Role of astroglial glutamate transport on cerebral glucose metabolism in vivo : a pharmacological challenge with clozapine

Detalhes bibliográficos
Autor(a) principal: Rocha, Andréia Silva da
Data de Publicação: 2019
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Biblioteca Digital de Teses e Dissertações da UFRGS
Texto Completo: http://hdl.handle.net/10183/201659
Resumo: After many decades being considered only as neuronal supporters, astrocytes are now fully integrated in the modern neuroscience as very resourceful and valuable brain cells. In this context, the contribution of astrocytes on many brain functions has become an important subject of discussion. In this regard, a topic that still remains under debate is the astrocytic participation on glucose brain metabolism and, consequently, on the uptake of the glucose analogous molecule 2-Deoxy-2-[18F]Fluoroglucose ([18F]FDG), detected by the positron emission tomography (PET). [18F]FDG-PET imaging does not offer cellular resolution, although, the resulting image reflects cellular and sub-cellular interactions with the radiopharmaceutical molecule. Until recently, the brain [18F]FDG uptake was interpreted mostly as a direct result of neuronal activity, with other cells being only seen as bystanders. However, recent studies have shown important associations between astrocyte function and [18F]FDG-PET signal, suggesting a contribution, at least partially, of these cells. Aiming to evaluate if a decline on an astrocytic function would impact on [18F]FDG-PET signal, we performed, in adult rodents, a pharmacological challenge with clozapine. This drug is known to decrease, on astrocytes, glutamate transport and the glutamate transporter 1 (GLT-1) levels. This target was chosen because strong evidence points to the activity of GLT-1 as an important trigger for glucose uptake in astrocytes. Our work focused on the region where GLT-1 is most abundant: cortex. A six-week treatment with clozapine caused, in adult rats, cortical: [18F]FDG hypometabolism, reduced GLT-1 density and expression. Alongside, was found a decline on glutamate transport, indexed by D-aspartate uptake, in cortical slices. A similar outcome was observed in cortical astrocyte primary cultures: a decrease in GLT-1 levels along with reduced D-aspartate and 2-Deoxyglucose uptake. This work provides evidence that clozapine reduces [18F]FDG-microPET signal. Our results indicate that astrocytes are, at least partially, the cells underlying the glucose brain metabolism response to clozapine. Also, it suggests the reduction on GLT-1 levels/glutamate transport in astrocytes as a mechanism by which this response could be generated. These results raise the need for a reevaluation in the way that brain research and clinical [18F]FDG-PET data are interpreted, paying particular attention to the potential contribution of cells other than just neurons. Additionally, clozapine is a drug approved for clinical use, therefore, this phenomenon should be carefully investigated in patients under its treatment.
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spelling Rocha, Andréia Silva daZimmer, Eduardo RigonSouza, Diogo Onofre Gomes de2019-11-13T03:51:27Z2019http://hdl.handle.net/10183/201659001097879After many decades being considered only as neuronal supporters, astrocytes are now fully integrated in the modern neuroscience as very resourceful and valuable brain cells. In this context, the contribution of astrocytes on many brain functions has become an important subject of discussion. In this regard, a topic that still remains under debate is the astrocytic participation on glucose brain metabolism and, consequently, on the uptake of the glucose analogous molecule 2-Deoxy-2-[18F]Fluoroglucose ([18F]FDG), detected by the positron emission tomography (PET). [18F]FDG-PET imaging does not offer cellular resolution, although, the resulting image reflects cellular and sub-cellular interactions with the radiopharmaceutical molecule. Until recently, the brain [18F]FDG uptake was interpreted mostly as a direct result of neuronal activity, with other cells being only seen as bystanders. However, recent studies have shown important associations between astrocyte function and [18F]FDG-PET signal, suggesting a contribution, at least partially, of these cells. Aiming to evaluate if a decline on an astrocytic function would impact on [18F]FDG-PET signal, we performed, in adult rodents, a pharmacological challenge with clozapine. This drug is known to decrease, on astrocytes, glutamate transport and the glutamate transporter 1 (GLT-1) levels. This target was chosen because strong evidence points to the activity of GLT-1 as an important trigger for glucose uptake in astrocytes. Our work focused on the region where GLT-1 is most abundant: cortex. A six-week treatment with clozapine caused, in adult rats, cortical: [18F]FDG hypometabolism, reduced