Abstracts

Rationale: Mesial temporal lobe epilepsy (MTLE) is one of the most common forms of human epilepsy, whose pathological hallmarks are neuronal loss and synaptic reorganization in the hippocampus. The current study was conducted to further explore data obtained from gene expression studies performed in hippocampal tissue obtained from patients with MTLE who underwent surgery for medically refractory seizures.Methods: We established and compared gene expression profiles of MTLE patients with positive family history [(+)FH] (n=4), MTLE with negative family history [(-)FH] (n=4) and autopsy controls (n=3) using Gene Set Enrichment Analysis (GSEA, http://www.broadinstitute.org/gsea/index.jsp) and Connectivity Map analysis (C-MAP, http://www.broadinstitute.org/cmap/index.jsp).Results: Transcriptional profiling by microarray analysis revealed that MTLE patients with (+)FH had 170 differentially expressed genes; whereas, MTLE patients with (-)FH had 341, when compared to controls. GSEA applied to the gene expression profile of patients with (+)FH demonstrated enriched gene sets involved in cellular proliferation, MYC and AKT1 signaling pathways, inhibition of DNA methylation and histone deacetylation, and synthesis of myelin constituents. The same analysis on the gene expression profile of patients with (-)FH showed enriched gene sets mainly involved in oxidative stress and electron transport chain. The C-MAP analysis applied to the gene expression signature of patients with (+)FH demonstrated a negative correlation with IL-6 and glycogen synthase kinase-3 inhibitors (connectivity score -0.692 and -0.568, respectively). IL-6 activation in epilepsy may play a role protecting the central nervous system (CNS) from seizure-induced damage, while glycogen synthase kinase-3 activates WNT pathway and may contribute to the regulation of neuronal survival and homeostasis in the CNS. C-MAP analysis applied to the gene signature of patients with (-)FH showed a negative correlation with the signatures for TNF-?/NF-?? and HSP90 inhibitors (connectivity score -0.697 and -0.238, respectively). These inhibitors mediate the inactivation of cell survival pathways. Interestingly, there was no overlap between the enriched gene sets and molecules from the C-MAP database that had a significant negative correlation in the gene expression profiles from both MTLE patients groups, (+)FH and (-)FH.Conclusions: Overall, our data demonstrate for the first time the use of in silico approaches to identify enriched gene sets and search for potential new compounds for the treatment of patients with MTLE based on its gene expression profile. Furthermore, GSEA and C-MAP analysis revealed a clear difference in gene expression profiles of MTLE patients with and without familial recurrence of the disease. Supported by: FAPESP.