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Open Access Research article

Fetal asphyctic preconditioning alters the transcriptional response to perinatal asphyxia

Kimberly EM Cox-Limpens123*, Johan SH Vles13, Daniel LA van den Hove14, Luc JI Zimmermann12 and Antonio WD Gavilanes125

Author Affiliations

1 School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, Room 1.152, Maastricht 6229 MD, The Netherlands

2 Department of Pediatrics, Maastricht University Medical Center (MUMC), postbus 5800, Maastricht 6202, AZ, The Netherlands

3 Department of Pediatric Neurology, Maastricht University Medical Center (MUMC), P.Debyelaan 25, Maastricht 6229, HX, The Netherlands

4 Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Fuechsleinstrasse 15, Wuerzburg 97080, Germany

5 Institute of Biomedicine, Faculty of Medicine, Catholic University of Guayaquil, Av. Carlos Julio Arosemena Km. 1 1/2 vía Daule, Guayaquil, Ecuador

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BMC Neuroscience 2014, 15:67  doi:10.1186/1471-2202-15-67

Published: 29 May 2014

Abstract

Background

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.

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.

Results

We 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.

Conclusions

This 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.

Keywords:
Perinatal Asphyxia; Fetal Preconditioning; Neonatal Brain,Neuroprotection; Microarray,Oxidative stress; Ubiquitination; Epigenetics