Enquiring beneath the surface: can a gene expression assay shed light into the heterogeneity among newborns with neonatal encephalopathy?

Balada, Rafael; Tebé, Cristian; León, M.L. Villalobos; Arca, Gemma; Alsina, Miguel; Castells, Alba Aina; Alcántara, Soledad; García‐Alix, Alfredo

doi:10.1038/s41390-020-0764-2

Cited by 8 publications

(5 citation statements)

References 36 publications

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“…In the previously mentioned study by Lucchi et al, the authors observed elevated expression of PPARγ in the same group of interneurons herein described for TLR8 (i.e. SOM, PARV) and Balada et al [ 40 ] showed that in patients with neonatal encephalopathy the expression of PPARγ and TLR8 (during the first 4 days of life) was increased in relation to controls. Considering the above data, it would be interesting to test the hypothesis whether treatment of epileptic mice with PPARγ ligands (e.g.…”

Section: Discussionsupporting

confidence: 68%

Expression of toll like receptor 8 (TLR8) in specific groups of mouse hippocampal interneurons

et al. 2022

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Toll-like receptors (TLR) are one of the main constituents of the innate immune system in mammals. They can detect conserved microbial structures (pathogen-associated molecular patterns) and host-derived ligands that are produced during cellular stress and damage (danger-associated molecular patterns) and may then initiate an intracellular signaling cascade leading to the expression of pro-inflammatory cytokines and immediate immune responses. Some TLR (TLR1, 2, 4, 5, and 6) are expressed on the cell surface while others (TLR3, 7, 8 and 9) are present on the surface of endosomes and their ligands require internalization before recognition is possible. Several TLR have also been detected in neurons where they may serve functions that are not related to immune responses. TLR2, 3, and 4 have been described in cortical neurons and, for TLR4, a seizure-promoting role in epilepsies associated with inflammation has been shown. TLR3, 7, and 8 expressed in neurons seem to influence the growth or withdrawal of neurites and robust activation of TLR8 in neurons may even induce neuronal death. The goal of the current study was to investigate the expression of TLR8 in the hippocampus of mice during postnatal development and in adulthood. We focused on three functionally distinct groups of GABAergic interneurons characterized by the expression of the molecular markers parvalbumin, somatostatin, or calretinin, and we applied double fluorescence immunohistochemistry and cell counts to quantify co-expression of TLR8 in the three groups of GABA-interneurons across hippocampal subregions. We found subregion-specific differences in the expression of TLR8 in these interneurons. During postnatal development, TLR8 was detected only in mice older than P5. While only a small fraction of hippocampal calretinin-positive interneurons expressed TLR8, most parvalbumin-positive interneurons in all hippocampal subregions co-expressed TLR8. Somatostatin-positive interneurons co-expressing TLR8 were mainly present in hippocampal sector CA3 but rare in the dentate gyrus and CA1. High expression of TLR8 in parvalbumin-interneurons may contribute to their high vulnerability in human temporal lobe epilepsy.

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Section: Discussionsupporting

confidence: 68%

Expression of toll like receptor 8 (TLR8) in specific groups of mouse hippocampal interneurons

et al. 2022

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“…Finally, studies concerning alterations in the abundance of RNA for several inflammation markers were also reported. Proliferator-activated receptor gamma (PPARG), matrix metallopeptidase 9 (MMP-9), interleukin (IL)-8, heat shock protein family A (Hsp70) member 1A (HSPA1A), and toll-like receptor 8 (TLR8) were found to be increased in the whole blood of the HIE group, while C–C motif chemokine receptor 5 (CCR5) was decreased [ 20 ]. Since these approaches to identify biomarkers are recent, due to the lack of corroborating evidence from different authors, no objective conclusion can be drawn about the use of the aforementioned analytes as potential biomarkers.…”