GLT-1 density and expression. Alongside, was found a decline on glutamate transport, indexed by D-aspartate uptake, in cortical slices. A similar outcome was observed in cortical astrocyte primary cultures: a decrease in GLT-1 levels along with reduced D-aspartate and 2-Deoxyglucose uptake. This work provides evidence that clozapine reduces [18F]FDG-microPET signal. Our results indicate that astrocytes are, at least partially, the cells underlying the glucose brain metabolism response to clozapine. Also, it suggests the reduction on GLT-1 levels/glutamate transport in astrocytes as a mechanism by which this response could be generated. These results raise the need for a reevaluation in the way that brain research and clinical [18F]FDG-PET data are interpreted, paying particular attention to the potential contribution of cells other than just neurons. Additionally, clozapine is a drug approved for clinical use, therefore, this phenomenon should be carefully investigated in patients under its treatment.Depois de muitas décadas sendo considerados apenas coadjuvantes dos neurônios, os astrócitos estão agora totalmente integrados na neurociência moderna como células cerebrais muito valiosas. Nesse contexto, a contribuição astrocitária em diversas funções cerebrais se torna um importante ponto de discussão. Acerca disso, um tópico amplamente debatido é a participação dos astrócitos no metabolismo cerebral de glicose e, consequentemente, na captação da molécula de [18F]Fluorodeoxyglucose ([18F]FDG), detectada pela tomografia por emissão de pósitrons (PET). O [18F]FDG-PET não apresenta resolução celular, entretanto, a imagem resultante reflete interações celulares e sub-celulares com o radiofármaco. Até recentemente, a captação de [18F]FDG no encéfalo vinha sendo interpretada, sobretudo, como um resultado direto da atividade neuronal, com outras células sendo vistas apenas como meras espectadoras. No entanto, estudos recentes demonstraram importantes associações entre a função astrocitária e o sinal do [18F]FDG-PET, sugerindo uma contribuição, ao menos parcial, dessas células. Assim, a fim de investigar se o declínio de uma função astrocitária teria impacto no sinal de [18F]FDG-PET, realizamos, em roedores, um desafio farmacológico com clozapina. Este fármaco já demonstrou reduzir os níveis do transportador de glutamato 1 (GLT-1) e o transporte de glutamato astrocitário. Este alvo foi escolhido pois fortes evidências apontam para a atividade de GLT-1 como um importante gatilho para a captação de glicose em astrócitos. Nosso trabalho focou na região onde GLT-1 é mais abundante: o córtex. Um tratamento de seis semanas com clozapina causou, em ratos adultos, na região cortical: hipometabolismo de [18F]FDG, redução na expressão e na densidade de GLT-1. Paralelamente, foi encontrado um declínio no transporte de glutamato, indexado pela captação de D-aspartato, em fatias corticais. Um efeito similar foi observado em culturas corticais primárias de astrócitos: diminuição nos níveis de GLT-1, juntamente com a captação reduzida de D-aspartato e 2-Deoxiglicose. Este trabalho fornece evidências de que a clozapina reduz o sinal do [18F]FDG-microPET. Nossos resultados indicam que os astrócitos são, pelo menos parcialmente, as células responsáveis pela resposta do metabolismo cerebral de glicose à clozapina. Além disso, sugerem a redução nos níveis de GLT-1/transporte de glutamato em astrócitos como o mecanismo pelo qual essa resposta possa ter sido gerada. Esses resultados despertam a necessidade de uma reavaliação na forma como os dados do [18F]FDG-PET são interpretados, salientando a pontencial contribuição de outras células além dos neurônios. Além disso, a clozapina é aprovada para uso clínico, portanto, esse fenômeno deve ser cuidadosamente investigado em pacientes sob tratamento com esse fármaco.application/pdfengAstrócitosÁcido glutâmicoClozapinaGlucose : MetabolismoFluordesoxiglucose F18Role of astroglial glutamate transport on cerebral glucose metabolism in vivo : a pharmacological challenge with clozapineO papel do transporte glutamatérgico astrocitário no metabolismo de glicose cerebral in vivo : um desafio farmacológico com clozapinainfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisUniversidade Federal do Rio Grande do SulInstituto de Ciências Básicas da SaúdePrograma de Pós-Graduação em Ciências Biológicas: BioquímicaPorto Alegre, BR-RS2019mestradoinfo:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSTEXT001097879.pdf.txt001097879.pdf.txtExtracted Texttext/plain161412http://www.lume.ufrgs.br/bitstream/10183/201659/2/001097879.pdf.txte6f392404c61383849d748e71b146236MD52ORIGINAL001097879.pdfTexto completo (inglês)application/pdf2581418http://www.lume.ufrgs.br/bitstream/10183/201659/1/001097879.pdf0b72a4970aafa0bbd78e1b7240a42701MD5110183/2016592022-08-10 04:45:48.291473oai:www.lume.ufrgs.br:10183/201659Biblioteca Digital de Teses e Dissertaçõeshttps://lume.ufrgs.br/handle/10183/2PUBhttps://lume.ufrgs.br/oai/requestlume@ufrgs.br||lume@ufrgs.bropendoar:18532022-08-10T07:45:48Biblioteca Digital de Teses e Dissertações da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false
