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Synaptoprotection in Perinatal Asphyxia: An Experimental Approach.

ABSTRACT: Perinatal asphyxia (PA) is an obstetric complication occurring when the oxygen supply to the newborn is temporally interrupted. This health problem is associated with high morbimortality in term and preterm neonates. It severely affects the brain structure and function, involving cortical, hippocampal, and striatal loss of neurons. Nearly 25% of PA survivor newborns develop several neurodevelopmental disabilities. Behavioral alterations, as well as the morphological and biochemical pathways involved in PA pathophysiology, have been studied using an animal model that resembles intrauterine asphyxia. Experimental evidence shows that PA induces synaptic derangement. Then, synaptic dysfunction embodies a putative target for neuroprotective strategies. Over the last years, therapeutic hypothermia (TH), the only treatment available, has shown positive results in the clinic. Several pharmacological agents are being tested in experimental or clinical trial studies to prevent synaptopathy. Preservation of the synaptic structure and function, i.e., "synaptoprotection," makes up a promising challenge for reducing incidental neurodevelopmental disorders associated with PA. Accordingly, here, we summarize and review the findings obtained from the referred experimental model and propose a renewed overview in the field.

SUBMITTER: Herrera MI

PROVIDER: S-EPMC7539062 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Synaptoprotection in Perinatal Asphyxia: An Experimental Approach.

Herrera María Inés MI Kobiec Tamara T Kölliker-Frers Rodolfo R Otero-Losada Matilde M Capani Francisco F

Frontiers in synaptic neuroscience 20200923

Perinatal asphyxia (PA) is an obstetric complication occurring when the oxygen supply to the newborn is temporally interrupted. This health problem is associated with high morbimortality in term and preterm neonates. It severely affects the brain structure and function, involving cortical, hippocampal, and striatal loss of neurons. Nearly 25% of PA survivor newborns develop several neurodevelopmental disabilities. Behavioral alterations, as well as the morphological and biochemical pathways invo ...[more]

PMID: 33071771

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Project description: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.

Dataset Information

Synaptoprotection in Perinatal Asphyxia: An Experimental Approach.

Publications

Synaptoprotection in Perinatal Asphyxia: An Experimental Approach.

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