Section: Resultsmentioning

confidence: 99%

Biomarkers of hypoxic–ischemic encephalopathy: a systematic review

et al. 2023

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Background Current diagnostic criteria for hypoxic–ischemic encephalopathy in the early hours lack objective measurement tools. Therefore, this systematic review aims to identify putative molecules that can be used in diagnosis in daily clinical practice (PROSPERO ID: CRD42021272610). Data sources Searches were performed in PubMed, Web of Science, and Science Direct databases until November 2020. English original papers analyzing samples from newborns > 36 weeks that met at least two American College of Obstetricians and Gynecologists diagnostic criteria and/or imaging evidence of cerebral damage were included. Bias was assessed by the Newcastle–Ottawa Scale. The search and data extraction were verified by two authors separately. Results From 373 papers, 30 met the inclusion criteria. Data from samples collected in the first 72 hours were extracted, and increased serum levels of neuron-specific enolase and S100-calcium-binding protein-B were associated with a worse prognosis in newborns that suffered an episode of perinatal asphyxia. In addition, the levels of glial fibrillary acidic protein, ubiquitin carboxyl terminal hydrolase isozyme-L1, glutamic pyruvic transaminase-2, lactate, and glucose were elevated in newborns diagnosed with hypoxic–ischemic encephalopathy. Moreover, pathway analysis revealed insulin-like growth factor signaling and alanine, aspartate and glutamate metabolism to be involved in the early molecular response to insult. Conclusions Neuron-specific enolase and S100-calcium-binding protein-B are potential biomarkers, since they are correlated with an unfavorable outcome of hypoxic–ischemic encephalopathy newborns. However, more studies are required to determine the sensitivity and specificity of this approach to be validated for clinical practice.

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“…Currently, perinatal asphyxia affects approximately 4 million newborns annually worldwide [ 3 ]. About 15–25% of these newborns die in the neonatal period, up to 25% of survivors develop neurological deficits, and 10–30% have retarded psychomotor development [ 4 , 5 ]. Studies analyzing the long-term consequences in preschool children after perinatal asphyxia have shown that cerebral palsy develops in 5.5–52% [ 6 , 7 , 8 , 9 ], severe disability in 11–19% [ 6 ], various motor impairments in 1.3–40% [ 2 , 8 , 9 , 10 ], hearing loss in 2–20% [ 6 , 9 , 10 ], vision defects in 1.8–40% [ 6 , 9 , 11 ], speech disorders in 4.2–21% [ 6 , 7 , 8 ], epilepsy in 13%, and cognitive impairment in 31% [ 1 , 2 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Currently, hypothermia remains the only available treatment option for neonates after perinatal asphyxia with variable and/or transient medical benefits [ 5 , 21 , 22 , 23 ]. Some studies show that treating perinatal asphyxia with hypothermia improves survival and reduces the incidence of long-term complications, such as severe disability, epilepsy, and the severity of cerebral palsy [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…Both preclinical and clinical studies show that treatment with hypothermia does not reduce the problems associated with memory impairment [ 29 , 30 ]. Unfortunately, this method of treating children with perinatal asphyxia, if successful, is only temporary or incomplete [ 5 , 6 , 23 , 31 ]. The above is confirmed by data showing that about 10% of infants with perinatal asphyxia treated with hypothermia have epilepsy, 20% have cerebral palsy [ 5 , 6 ], and about half die [ 31 ] or develop severe functional deficits [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

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Hypothermia after Perinatal Asphyxia Does Not Affect Genes Responsible for Amyloid Production in Neonatal Peripheral Lymphocytes

Tarkowska

Furmaga-Jabłońska

Bogucki

et al. 2022

JCM

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In this study, the expression of the genes of the amyloid protein precursor, β-secretase, presenilin 1 and 2 by RT-PCR in the lymphocytes of newborns after perinatal asphyxia and perinatal asphyxia treated with hypothermia was analyzed at the age of 15–21 days. The relative quantification of Alzheimer’s-disease-related genes was first performed by comparing the peripheral lymphocytes of non-asphyxia control versus those with asphyxia or asphyxia with hypothermia. In the newborns who had perinatal asphyxia, the peripheral lymphocytes presented a decreased expression of the amyloid protein precursor and β-secretase genes. On the other hand, the expression of the presenilin 1 and 2 genes increased in the studied group. The expression of the studied genes in the asphyxia group treated with hypothermia had an identical pattern of changes that were not statistically significant to the asphyxia group. This suggests that the expression of the genes involved in the metabolism of the amyloid protein precursor in the peripheral lymphocytes may be a biomarker of progressive pathological processes in the brain after asphyxia that are not affected by hypothermia. These are the first data in the world showing the role of hypothermia in the gene changes associated with Alzheimer’s disease in the peripheral lymphocytes of newborns after asphyxia.

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Enquiring beneath the surface: can a gene expression assay shed light into the heterogeneity among newborns with neonatal encephalopathy?

Cited by 8 publications

References 36 publications

Expression of toll like receptor 8 (TLR8) in specific groups of mouse hippocampal interneurons

Expression of toll like receptor 8 (TLR8) in specific groups of mouse hippocampal interneurons

Biomarkers of hypoxic–ischemic encephalopathy: a systematic review

Hypothermia after Perinatal Asphyxia Does Not Affect Genes Responsible for Amyloid Production in Neonatal Peripheral Lymphocytes

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