dc.title.pt_BR.fl_str_mv Role of astroglial glutamate transport on cerebral glucose metabolism in vivo : a pharmacological challenge with clozapine
dc.title.alternative.pt.fl_str_mv O papel do transporte glutamatérgico astrocitário no metabolismo de glicose cerebral in vivo : um desafio farmacológico com clozapina
title Role of astroglial glutamate transport on cerebral glucose metabolism in vivo : a pharmacological challenge with clozapine
spellingShingle Role of astroglial glutamate transport on cerebral glucose metabolism in vivo : a pharmacological challenge with clozapine
Rocha, Andréia Silva da
Astrócitos
Ácido glutâmico
Clozapina
Glucose : Metabolismo
Fluordesoxiglucose F18
title_short Role of astroglial glutamate transport on cerebral glucose metabolism in vivo : a pharmacological challenge with clozapine
title_full Role of astroglial glutamate transport on cerebral glucose metabolism in vivo : a pharmacological challenge with clozapine
title_fullStr Role of astroglial glutamate transport on cerebral glucose metabolism in vivo : a pharmacological challenge with clozapine
title_full_unstemmed Role of astroglial glutamate transport on cerebral glucose metabolism in vivo : a pharmacological challenge with clozapine
title_sort Role of astroglial glutamate transport on cerebral glucose metabolism in vivo : a pharmacological challenge with clozapine
author Rocha, Andréia Silva da
author_facet Rocha, Andréia Silva da
author_role author
dc.contributor.author.fl_str_mv Rocha, Andréia Silva da
dc.contributor.advisor1.fl_str_mv Zimmer, Eduardo Rigon
dc.contributor.advisor-co1.fl_str_mv Souza, Diogo Onofre Gomes de
contributor_str_mv Zimmer, Eduardo Rigon
Souza, Diogo Onofre Gomes de
dc.subject.por.fl_str_mv Astrócitos
Ácido glutâmico
Clozapina
Glucose : Metabolismo
Fluordesoxiglucose F18
topic Astrócitos
Ácido glutâmico
Clozapina
Glucose : Metabolismo
Fluordesoxiglucose F18
description After many decades being considered only as neuronal supporters, astrocytes are now fully integrated in the modern neuroscience as very resourceful and valuable brain cells. In this context, the contribution of astrocytes on many brain functions has become an important subject of discussion. In this regard, a topic that still remains under debate is the astrocytic participation on glucose brain metabolism and, consequently, on the uptake of the glucose analogous molecule 2-Deoxy-2-[18F]Fluoroglucose ([18F]FDG), detected by the positron emission tomography (PET). [18F]FDG-PET imaging does not offer cellular resolution, although, the resulting image reflects cellular and sub-cellular interactions with the radiopharmaceutical molecule. Until recently, the brain [18F]FDG uptake was interpreted mostly as a direct result of neuronal activity, with other cells being only seen as bystanders. However, recent studies have shown important associations between astrocyte function and [18F]FDG-PET signal, suggesting a contribution, at least partially, of these cells. Aiming to evaluate if a decline on an astrocytic function would impact on [18F]FDG-PET signal, we performed, in adult rodents, a pharmacological challenge with clozapine. This drug is known to decrease, on astrocytes, glutamate transport and the glutamate transporter 1 (GLT-1) levels. This target was chosen because strong evidence points to the activity of GLT-1 as an important trigger for glucose uptake in astrocytes. Our work focused on the region where GLT-1 is most abundant: cortex. A six-week treatment with clozapine caused, in adult rats, cortical: [18F]FDG hypometabolism, reduced GLT-1 density and expression. Alongside, was found a decline on glutamate transport, indexed by D-aspartate uptake, in cortical slices. A similar outcome was observed in cortical astrocyte primary cultures: a decrease in GLT-1 levels along with reduced D-aspartate and 2-Deoxyglucose uptake. This work provides evidence that clozapine reduces [18F]FDG-microPET signal. Our results indicate that astrocytes are, at least partially, the cells underlying the glucose brain metabolism response to clozapine. Also, it suggests the reduction on GLT-1 levels/glutamate transport in astrocytes as a mechanism by which this response could be generated. These results raise the need for a reevaluation in the way that brain research and clinical [18F]FDG-PET data are interpreted, paying particular attention to the potential contribution of cells other than just neurons. Additionally, clozapine is a drug approved for clinical use, therefore, this phenomenon should be carefully investigated in patients under its treatment.
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