9 results on '"Leitão, Ricardo Alexandre"'
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2. Methamphetamine and the Blood–Brain Barrier
- Author
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Leitão, Ricardo Alexandre, primary, Coelho-Santos, Vanessa, additional, and Silva, Ana Paula, additional
- Published
- 2016
- Full Text
- View/download PDF
3. List of Contributors
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Abdalla, Renata Rigacci, primary, Abekawa, Tomohiro, additional, Adamczyk, Przemysław, additional, Adams, Wendy, additional, Addy, Peter H., additional, Ago, Yukio, additional, Álvaro-Bartolomé, María, additional, Andellini, Martina, additional, Andrzejewski, Matthew E., additional, Angarita, Gustavo A., additional, Angoa-Pérez, Mariana, additional, Anneken, John H., additional, Antunes, Luís, additional, Ardakani, Yalda Hosseinzadeh, additional, Aydin, Mustafa, additional, Badri, Nima, additional, Bajpai, Ram C., additional, Barbosa, Daniel José, additional, Barrós-Loscertales, Alfonso, additional, Basu, Debasish, additional, Becker, Benjamin, additional, Beckley, Jacob T., additional, Bermejo, Pablo García, additional, Berro, Laís F., additional, Blaker, Amanda L., additional, Bodoki, Ede, additional, Borowiak, Krzysztof, additional, Bowen, Scott E., additional, Broderick, Patricia A., additional, Brogaard, Berit, additional, Brolese, Giovana, additional, Brunt, T.M., additional, Buchborn, T., additional, Butelman, Eduardo R., additional, Caetano, Raul, additional, Campos, Sónia, additional, Canavan, Sofija V., additional, Capela, João Paulo, additional, Carta, Manolo, additional, Carvalho, Félix, additional, Carvelli, Lucia, additional, Catlow, Briony J., additional, Chang, Young-Tae, additional, Chaturvedi, Himanshu K., additional, Chilachava, Lela, additional, Choodum, Aree, additional, Clough, Shannon J., additional, Coelho-Santos, Vanessa, additional, Coimbra, Ana Maria, additional, Collins, Stuart A., additional, Cormand, Bru, additional, Dahan, Albert, additional, Dakwar, Elias, additional, Dávalos E., Antonio, additional, de Jong, Cor, additional, de Lourdes Bastos, Maria, additional, Del Bigio, Marc R., additional, Dembińska, Teresa, additional, Deveci, Ugur, additional, Dieterich, D.C., additional, Dijkstra, Boukje, additional, Dluzen, Dean E., additional, Dubocovich, Margarita L., additional, Esperón, Carlos García, additional, Fang, Chun-Kai, additional, Farnia, Vahid, additional, Félix, Luís, additional, Fernàndez-Castillo, Noelia, additional, Flack, Daniel, additional, Frauger, Elisabeth, additional, Frohlich, Joel, additional, Fukushiro, Daniela F., additional, García, Daniel A., additional, Julia García-Fuster, M., additional, García-Sevilla, Jesús A., additional, Garland, Eric L., additional, Gatzia, Dimitria Electra, additional, Gelazonia, Lia, additional, Ghosh, Abhishek, additional, Gigengack, Roy, additional, Golshani, Senobar, additional, Gonçalves, Joana, additional, González-Maeso, Javier, additional, Gorman, Ingmar, additional, Grandy, David K., additional, Grecksch, G., additional, Greer, Alissa M., additional, Gudelsky, Gary A., additional, Guillot, Casey, additional, Gulley, Joshua M., additional, Hagino, Yoko, additional, Hallock, Robert M., additional, Hankosky, Emily R., additional, Hanks, James B., additional, Hart, Carl, additional, Hasselmann, H.W.W., additional, Hida, Hirotake, additional, Hodges, Sarah E., additional, Holder, Nicole, additional, Hollais, André W., additional, Höllt, V., additional, Horacek, Jiri, additional, Howard, Matthew O., additional, Howells, Fleur Margaret, additional, Hsin-Hsien Yeh, Skye, additional, Huang, Mei, additional, Hutchinson, Anthony J., additional, Hwang, Jeng-Jong, additional, Ikeda, Kazutaka, additional, Iudicello, Jennifer E., additional, Jalloh, Ahmad, additional, Jamali, Bardia, additional, Japaridze, Nadezhda, additional, Jodo, Eiichi, additional, Joordens, Chantele, additional, Kalayasiri, Rasmon, additional, Kamal, Rama, additional, Kamegaya, Etsuko, additional, Katayama, Tadahiro, additional, Keasling, Adam W., additional, Kikura-Hanajiri, Ruri, additional, Kirkpatrick, Matthew, additional, Kiss, Béla, additional, Kočárová, Rita, additional, Kokane, Saurabh