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Previous issue date: 2004 === Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) === Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) === Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) === Fundo de Auxílio aos Docentes e Alunos (FADA) === Programa de Apoio a Núcleos de Excelência (PRONEX) === A mitocondria e importante no processo de manutencao da homeostase do calcio, na manutencao do potencial de membrana do neuronio, no processo de apoptose e na formacao de radicais livres (RL). Essas caracteristicas relacionam a mitocondria com a excitotoxicidade vista na epilepsia .Lesoes do DNA mitocondrial (DNAmt) via lesao oxidativa sao vistas em varias doencas sendo presumivel seu) aparecimento na epilepsia pela presenca de RL, ja largamente documentada nessa patologia. Nosso objetivo, no presente estudo, foi avaliar o possivel envolvimento da mitocondria no processo de epileptogenese, no modelo de epilepsia do lobo temporal induzido por pilocarpina. Para tanto, nos propusemos al avaliar o aparecimento de alteracoes do DNAmt, bem como o ocorrencia del disfuncoes de proteinas da cadeia respiratoria. Delecoes ou alteracoes da quantidade das moleculas de DNAmt e disfuncoes da citocromo c oxidade e na succinato desidrogenase foram estudadas em hipocampos de ratos submetidos ao modelo de epilepsia induzida por pilocarpina, com as tecnicas de Southern Blot ,I PCR, histoquimica, Western Blot e Imunohistoquimica. Foram utilizados animais) durante a fase cronica do modelo, quando inicia-se o aparecimento de crises) espontaneas e recorrentes. A analise do DNAmt nao mostrou deplecao ou um aumento de delecoes dos DNAmt nos animais experimentais. Esses dados sugerem que danos do DNAmt nao estejam envolvidos na patogenese da epilepsiaa(au) === Mitochondria have important fuctions in intracellular calcium homeostases, maintenance of neuronal membrane potential, apoptotic signalling and in free radicals production. These features may link mitochondria to a possible role on epilepsy excitotoxicity. Mitochondrial DNA (mtDNA) damage by oxidative lesions are observed in many diseases and it is supposed to occur in epilepsy due to the well
stabilished presence of free radicals in this disease. Our aim in this study was to evaluate the possible role of mitochondria in epilepy. The study was performed in the pilocarpine model of temporal lobe epilepsy by studying mtDNA and respiratory chain proteins abnormalities. Deletions or quantitative alterations of mtDNA and dysfuntion of cytocrome c oxidase and succinate dehydrogenase were studied with Southern Blot, polymerase chain reaction (PCR), histochemistry, imunohistochemistry and Western Blot techniques. The animals were in chronic phase of the PILO model of epilepsy when spontaneous and recurrent seizures begin to occur. No mtDNA depletion was observed and increased frequency of mtDNA damage was not detected in epileptic animals. These data do not support the involvement of mtDNA damage in the pathogenesis epilepsy. The expression and distribution of the respiratory chain proteins (COX I, COX IV, SDH) enzymes studied were similar in both groups (control and epileptic animals) in the hippocampus. Furthermore, no difference in COX activity was observed by hystochemistry. The preservation of mtDNA and respiratory chain proteins show a relative maintenance of basal metabolism in epileptic hippocampus. Such data is reinforced by previous study that show no changes in glucose utilization in the chronic phase of this same model of epilepsy. It has been reported that NA+/K+ ATPase is upregulated in epilepsy, and this enzyme is crucial to the maintenance of membrane potential. In addition, this enzyme is highly dependent of mitochondrial ATP production. Considering that NA+/K+ ATPase is upregulated in epilepsy, we would expect a propotional increase in mitochondrial activity to mantain ATPase well function. However, our data do not
demonstrate this increase in activity, which could indicate abnormalities in the link between energetic need and mitochondrial function. This hypothesis could be a possible target for future studies. === BV UNIFESP: Teses e dissertações
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