tede/bitstreams/a65c1b41-f423-44a3-ae93-842716f27854/download4460e5956bc1d1639be9ae6146a50347MD52ORIGINALDissertação - Gustavo Almeida de Carvalho - 2020.pdfDissertação - Gustavo Almeida de Carvalho - 2020.pdfapplication/pdf3386190http://repositorio.bc.ufg.br/tede/bitstreams/31a33ffb-6f49-4cd1-92b4-fb33e28a87f4/download23598dc48f42033e003b5814caa1d4bdMD53tede/123852022-10-21 09:36:20.321http://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 Internationalopen.accessoai:repositorio.bc.ufg.br:tede/12385http://repositorio.bc.ufg.br/tedeRepositório InstitucionalPUBhttp://repositorio.bc.ufg.br/oai/requesttasesdissertacoes.bc@ufg.bropendoar:2022-10-21T12:36:20Repositório Institucional da UFG - Universidade Federal de Goiás (UFG)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 |
dc.title.pt_BR.fl_str_mv |
Efeito antipsicótico de novos inibidores do transportador de prolina (SLC6A7) |
dc.title.alternative.eng.fl_str_mv |
Antipsychotic effect of new proline transporter inhibitors (SLC6A7) |
title |
Efeito antipsicótico de novos inibidores do transportador de prolina (SLC6A7) |
spellingShingle |
Efeito antipsicótico de novos inibidores do transportador de prolina (SLC6A7) Carvalho, Gustavo Almeida de Transportador de prolina SLC6A7 Esquizofrenia Antipsicóticos Proline transporters Schizophrenia Antipsychotics CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Efeito antipsicótico de novos inibidores do transportador de prolina (SLC6A7) |
title_full |
Efeito antipsicótico de novos inibidores do transportador de prolina (SLC6A7) |
title_fullStr |
Efeito antipsicótico de novos inibidores do transportador de prolina (SLC6A7) |
title_full_unstemmed |
Efeito antipsicótico de novos inibidores do transportador de prolina (SLC6A7) |
title_sort |
Efeito antipsicótico de novos inibidores do transportador de prolina (SLC6A7) |
author |
Carvalho, Gustavo Almeida de |
author_facet |
Carvalho, Gustavo Almeida de |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Pinto, Mauro Cunha Xavier |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/0868250984727943 |
dc.contributor.referee1.fl_str_mv |
Pinto, Mauro Cunha Xavier |
dc.contributor.referee2.fl_str_mv |
Menegatti, Ricardo |
dc.contributor.referee3.fl_str_mv |
Leite, Jacqueline Alves |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/1650832043824574 |
dc.contributor.author.fl_str_mv |
Carvalho, Gustavo Almeida de |
contributor_str_mv |
Pinto, Mauro Cunha Xavier Pinto, Mauro Cunha Xavier Menegatti, Ricardo Leite, Jacqueline Alves |
dc.subject.por.fl_str_mv |
Transportador de prolina SLC6A7 Esquizofrenia Antipsicóticos |
topic |
Transportador de prolina SLC6A7 Esquizofrenia Antipsicóticos Proline transporters Schizophrenia Antipsychotics CIENCIAS BIOLOGICAS::FARMACOLOGIA |
dc.subject.eng.fl_str_mv |
Proline transporters Schizophrenia Antipsychotics |
dc.subject.cnpq.fl_str_mv |
CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
Schizophrenia is a serious psychiatric disorder that expresses a complex set of positive, negative and/or cognitive symptoms. Some hypotheses attempt to explain the cause of schizophrenia, one of which is the glutamatergic hypothesis based on pharmacological evidence and pathophysiological studies that point to a hypofunction of NMDA receptor signaling in the brain. Proline transporters (SLC6A7) are predominantly expressed in the central nervous system (CNS) and are associated with glutamatergic neurotransmission, however, their role in regulating neural function and pharmacological potential is little known. The objective of this work was to pharmacologically characterize new prototypes of proline transporter inhibitors (SLC6A7) and to test the effect of one of these in a ketamine-induced psychosis model. The results presented here demonstrate that the compounds LQFM 215, LQFM 216 and LQFM 217 have a low impact on the viability of LUHMES cells and in culture of peripheral neurons and are capable of reducing the uptake of intracellular proline in synaptosomes. The compound LQFM 215 had a greater impact on the viability of LUHMES cells as well as on peripheral neurons and a greater inhibitory effect on the uptake of proline. In the behavior of mice, the compound LQFM 215 reduced the mobility of the animals, without prejudice to the working memory in the highest tested dose of 10 mg/kg and was not able to induce anxious or depressive behaviors. In the marble burying test the compound LQFM 215 in all the tested doses of 2.5, 5 and 10 mg/kg was able to stimulate this behavior. By testing the compound LQFM 215 in the ketamine-induced psychosis model, he was able to reduce the animals' induced hyperlocomotion at the tested doses of 20 and 30 mg/kg. The set of these results indicates that the compound LQFM 215 is a neuroactive compound with an effect on the mobility of animals and with antipsychotic potential. This work demonstrates that PROT inhibitors can be targets for the development of new antipsychotics. |
publishDate |
2020 |
dc.date.issued.fl_str_mv |
2020-05-29 |
dc.date.accessioned.fl_str_mv |
2022-10-21T12:36:20Z |
dc.date.available.fl_str_mv |
2022-10-21T12:36:20Z |
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.citation.fl_str_mv |
CARVALHO, G. A. Efeito antipsicótico de novos inibidores do transportador de prolina (SLC6A7). 2020. 67 f. Dissertação (Mestrado em Ciências Biológicas) - Universidade Federal de Goiás, Goiânia, 2020. |
dc.identifier.uri.fl_str_mv |
http://repositorio.bc.ufg.br/tede/handle/tede/12385 |
dc.identifier.dark.fl_str_mv |
ark:/38995/0013000000szw |
identifier_str_mv |
CARVALHO, G. A. Efeito antipsicótico de novos inibidores do transportador de prolina (SLC6A7). 2020. 67 f. Dissertação (Mestrado em Ciências Biológicas) - Universidade Federal de Goiás, Goiânia, 2020. ark:/38995/0013000000szw |
url |
http://repositorio.bc.ufg.br/tede/handle/tede/12385 |
dc.language.iso.fl_str_mv |
por |
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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 |
164 |
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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) |
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UFG |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Instituto de Ciências Biológicas - ICB (RG) |
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Universidade Federal de Goiás |
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