S., additional, Kreek, Mary Jeanne, additional, Kufahl, Peter R., additional, Kuhn, Donald M., additional, Kumazawa, Takeshi, additional, Kusljic, Snezana, additional, Łabuz, Krzysztof, additional, Lapeyre-Mestre, Maryse, additional, Laranjeira, Ronaldo Ramos, additional, Lawrence, Andrew J., additional, Lee, Byung Dae, additional, Leitão, Ricardo Alexandre, additional, Leung, L. Stan, additional, Li, Chiang-Shan R., additional, Li, Meng, additional, Lin, Qing, additional, Loghin, Felicia, additional, López-Cancio M., Elena, additional, Lyke, Jennifer, additional, Lyvers, Michael, additional, Macdonald, Scott, additional, Madruga, Clarice Sandi, additional, Maes, Michael, additional, Maher, Timothy J., additional, Ma, Jingyi, additional, Mandyam, Chitra D., additional, Mardones, Claudia, additional, Martin, Gina, additional, Massaro, Luciana, additional, Matsuda, Toshio, additional, McMaster, M.T.B., additional, Melloni, Richard H., additional, Meltzer, Herbert Y., additional, Micallef, Joëlle, additional, Mironidou-Tzouveleki, Maria, additional, Mishina, Masayoshi, additional, Mitsuhiro, Sandro, additional, Montag, Christian, additional, Moore, Elisabeth, additional, Morgan, Erin E., additional, Morgan, Peter T., additional, Morimoto, Satoshi, additional, Morrison, Thomas R., additional, Moszczynska, Anna, additional, Mouri, Akihiro, additional, Napolitano, Antonio, additional, Neugebauer, Nichole M., additional, NicDaeid, Niamh, additional, Nichols, Charles D., additional, Nizama-Valladolid, Martin, additional, Noda, Yukihiro, additional, Northrop, Nicole A., additional, Olive, M. Foster, additional, Ostrow, Rory D., additional, Oudejans, Linda C.J., additional, Palenicek, Tomas, additional, Pandey, Arvind, additional, Papp, Mariusz, additional, Passos, Ioannis D., additional, Paudel, Madan Kumar, additional, Perillo, Maria A., additional, Perry, Christina J., additional, Petronijević, Nataša, additional, Phattanarudee, Siripan, additional, Pinsky, Ilana, additional, Pochkhidze, Nino, additional, Pop, Anca, additional, Possa, Marianne, additional, Potocka-Banaś, Barbara, additional, Quednow, Boris B., additional, Radonjić, Nevena V., additional, Rajagopal, Lakshmi, additional, Ribasés, Marta, additional, Ricci, Lesley A., additional, Rosales, Carola Vergara, additional, Rouini, Mohammad-Reza, additional, Sanchez-Ramos, Juan, additional, Santos-Baldaia, Renan, additional, Sarkar, Siddharth, additional, Sasaki-Tabata, Kaori, additional, Sato, Naomi, additional, Sato, Tomonori, additional, Sawada, Wakako, additional, Schuch, Silvia Bassani, additional, Sekita, Setsuko, additional, Serrano, Eduardo Alvear, additional, Sheikholeslami, Behjat, additional, Shirota, Osamu, additional, Silva, Ana Paula, additional, Simola, Nicola, additional, Simon, Derek P., additional, Sora, Ichiro, additional, Sordi, Anne Orgler, additional, Spring, Mitchell G., additional, Stebelska, Katarzyna, additional, Sugimura, Haruhiko, additional, Suzuki, Yoshiaki, additional, Takuma, Kazuhiro, additional, Tanaka, Hiroyuki, additional, Torkamanian, Meshkat, additional, Towiwat, Pasarapa, additional, Turina, Anahí V., additional, Tyls, Filip, additional, van Amsterdam, J.G.C., additional, van den Brink, W., additional, van den Buuse, Maarten, additional, Van Horn, John Darrell, additional, van Noorden, Martijn, additional, van Velzen, Monique, additional, Venâncio, Carlos, additional, von Baer, Dietrich, additional, von Diemen, Lisia, additional, Walter, Martin, additional, Wang, Fang, additional, Weber, Erica, additional, Winkler, Petr, additional, Woods, Steven Paul, additional, Woodward, John J., additional, Wu, Chun-Fu, additional, Wuo-Silva, Raphael, additional, Xu, Wang, additional, Yamamoto, Bryan K., additional, Yamamoto, Hideko, additional, Yamamoto, Toshifumi, additional, Yang, Jing-Yu, additional, Zhai, Duanting, additional, Zhvania, Mzia, additional, and Zjawiony, Jordan K., additional
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- 2016
- Full Text
- View/download PDF
4. Role of aquaporin-4 in methamphetamine-induced blood-brain barrier dysfunction and cerebral edema formation
- Author
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Leitão, Ricardo Alexandre Gomes and Silva, Ana Paula
