Resumo

Introduction: Epilepsy is a prevalent severe neurological condition affecting approximately 50 million people worldwide. Genetic factors are known to contribute to the development of epilepsies but the molecular changes occurring in hippocampal cells are still largely unknown. Epigenetic regulation of gene expression is implicated in normal neural development and its involvement in neurological disorders has been recently suggested. Objective: To conduct a large-scale expression profiling of genes involved in epigenetic regulation in hippocampal cells during the course of epileptogenesis, from the early events post status epilepticus (SE) to the onset of recurrent spontaneous seizures, in an experimental model of epilepsy. Methods: Wistar adult male rats were subjected to the pilocarpine model of temporal lobe epilepsy. Animals were treated with either 350 mg/kg pilocarpine or saline solution (control). Hippocampi were obtained 3 days post-SE (D3, n=5), 7 days post-SE (D7, n=5), and immediately after the first spontaneous seizure (Chronic, n=5). RNA was extracted from hippocampal cells and gene expression evaluated by microarrays covering the entire rat transcriptome. Statistically significant differences among treatments (P<0.05) were determined by two-way ANOVA with Bonferroni as post-hoc test. Results: From a total of 171 epigenetic-related genes interrogated within the arrays, nine displayed significant differential expression in pilocarpine-treated animals. Genes involved in histone modification (Ctbp1, Hdac4, and Hdac11), DNA methylation (Mbd1 and Mbd3), and chromatin remodeling (Cbx6, Arid2, and Chd3) were found permanently hypoexpressed after SE (D3, D7 and Chronic groups) (p<0.001). A gene encoding another chromatin-associated protein, Phf5a, was also differentially expressed in animals from D7 and Chronic groups (p<0.001). Conclusion: These findings suggest epigenetic changes occurring after SE, which may induce long-lasting changes in gene expression patterns of hippocampal cells, with potential relevance to the development of epilepsy. Financial support: FAPESP, CNPq, Capes, CETGEN, INNT.