Expressão gênica diferencial em pacientes com epilepsia do lobo temporal: revisão sistemática acoplada a análise de bioinformática

Abstract

Introduction: Temporal Lobe Epilepsy associated with Hippocampal Sclerosis I (TLE-EH) is the most common type of partial epilepsy in adults. Characterized by a complex pathological process, which involves neuronal losses, reorganization of synapses, inflammation and molecularly by the global reorganization of gene expression, in addition to a refractoriness of 30% of patients to existing antiepileptic drugs (AEDs). Many gene expression studies, both in animal models and in humans, seek to investigate the molecular alterations underlying the epileptogenic process, but due to the heterogeneity of the studies, it was necessary to carry out a careful systematic review with the objective of identifying the consistent genes that participate of the epileptogenic process in humans with ELT-EH. Methodology: This is a systematic review registered in PROSPERO under the ID number: CRD42020180745, according to the protocol described by prism 2020. We carried out the search on January 30, 2021, using the PubMed and LILACS databases. EMBASE and SIGLE, open gray, with the keywords: “Gene Expression” AND “Epilepsy”; “Gene Expression” AND “Seizure”; “Protein Expression” AND “Seizure” AND “Human”; “Protein Expression” AND “Epilepsy” AND “Human”. The results extracted and analyzed had a focus on gene expression data, as well as tissue, molecules, and techniques evaluated. In addition, for genes that are differentially expressed and consistent in more than one study, we proceed with bioinformatics analyses, such asassessingg the functional categories of the Gene Ontology (GO) and searching for regulators of gene expression, such as validated microRNAs (miRs) experimentally and analysis of transcriptional factors. To reduce biases, three researchers independently performed all steps and inclusion and exclusion criteria were applied for study eligibility. Results: 202 studies met the eligibility criteria, with 448 genes studied in ELT-EH. 95 genes at least twice, of which 47 showed consistent data. Thirty-four genes were up-regulated in the brain, seven down regulated and six genes showed no statistically significant difference. The 41 genes were submitted to functional analysis in GO to obtain pathways in molecular function, cellular component,s and biological processes. To analyzes activating ways; we got seven genes with the potential for transcriptional regulation. As for the analysis of miRs, for the 34 genes up-regulated in epileptic tissue, we found 105 validated miRs in total for the seven genes with reduced expression. Furthermore, we found more than three validated miRs from the overexpressed genes: BCL2, DNMT1, TLR4, BDNF, NFKB1, VEGFA, CASP3, TNF, COX2 and from the negatively regulated genes GSK3B AND HCN2. Conclusion: In this sense, our work provides a compilation of vital information on gene expression associated with drug-resistant ELT and its regulators. In addition, it subsidizes precious data for future studies of discovering and validating new therapeutic targets based on manipulating gene expression in mTLE.