- Subjects
Partenolídeo ,Astrócitos ,Ciências Médicas::Ciências da Saúde [Domínio/Área Científica] ,Comportamento animal ,Aquaporina-4 ,Methamphetamine ,Parthenolide ,Blood–brain barrier ,Edema cerebral ,Neuroinflammation ,Astrocytes ,Brain edema ,Fator de necrose tumoral alfa ,Tumor necrosis factor-alpha ,Metanfetamina ,Barreira hematoencefálica ,Ciências Naturais::Ciências Biológicas [Domínio/Área Científica] ,Neuroinflamação ,Aquaporin-4 ,Animal behavior - Abstract
Tese de doutoramento em Engenharia Biomédica, apresentada à Faculdade de Ciências e Tecnologia da Universidade de Coimbra Methamphetamine (METH) is a powerful psychostimulant drug of abuse that has gained worldwide popularity, and its use originates severe health problems. Despite extensive characterization of METH-induced neurotoxicity over the last years, many questions remain unanswered. Several reports have demonstrated that oxidative stress, mitochondrial dysfunction, and neuroinflammation are some of the neurotoxic features of METH. More recently, it was shown that METH compromises the blood-brain barrier (BBB) and causes a disturbance in the water homeostasis leading to brain edema. Additionally, it is well known that astrocytes play a crucial role in modulating BBB structure and function, as well as in regulating brain water content. However, the effect of METH on the crosstalk between brain endothelial cells (ECs) and astrocytes has never been addressed before. Also, water fluxes that take place between the different compartments of the brain, and between brain parenchyma and the blood are highly controlled. Thus, disturbances in this well-regulated homeostasis cause brain edema, which will have deleterious effects on brain function. Importantly, the water transport at BBB is regulated by water channels, aquaporins (AQPs), and AQP4 is the most important at the Central Nervous System, being express on astrocytic endfeet in contact with brain vessels. Brain edema is a hallmark of several neuropathologies, and METH consumption is not an exception. Yet, to date, nothing is known about the role of AQP4 under METH conditions. Furthermore, AQP4 has two isoforms, M1 and M23, and the ratio M1/M23 regulates water homeostasis since M23 stabilizes the channel function but M1 disrupts the AQP4 structure. Taking into consideration all the gaps in this field, it is urgent to clarify the role of AQP4 in METH-induced BBB dysfunction and brain edema formation. The present thesis is divided into 5 chapters. In chapter 1 is presented a review of the literature about the different themes that were explored in the laboratory and detailed in the following chapters. In chapter 2, the impact of METH on astrocytes-ECs crosstalk was investigated with a particular interest in the role of tumor necrosis factor alpha (TNF-α). After observing that METH increased TNF-α released by both astrocytes and ECs, it was also proved that this proinflammatory cytokine was responsible for endothelial permeability through the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. These in vitro results were corroborated by animal studies showing an increase of BBB permeability and TNF-α levels in the mice striatum, which was prevented by NF-κB pathway blockade. Overall, it was shown that TNF-α/NF-κB signaling pathway has a key role in METH-induced BBB dysfunction. Next, in chapter 3, it was investigated the direct effect of METH on AQP4 system concluding that METH, besides BBB dysfunction, is also able to induce a cytotoxic brain edema and depressive-like behavior. Curiously, AQP4 was shown to have a predominant role of such alterations since its inhibition prevented all the effects observed in mice. Moreover, AQP4 via reactive oxygen species (ROS) production was involved in cell swelling and altered astrocyte morphology triggered by METH since AQP4 knockdown or its pharmacological blockade, as well as an antioxidant treatment (namely vitamin C) were able to prevent METH effects in astrocytes. In conclusion, AQP4 was identified as a new target against METH-induced neurogliovascular dysfunction and depressive-like behavior. Following the results observed in chapter 2 and 3, a new strategy