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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:ObjectiveTotal tau (T-tau), phosphorylated tau (p-Tau) and Beta-Amyloid 1-42 (AB42) in Cerebrospinal Fluid (CSF) are useful biomarkers in neurodegenerative diseases. The aim of the study was to investigate the role of these and other CSF biomarkers (T-tau, p-Tau, AB42, S100B and NSE), during hypoxia-reoxygenation in a newborn pig model.DesignThirty newborn pigs were included in a study of moderate or severe hypoxia. The moderate hypoxia group (n = 12) was exposed to global hypoxia (8% O2) until Base excess (BE) reached -15 mmol/l. The pigs in the group exposed to severe hypoxia (n = 12) received 8% O2 until BE reached -20 mmol/l or mean Blood Pressure fell below 20 mm Hg, The control group (n = 6) was kept at room air. For all treatments, the CSF was collected at 9.5 hours after the intervention.ResultsThe level of AB42 in CSF was significantly lower in the pigs exposed to severe hypoxia compared with the control group, 922(SD +/-445)pg/ml versus. 1290(SD +/-143) pg/ml (p<0.05), respectively. Further, a non-significant reduction of AB42 was observed in the group exposed to moderate hypoxia T-tau and p-Tau revealed no significant differences between the intervention groups and the control group, however a significantly higher level of S100B was seen in the CSF of pigs receiving hypoxia in comparison to the level in the control group. Further on, there was a moderate negative correlation between the levels of AB42 and S100B in CSF, as well as a moderate negative correlation between Lactate in blood at end of hypoxia and AB42 in CSF.InterpretationThis is the first study to our knowledge that demonstrated a significant drop in AB42 in CSF after neonatal hypoxia. Whether or not this has an etiological basis for adult neurodegenerative disorders needs to be studied with additional experiments and epidemiological studies. AB42 and S100B are significantly changed in neonatal pigs subjected to hypoxia compared to controls and thus may be valuable biomarkers of perinatal asphyxia.

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.

Project description:Perinatal asphyxia (PA) still occurs in about three to five per 1,000 deliveries in developed countries; 20% of these infants show hypoxic-ischemic encephalopathy (HIE) on brain magnetic resonance imaging (MRI). The aim of our study was to apply metabolomic analysis to newborns undergoing therapeutic hypothermia (TH) after PA to identify a distinct metabotype associated with the development of HIE on brain MRI. We enrolled 53 infants born at >35 weeks of gestation with PA: 21 of them showed HIE on brain MRI (the "HIE" group), and 32 did not (the "no HIE" group). Urine samples were collected at 24, 48 and 72 hours of TH. Metabolomic data were acquired using high-resolution mass spectrometry and analyzed with univariate and multivariate methods. Considering the first urines collected during TH, untargeted analysis found 111 relevant predictors capable of discriminating between the two groups. Of 35 metabolites showing independent discriminatory power, four have been well characterized: L-alanine, Creatine, L-3-methylhistidine, and L-lysine. The first three relate to cellular energy metabolism; their involvement suggests a multimodal derangement of cellular energy metabolism during PA/HIE. In addition, seven other metabolites with a lower annotation level (proline betaine, L-prolyl-L-phenylalanine, 2-methyl-dodecanedioic acid, S-(2-methylpropionyl)-dihydrolipoamide-E, 2,6 dimethylheptanoyl carnitine, Octanoylglucuronide, 19-hydroxyandrost-4-ene-3,17-dione) showed biological consistency with the clinical picture of PA. Moreover, 4 annotated metabolites (L-lysine, L-3-methylhistidine, 2-methyl-dodecanedioic acid, S-(2-methylpropionyl)-dihydrolipoamide-E) retained a significant difference between the "HIE" and "no HIE" groups during all the TH treatment. Our analysis identified a distinct urinary metabotype associated with pathological findings on MRI, and discovered 2 putative markers (L-lysine, L-3-methylhistidine) which may be useful for identifying neonates at risk of developing HIE after PA.

Dataset Information

Synaptoprotection in Perinatal Asphyxia: An Experimental Approach.

Publications

Synaptoprotection in Perinatal Asphyxia: An Experimental Approach.

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