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(Mdma; “Ecstasy”) on Rat Brain Mitochondria

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(Mdma; “Ecstasy”) on Rat Brain Mitochondria Ema Luís Pereira Gomes Alves NEUROTOXICITY OF METHYLENEDIOXYMETHAMPHETAMINE (MDMA; ECSTASY) ON RAT BRAIN MITOCHONDRIA Porto, 2007 Ema Luis Pereira Gomes Alves Neurotoxicity of methylenedioxymethamphetamine (MDMA;”ecstasy”) on rat brain mitochondria Porto 2007 Neurotoxicity of methylenedioxymethamphetamine (MDMA;”ecstasy”) on rat brain mitochondria Ema Luis Pereira Gomes Alves Dissertação apresentada à Faculdade de Farmácia da Universidade do Porto para obtenção do grau de doutor em toxicologia. Dissertation presented to the Faculty of Pharmacy of the University of Porto to to obtain a PhD degree in toxicology. Supervisor Professor Doutor Félix Dias Carvalho Professor Associado com Agregação da Faculdade de Farmácia da Universidade do Porto, Porto, Portugal. Co-Supervisor Doutora Maria Teresa Burnay Summavielle Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto Portugal Departamento de Ciências Biomédicas, Escola Superior de Tecnologias da Saúde (ESTSP), Instituto Politécnico do Porto (IPP), Porto, Portugal Co-Supervisor Professor Doutor José Barata Cutódio Departamento de Bioquímica, Faculade de Farmácia, Universidade de Coimbra, Coimbra, Portugal III “Para ser grande, sê inteiro: nada teu exagera ou exclui. Sê todo em cada coisa. Põe quanto és no mínimo que fazes. Assim em cada lago a lua toda brilha, porque alta vive.” Ricardo Reis Ao(s) Professore(s) Doutore(s) Félix Dias Carvalho e Maria Teresa Burnay Summavielle. Aos meus pais e irmãos. À memória da minha avó. VII O Decreto de Lei 288/70, art. 8, § 2,refere: “ É admitido na elaboração da dissertação o aproveitamento, total ou parcial, do resultado de trabalhos já publicados, mesmo em colaboração, devendo, neste caso, o candidato esclarecer qual a sua contribuição pessoal” Neste sentido, integram esta dissertação resultados publicados nos trabalhos seguidamente enumerados, para os quais contribuiu pessoalmente, preparando todo o material experimental, procedendo às determinações analíticas, organização e análise dos resultados e redacção do texto, em colaboração com os restantes autores. Artigos originais e comunicações apresentadas em congressos cujos resultados integram este trabalho: Artigos publicados em revistas internacionais: Alves E, Summavielle T, Alves CJ, Gomes-da-Silva J, Custódio JB, Fernandes E, Bastos ML, Tavares MA, Carvalho F (2007) Monoamine oxidase-B mediates ecstasy- induced neurotoxic effects to adolescent rat brain mitochondria. J Neurosci. 27:10203- 10210. Alves E, Summavielle T, Alves CJ, Custódio JB, Fernandes E, Bastos ML, Tavares MA, Carvalho F (2007) Ecstasy-induced oxidative stress to adolescent rat brain mitochondria in vivo: influence of monoamine oxidase type A. (submitted). Alves E, Binienda Z, Carvalho F, Fernandes E, Bastos ML, Tavares MA, Summavielle T (2007) Acetyl-L-carnitine provides effective in vivo neuroprotection over MDMA- induced neurotoxicity in adolescent rat brain mitochondria (in preparation) Alves E, Custódio JB, Summavielle T, Melo P, Bastos ML, Carvalho F (2007) Neurotoxicity and mitochondria (in preparation) IX Comunicações orais apresentadas em congressos nacionais: Alves, E., Summavielle, T., Gomes-da-Silva, J., Custódio, J.B., Fernandes, E., Bastos, M.L., Carvalho, F. “Long-Term” effects of MDMA exposure in adolescent male rats: abnormal thermoregulation, oxidative stress and mtDNA deletions in isolated whole brain mitochondria. Annual Meeting of the Portuguese Society of Pharmacology. Lisbon, December 5-7, 2005, Portugal. Alves, E., Summavielle, T., Gomes-da-Silva, J., Custódio, J.B., Fernandes, E., Bastos, M.L., Carvalho, F. Effects of MDMA exposure in adolescent male rats. IBMC. PhD Training seminars. Porto, March 22, 2006, Portugal. Alves, E., Summavielle, T., Alves, C., Gomes-da-Silva, J., Monteiro, P., Fernandes, E., Bastos, M.L., Carvalho, F. Monoamine oxidase B mediates ecstasy-induced neurotoxic effects in adolescent’s rat brain mitochondria. Annual Meeting of the Portuguese Society of Pharmacology. Porto, December 5-7, 2006, Portugal. Alves, E., Summavielle, T., Alves, C., Gomes-da-Silva, J., Monteiro, P., Fernades, E., Bastos, M.L., Carvalho, F. Monoamine oxidase B mediates ecstasy-induced neurotoxic effects in adolescent’s rat brain mitochondria. Annual meeting of the Portuguese Society of Pharmacology. Coimbra, December 5-7, 2007, Portugal. Comunicações em painel apresentadas em congressos internacionais: Alves, E., Summavielle, T., Faria, R., Gomes-da-Silva, J., Custódio, J.B., Fernandes, E., Bastos, M.L., Carvalho, F. MDMA exposure in adolescent male rats induces long- term abnormal thermoregulation and oxidative stress in whole-brain mitochondria. Satellite Meeting of the International Society for