to counteract the negative effects of METH was applied by using a natural flower product. Thus, in chapter 4, it was proved that parthenolide (PTL), a feverfew plant extract, has an anti-inflammatory role and prevented METH-induced BBB permeability and brain edema. Additionally, TNF-α via activation of its receptor 1 (TNFR1) was involved in astrocytic swelling induced by METH. In sum, PTL plays a beneficial role against neuroinflammation and neurogliovascular dysfunction triggered by METH. Finally, in chapter 5, a general discussion is presented. Overall, the present work shows that METH interferes with brain water homeostasis and BBB function, culminating in behavioral abnormalities. Moreover, both neuroinflammation and oxidative stress are involved in such negative effects of METH, and new strategies to counteract these deleterious consequences were identified, such as AQP4 blockade and the use of PTL. A metanfetamina (MET) é uma droga de abuso muito viciante com grande popularidade mundial, e que causa sérios problemas de saúde. Apesar da extensa caracterização da sua neurotoxicidade nos últimos anos, muitas questões continuam sem resposta. Alguns estudos têm mostrado que o stresse oxidativo, a disfunção mitocondrial e a neuroinflamação são alguns dos efeitos nefastos da MET. Mais recentemente demonstrou-se que a MET interfere com a função normal da barreira hematoencefálica (BHE), causando alterações na homeostase da água o que pode levar a uma situação de edema cerebral. Para além disso, sabe-se também que os astrócitos têm um papel muito importante na modulação da estrutura e função da BHE, bem como na regulação do conteúdo de água cerebral. No entanto, o efeito da MET na comunicação entre as células endoteliais (CEs) e os astrócitos nunca foi estudado anteriormente. Por outro lado, o movimento de moléculas de água entre os diferentes compartimentos do cérebro e entre o parênquima cerebral e a corrente sanguínea ocorre de forma controlada. Assim, distúrbios nesta homeostase irão causar uma situação de edema, o qual terá um impacto negativo na função cerebral. O transporte de água na BHE é regulado por canais de água, denominados aquaporinas (AQPs), sendo que a AQP4 é a mais importante no Sistema Nervoso Central, e encontra-se expressa nas terminações dos astrócitos que contactam com os vasos cerebrais. De facto, o edema cerebral ocorre em muitas neuropatologias, e o consumo de MET não é exceção. No entanto, o papel da AQP4 nos efeitos da MET é ainda desconhecido. Além disso, a AQP4 tem duas isoformas, a M1 e a M23, e é a sua proporção que regula a homeostase da água, uma vez que a presença da isoforma M23 estabiliza a função do canal de água enquanto a isoforma M1 causa alterações na função da AQP4. Deste modo, é importante esclarecer o papel da AQP 4 na disfunção da barreira hematoencefálica e na formação do edema cerebral induzidos por MET. A presente tese está dividida em 5 capítulos. No capítulo 1 é apresentada uma revisão da literatura sobre os diversos temas estudados no laboratório e detalhados nos capítulos seguintes. No capítulo 2 investigou-se o efeito da MET na comunicação entre astrócitos e CEs com particular interesse no papel do fator de necrose tumoral alfa (TNF-α). Depois de mostrar um aumento da libertação de TNF-α induzido por MET, quer pelos astrócitos quer pelas CEs, provou-se que esta citocina pró-inflamatória estava envolvida no aumento da permeabilidade das CEs através da ativação da via de sinalização do fator nuclear kappa B (NF-κB). Estes resultados foram corroborados por estudos em animais onde se observou um aumento da permeabilidade da BHE e dos níveis de TNF-α no estriado de murganho, efeitos estes que foram prevenidos pelo bloqueio da via do NF-κB. Deste modo, conclui-se que a via de sinalização do TNF-α/NF-κB está envolvida na disfunção da BHE induzida por MET. De seguida, no capítulo 3 avaliou-se o impacto direto da MET no sistema da AQP4 e foi possível demonstrar que esta droga de abuso, para além de induzir uma disfunção da BHE, também originou um edema cerebral citotóxico e comportamento do tipo depressivo. Curiosamente, a AQP4 teve um papel predominante nestas alterações já que o seu bloqueio preveniu todos os