Abstract
BackgroundGenomic reprogramming is thought to be, at least in part, responsible for the protective effect of brain preconditioning. Unraveling mechanisms of this endogenous neuroprotection, activated by preconditioning, is an important step towards new clinical strategies for treating asphyctic neonates.Therefore, we investigated whole-genome transcriptional changes in the brain of rats which underwent perinatal asphyxia (PA), and rats where PA was preceded by fetal asphyctic preconditioning (FAPA). Offspring were sacrificed 6 h and 96 h after birth, and whole-genome transcription was investigated using the Affymetrix Gene1.0ST chip. Microarray data were analyzed with the Bioconductor Limma package. In addition to univariate analysis, we performed Gene Set Enrichment Analysis (GSEA) in order to derive results with maximum biological relevance.ResultsWe observed minimal, 25% or less, overlap of differentially regulated transcripts across different experimental groups which leads us to conclude that the transcriptional phenotype of these groups is largely unique. In both the PA and FAPA group we observe an upregulation of transcripts involved in cellular stress. Contrastingly, transcripts with a function in the cell nucleus were mostly downregulated in PA animals, while we see considerable upregulation in the FAPA group. Furthermore, we observed that histone deacetylases (HDACs) are exclusively regulated in FAPA animals.ConclusionsThis study is the first to investigate whole-genome transcription in the neonatal brain after PA alone, and after perinatal asphyxia preceded by preconditioning (FAPA). We describe several genes/pathways, such as ubiquitination and proteolysis, which were not previously linked to preconditioning-induced neuroprotection. Furthermore, we observed that the majority of upregulated genes in preconditioned animals have a function in the cell nucleus, including several epigenetic players such as HDACs, which suggests that epigenetic mechanisms are likely to play a role in preconditioning-induced neuroprotection.
Highlights
Genomic reprogramming is thought to be, at least in part, responsible for the protective effect of brain preconditioning
In the dentate gyrus (DG) we observed a significant difference in activated Caspase-3 signal intensity with one-way ANOVA (p = 0.014), and post-hoc Bonferroni tests showed an increase of activated Caspase-3 signal intensity in the perinatal asphyxia (PA) group compared to the control animals (111,5% compared to control, p < 0.05)
No significant difference was observed for the preconditioned Perinatal Asphyxia preceded by Fetal Asphyctic preconditioning (FAPA) group, indicating functional fetal preconditioning
Summary
Genomic reprogramming is thought to be, at least in part, responsible for the protective effect of brain preconditioning. Unraveling mechanisms of this endogenous neuroprotection, activated by preconditioning, is an important step towards new clinical strategies for treating asphyctic neonates. A different promising approach is studying endogenous brain protection provided by the physiological pheno menon of preconditioning. It was first described in the brain in 1964 with a report of prolonged survival in rats who underwent brief anoxia before a second anoxia period [5]. It has been suggested that genomic reprogramming can explain a large part of these mechanisms and genome-wide microarray technology provides an excellent tool to investigate this neuroprotective reprogramming in experimental models [7]
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