Neurochemistry/European Society for Neurochemistr : Cellular and Molecular Mechanisms of Drugs of Abuse and Neurotoxicity: Cocaine, GHB and substituted amphetamines. Venice, August 16 -19, 2005, Italy. X Alves, E., Summavielle, T., Alves, C., Gomes-da-Silva, J., Monteiro, P., Fernandes, E., Bastos, M.L., Carvalho, F.. Monoamine-oxidase B mediates ecstasy-induced neurotoxic effects in adolescent’s rat brain mitochondria. Neuroscience 2006. Atlanta, 1 October 14-18, 2006, EUA. Alves, E., Binienda, Z., Gonçalves, A., Fernandes, E., Carvalho, F., Summavielle, T. Acetyl-L-carnitine provides neuroprotection against MDMA-induced neurotoxicity through prevention of mitochondrial dysfunction. First Annual International Drug Abuse Research Society (IDARS) Meeting, pre-satellite meeting of the International Society for Neurochemistry and American Society for Neurochemistry. Merida, August 14-17, 2007, Mexico. Alves, E., Binienda, Z., Gonçalves, A., Fernandes, E., Carvalho, F., Summavielle, T. Methylenedioxymethamphetamine-induced mitochondrial damage in CNS: protective effects of acetyl-L-carnitine. Neuroscience 2007. San Diego, November 3-7, 2007, EUA. Comunicações em painel apresentadas em congressos nacionais: Neurobehaviour Unit, IBMC, University of Porto and Toxicology Department of the Faculty of Pharmacy, University of Porto. “Ecstasy, um tóxico cerebral”. Brain Awarness Week (BAW) . Lisbon, December 13, 2005,Pavilhão do Conhecimento, Portugal. Alves, E., Summavielle, T., Faria, R., Gomes-da-Silva, J., Custódio, J.B., Fernandes, E., Bastos, M.L., Carvalho, F. MDMA exposure in adolescent male rats induces long- term abnormal thermoregulation and oxidative stress in isolated whole brain mitochondria. REQUIMTE 4th Annual Meeting. Fatima, March 31 to April 1st, 2006, Portugal. Alves, E., Summavielle, T., Alves, C., Gomes-da-Silva, J., Monteiro, P., Fernandes, E., Bastos, M.L., Carvalho, F. Ecstasy-induced neurotoxic effects in adolescent’s rat brain mitochondria. Protective effect of L-deprenyl. 2nd Symposium of Neurobiology and Drug Abuse (IBMC). Porto, June 21, 2006, Portugal. XI Alves, E., Binienda, Z., Gonçalves, A., Faria, R., Fernandes, E., Carvalho, F., Summavielle, T. In vivo neuroprotective effects of acetyl-L-carnitine against MDMA induced neurotoxicity at the mitochondrial level. 10th Meeting of the Portuguese Society for Neurosciences. Ofir, May 23-26, 2007, Portugal. Alves, E., Summavielle, T., Alves, C., Fernandes, E., Bastos, M.L., Tavares, M.A., Carvalho, F. Persistent mitochondrial oxidative stress in the adolescent rat brain after ecstasy administration. Link age meeting. Porto, November 28 to December 1, 2007, Portugal. XII Agradecimentos Thankwords Ao Professor Doutor Félix Dias de Carvalho: O Professor Félix foi um orientador fora de série. A ele agradeço o entusiasmo, a amizade, e principalmente a forma excelente como orientou todo o trabalho que integra esta tese. Agradeço ainda o apoio com que sempre pude contar nas decisões que fui tomando e os conselhos sabios e experientes sempre no sentido de me fazer ver e seguir os caminhos correctos. Não posso deixar de mencionar ainda a imensa disponibilidade que sempre demonstrou para ajudar a resolver todos os tipos de problemas com que me fui deparando ao longo deste percurso. Todos os obrigadas serão poucos para agradecer tudo o que fez por mim. À Professora Doutora Maria Teresa Burnay Summavielle: A Teresa foi a pessoa com quem mais proximamente pude contar durante estes três anos de trabalho. Um muito obrigada pela tua paciência, compreensão, ensinamento, apoio e sobretudo pelo ombro amigo que foste em situações bastante dificeis. Obrigada também pelos momentos agradáveis que proprorcionaste a todo o grupo, pela tua boa disposição e por todo o esforço que tens feito para gerir da melhor forma o Grupo do Neurocomportamento. Ao Professor Doutor José Barata Custódio: Por me ter ensinado a base de todos os procedimentos experimentais de que precisei para a realização desta dissertação. Um obrigada muito sincero. À Professora Doutora Maria Amélia Tavares: Foi, sem dúvida uma ajuda preciosa em tempos bastante dificéis e sem a qual a realização deste trabalho não seria possível. Muito obrigada por me ter acolhido no seu grupo de trabalho. À Professora Doutora Maria Joana da Costa Gomes da Silva: A Joana deu sem dúvida um contributo bastante importante para a realização da parte inicial desta tese. Um obrigada muito sincero. XIII À Professora Doutora Eduarda Fernades: Pelo trabalho que teve com a extracção da ecstasy e sem a qual a realização deste trabalho não seria possível. Muito obrigada. Ao Pedro Melo: Pela grande ajuda que disponibilizou na execução da parte gráfica desta tese, pela amizade sincera, e, sobretudo pela boa disposição. À Ana Magalhães: Pelos conselhos sábios, pela amizade e companheirismo. À Juliana:
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