efeitos observados nos murganhos. In vitro foi também possível comprovar o papel importante da AQP4 via produção de espécies reactivas de oxigénio já que o silenciamento deste canal de água ou a sua inibição farmacológica, bem como a exposição a um antioxidante (vitamina C) preveniram as alterações morfológicas induzidas pela MET nos astrócitos. Em conclusão, a AQP4 foi identificada como um alvo importante para prevenir as alterações neurogliovasculares e comportamento depressivo induzidos por MET. Na sequência dos efeitos negativos da MET observados nos capítulos 2 e 3, colocou-se a hipótese de uma nova abordagem com um produto natural de origem vegetal. Deste modo, no capítulo 4 concluíu-se que o partenolídeo (PTL), um extrato obtido da artemísia dos prados (Tanacetum parthenium), tem um papel anti-inflamatório e preveniu o aumento da permeabilidade da BHE e formação de edema cerebral induzidos por MET. Mais ainda, foi possível demonstrar que o TNF-α, através da ativação do seu recetor TNFR1, estava envolvido no aumento de volume dos astrócitos observado na presença de MET. Assim, este trabalho permitiu concluir que o PTL tem um feito benéfico em condições de neuroinflamação e disfunção neurogliovascular induzidos por MET. Por último, o capítulo 5 inclui uma discussão geral sobre os resultados obtidos nos capítulos anteriores. Em conclusão, esta tese permitiu mostrar que a MET interfere não só com a homeostase da água no cérebro, mas também com a função da BHE, e que estes efeitos podem conduzir a alterações comportamentais. Para além disso, demonstrou-se ainda que a neuroinflamação e o stresse oxidativo estão subjacentes aos efeitos negativos causados pela MET e foram identificadas duas abordagens para prevenir estes efeitos, tais como o bloqueio da AQP4 e o uso do partenolídeo.
- Published
- 2017
5. Chapter 15 - Methamphetamine and the Blood–Brain Barrier
- Author
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Leitão, Ricardo Alexandre, Coelho-Santos, Vanessa, and Silva, Ana Paula
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- 2016
- Full Text
- View/download PDF
6. Psychostimulants and brain edema
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Leitão, Ricardo Alexandre and Silva, Ana Paula
- Subjects
Cocaine ,3,4- methylenedioxymethamphetamine ,Brain edema ,Water imbalance ,Methamphetamine - Abstract
Psychostimulants consumption is a serious social and health problem worldwide. The increase in drug abuse has a huge socio-economic impact in society, and more precisely carries great costs in health treatments. In fact, it is well known that cocaine, 3,4-methylenedioxymethamphetamine (MDMA), amphetamine (AMPH) and methamphetamine (METH) have several neurotoxic effects, such as neurodegeneration, neuroinflammation and blood-brain barrier (BBB) disruption. Additionally, the increase of brain water content, a pathological condition also known as brain edema, has been associated with drugs use. Disturbances in the well-regulated water homeostasis may occur under several pathological conditions leading to severe alterations in brain function. Although several studies demonstrated a link between the abuse of psychostimulants and brain edema, very little is known about the underlying mechanisms that explain such brain alterations. The water transport across cell membrane is regulated by bi-directional water channels called aquaporins (AQPs). Noteworthy, the AQP4 channel has an important role in water transport across BBB, being one of the most important at the Central Nervous System (CNS). In fact, alterations in AQP4 can originate cerebral edema due to abnormal increase in water content and consequent brain swelling. Furthermore, inflammatory mediators also seem to have a role in brain edema formation since the modulation of their action has a beneficial impact in brain edema outcome. With the present review, we aim to summarize relevant information regarding the impact of psychostimulants on brain edema. Nevertheless, it is also evident that many questions remain unanswered. Thus, in order to improve the clinical outcome of human abusers, it is of crucial importance to understand what the role of AQP4 is. info:eu-repo/semantics/publishedVersion
