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Análise de genes envolvidos no modelo de epilepsia de lobo temporal induzido pela pilocarpina / Analysis of genes involved in the temporal lobe epilepsy induced by pilocarpine
Rafael Breglio Marchesini
DATA DE PUBLICAÇÃO
The epilepsies affect approximately 1% of the population worldwide. Temporal lobe epilepsy (TLE) is the most frequent and commonly resistant to clinical treatment. Animal models have been widely used in order to study the mechanisms underlying TLE, especially those induced by chemical agents or electrical stimulation. It is believed that these models present similar epileptogenesis to that of human epileptic tissues studied ex vivo. Among the various animals models available we decided to use the one induced by pilocarpine injections. This model is characterized by three different phases accordingly to phenomenological, histopathological and molecular aspects: acute phase, silent phase and chronic phase. Based on the presence of genes with differential expression patterns in the silent phase, it is believed that it is in this phase that occur the modifications in neuronal circuits that are essential to functional plasticity of the central nervous system under pathological conditions. The changes in hippocampal circuits occuring during the silent phase are the result of the damage caused by the status epilepticus (SE) induced by pilocarpine in the acute phase. These events will ultimately result in spontaneous recurrent seizures in the chronic phase of the model. The main objective of this work was to explore the action of genes that are induced during the silent phase of the pilocarpine model. These would be possibly related with the neuronal damage and the development of epileptogenesis through mechanisms associated with plasticity and neuronal reorganization. In addition, we aimed to explore futher the role of Interleukin1-beta (Il1b), which had been previously demonstrated to be involved in the increase of glutamate release during the acute phase of the pilocarpine model. To achieve these objectives we used a pos-transcriptional gene silencing strategy named RNA interference (RNAi) applied in vivo. It was defined a pattern of gene expression for Trkb and Plat, that are known to be involved with the silent phase. Besides that, the Toll like receptors genes family had the pattern of expression defined during the beginning of the silent phase, demonstrating the expression altered. These alterations seem to participate in the critical processes that occur in the silent phase, inflammatory processes that associated to the synaptic reorganization generated by the structural genes (TrkB and Plat), culminate in the chronic phase of the model. The expression of the genes Il1b and Il1ra were defined too, besides the silencing of them. The silencing in the acute phase of the pilocarpine model led to phenotypic alterations detectable in the animals that had the genes silenced. We believe that our results can provide relevant new information regarding the role of genes in the determination of epileptogenesis during the acute and silent phases of the pilocarpine model. In addition, we have demonstrated the fisibility of the using RNAi to study epileptogenesis in vivo