- Published
- 2015
7. Aquaporin-4 as a New Target against Methamphetamine-Induced Brain Alterations: Focus on the Neurogliovascular Unit and Motivational Behavior
- Author
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Leitão, Ricardo Alexandre, primary, Sereno, José, additional, Castelhano, João Miguel, additional, Gonçalves, Sónia Isabel, additional, Coelho-Santos, Vanessa, additional, Fontes-Ribeiro, Carlos, additional, Castelo-Branco, Miguel, additional, and Silva, Ana Paula, additional
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- 2017
- Full Text
- View/download PDF
8. Impact of methamphetamine on astrocytes and endothelial cells : role of aquaporin-4
- Author
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Leitão, Ricardo Alexandre Gomes, Silva, Ana Paula, and Duarte, Carlos Jorge Alves Miranda Bandeira
- Subjects
Astrócitos ,Metanfetamina ,Barreira hemato-encefálica ,Células endoteliais ,Aquaporina-4 - Abstract
Dissertação de mestrado em Biologia Celular e Molecular apresentada ao Departamento de Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de Coimbra. A metanfetamina (MET) é uma droga psicoestimulante altamente viciante cujo consumo na Europa tem vindo a aumentar nos últimos anos. Vários estudos têm demonstrado que o stress oxidativo, a excitotoxicidade, inflamação e a disfunção mitocondrial são alguns dos efeitos neurotóxicos da MET. Recentemente foi demonstrado que a MET compromete a função da barreira hemato-encefálica (BHE) e causa edema cerebral. A BHE é uma estrutura responsável por proteger o cérebro de compostos tóxicos, mas também permite a passagem de nutrientes e várias moléculas importantes para o parênquima cerebral. A função de barreira é determinada pelas células endoteliais, que em conjunto com os pericitos, astrócitos, lâmina basal, microglia e neurónios formam a unidade neurovascular. Entre as diferentes regiões cerebrais, bem como entre o parênquima cerebral e a corrente sanguínea, ocorre constantemente um grande fluxo de água e perturbações na homeostasia da água podem ter efeitos prejudiciais na função cerebral. As aquaporinas (AQPs) são canais de água responsáveis pelo transporte de água através da BHE, sendo a AQP4 uma das mais importantes no Sistema Nervoso Central (SNC). A AQP4 é expressa nas extremidades dos astrócitos que estão em contacto com os vasos sanguíneos. Além disso, alterações na AQP4 podem levar à formação de edema cerebral devido a um aumento anormal do conteúdo de água no cérebro e um consequente inchaço cerebral. De facto, o edema cerebral tem sido observado em várias neuropatologias, incluindo em condições de consumo de MET. Assim, o objetivo do presente trabalho foi avaliar se a MET induz alterações na expressão da AQP4 e qual o papel dos astrócitos na toxicidade induzida por MET em células endoteliais. Os nossos resultados mostram que a MET leva a um aumento da expressão de AQP4 em culturas primárias de astrócitos, sem interferir com os níveis da proteína glial fibrilar acídica (GFAP - Glial Fibrillary Acidic Protein). Além disso, também testámos o efeito desta droga num modelo animal de intoxicação por MET (binge). Com este protocolo mostrámos que a MET induz um aumento da expressão da AQP4 no hipocampo e uma diminuição no córtex pré-frontal, mostrando que as diferentes regiões apresentam diferente suscetibilidade para a MET. No entanto, quando avaliámos o conteúdo de água no cérebro total não observámos alterações significativas. Tendo em consideração o papel dos astrócitos na função da BHE, usámos para os estudos seguintes uma linha celular de células endoteliais de murganho (bEnd.3). Foi possível concluir que os meios condicionados de astrócitos (MCA) protegeram as células endoteliais (CEs) da morte celular induzida por MET (3 mM). No entanto, quando expusemos as CEs aos MCA 12 recolhidos de células expostas a concentração não tóxicas de MET (1 μM e 50 μM), observámos uma diminuição da expressão das proteínas das junções oclusivas (JOs), ocludina e claudina-5, mas não se verificou nenhum efeito na condição MCA controlo. Em suma, os nossos resultados mostram que a MET causa alterações na expressão da AQP4 quer em culturas primárias de astrócitos quer no hipocampo de murganhos. Além disso, os astrócitos numa situação controlo parecem proteger as células endoteliais da morte celular induzida por MET, mas quando previamente expostos a MET os astrócitos provavelmente libertam fatores que interferem negativamente com a expressão de proteínas da JOs o que em última análise pode aumentar a permeabilidade da barreira. Methamphetamine (METH) is a potent and highly addictive psychostimulant which consumption in Europe has been increased over the last years. Several reports have demonstrated that oxidative stress, excitotoxicity, inflammation and mitochondrial dysfunction are some of the neurotoxic features of METH. More recently, it was shown that METH can also compromise the blood-brain barrier (BBB) function and cause cerebral edema. BBB is a structure responsible for protecting the brain from toxic compounds, but nevertheless allows the passage of nutrients and several important molecules into the brain parenchyma. The barrier function is determined by the endothelial cells, that together with pericytes, astrocytes, basal lamina, microglia and neurons form the neurovascular unit. Large water fluxes continuously take place between the different compartments of the brain, as well as between the brain parenchyma and the blood. Disturbances in this well-regulated water homeostasis may have deleterious effects on brain function. Aquaporins (AQPs) are water channels that contribute to water transport across BBB, being AQP4 one of the most important at the Central Nervous System (CNS). AQP4 is express on astrocytic end-feet in contact with brain vessels. Moreover, alterations in AQPs can originate cerebral edema due to abnormally increased water content and consequent brain swelling. Indeed, brain edema has been observed in several neuropathologies, including under conditions of METH consumption. Therefore, the aim of the present work was to investigate if METH induces alterations in the expression of AQP4 and the role of astrocytes against METH-induced toxicity of endothelial cells. Our results show that METH leads to an increase of AQP4 expression in primary cultures of astrocytes, without interfering with the glial fibrillary acidic protein (GFAP) levels. Furthermore, we also tested the effect of the drug in an animal model of METH intoxication (binge paradigm). With this protocol we showed that METH leads to an increase of AQP4 expression in the hippocampus and to a decrease in the frontal cortex, demonstrating that different brain regions present different susceptibilities to METH. However, when the water content of whole brain was measured we did not observe significant alterations. Taking into consideration the role of astrocytes in the BBB function, we further used a mouse brain endothelial cell line (bEnd.3). It was possible to conclude that astrocyte-conditioned medium (ACM) was able to protect endothelial cells (ECs) against METH-induced cell death (3 mM). However, when we exposed the ECs to ACM collected from cells exposed to non-toxic METH concentrations (1 μM and 50 μM), we observed that both ACM METH conditions caused 14 a decreased in the expression of the tight junction proteins (TJs), occludin and claudin-5, without any effect of the ACM control. Overall, our results show that METH causes an increase in AQP4 expression in both primary cultures of astrocytes and in mice hippocampus using an acute METH administration protocol. Moreover, astrocytes in a control situation seem to protect the endothelial cells from METH-induced cell death, but when previously exposed to METH they probably release some factors that negatively interfere with the expression of TJs proteins that ultimately may increase barrier permeability.
- Published
- 2012
9. Impact of traumatic brain injury on astrocytes: role of neuropeptide Y
- Author
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Bernardo, Ana Luísa Marques, Martins, Ana Paula Pereira da Silva, and Leitão, Ricardo Alexandre
- Subjects
Cell death ,Traumatismo crânio-encefálico ,Neuropeptídeo Y ,Traumatic brain injury ,Astrócitos ,Oxidative stress ,Astrocytes ,Morte celular ,Neuropeptide Y ,Stress oxidativo - Published
- 2019
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