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Cited by 50Neonatal and fetal brain pathologyNeonatal Health and BiochemistryNeonatal and Maternal Infections

Free radicals and neonatal encephalopathy: mechanisms of injury, biomarkers, and antioxidant treatment perspectives

Open access
Martini, Silvia, Austin, Topun, Aceti, Arianna, Faldella, Giacomo, Corvaglia, Luigi·2020·Pediatric Research
DOI 10.1038/s41390-019-0639-6
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Abstract

Neonatal encephalopathy (NE), most commonly a result of the disruption of cerebral oxygen delivery, is the leading cause of neurologic disability in term neonates. Given the key role of free radicals in brain injury development following hypoxia-ischemia-reperfusion, several oxidative biomarkers have been explored in preclinical and clinical models of NE. Among these, antioxidant enzyme activity, uric acid excretion, nitric oxide, malondialdehyde, and non-protein-bound iron have shown promising results as possible predictors of NE severity and outcome. Owing to high costs and technical complexity, however, their routine use in clinical practice is still limited. Several strategies aimed at reducing free radical production or upregulating physiological scavengers have been proposed for NE. Room-air resuscitation has proved to reduce oxidative stress following perinatal asphyxia and is now universally adopted. A number of medications endowed with antioxidant properties, such as melatonin, erythropoietin, allopurinol, or N-acetylcysteine, have also shown potential neuroprotective effects in perinatal asphyxia; nevertheless, further evidence is needed before these antioxidant approaches could be implemented as standard care.

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  • Normal reference values for cord blood are available for nonprotein-bound iron (<6.91 mmol/L), isoprostane 8-iso-15(R)-PGF2a (<124.47 pg/mL), and advanced oxidation protein products (<80.39 mmol/dL).

    “Normal reference values for cord blood are available for nonproteinbound iron (<6.91 mmol/L), isoprostane 8-iso-15(R)-PGF2a (<124.47pg/mL), and advanced oxidation protein products (<80.39mmol/dL).112”

    From Umbilical cord pH, blood gases, and lactate at birth: normal values, interpretation, and clinical utility. (2023) · cites this paper as [112]

    The biomarker table in “Mechanisms of injury” (page unavailable) gives all three cord-blood reference thresholds, and the isoprostane value matches the claim. But it gives <6.91 μmol/L for nonprotein-bound iron and <80.39 μmol/dL for advanced oxidation protein products, not mmol/L and mmol/dL. (LLM, conf=0.93)

    Experimental — accuracy not yet measured

  • In cord blood, superoxide dismutase and glutathione peroxidase are positively related to HIE stages, and isoprostane 8-iso-15(R)-PGF2a to severity of perinatal asphyxia.

    “Among these, a few have been investigated in cord blood: superoxide dismutase and glutathione peroxidase are positively related to HIE stages, and isoprostane 8iso-15(R)-PGF2a to severity of perinatal asphyxia.”

    From Umbilical cord pH, blood gases, and lactate at birth: normal values, interpretation, and clinical utility. (2023) · cites this paper as [112]

    The antioxidant-enzyme discussion and Table 1 report that cord-blood superoxide dismutase and catalase correlate positively with Sarnat stage; they report elevated glutathione peroxidase in asphyxiated newborns, but not a correlation with stage. The Lipid peroxidation markers section reports that cord-blood 8-iso-15(R)-PGF2α correlates positively with asphyxia severity. Page numbers were not provided in our copy. (LLM, conf=0.94)

    Experimental — accuracy not yet measured

  • Specific antioxidant enzymes are released to counteract ROS; an imbalance results in oxidative stress.

    “Specific antioxidant enzymes are released to counteract ROS, where an imbalance results in oxidative stress.”

    From Umbilical cord pH, blood gases, and lactate at birth: normal values, interpretation, and clinical utility. (2023) · cites this paper as [112]

  • Small and heterogeneous studies and lack of reference standards have so far hindered the clinical validation of these markers.

    “However, small and heterogeneous studies and lack of reference standards have so far hindered the clinical validation of these markers.”

    From Umbilical cord pH, blood gases, and lactate at birth: normal values, interpretation, and clinical utility. (2023) · cites this paper as [112]

  • Current biomarkers of oxidative and nitrosative stress include antioxidant enzymes (superoxide dismutase, glutathione peroxidase, catalase), uric acid, nitric oxide, nonprotein-bound iron, lipid peroxidation markers (malondialdehyde, 4-hydroxynonenal, isoprostanes, neuroprostanes, neurofurans), protein oxidation markers (protein carbonyls, advanced oxidation protein products), and a DNA peroxid

    “Such biomarkers are antioxidant enzymes (superoxide dismutase, glutathione peroxidase, catalase), uric acid, nitric oxide, nonprotein-bound iron, lipid peroxidation markers (malondialdehyde, 4-hydroxynonenal, isoprostanes, neuroprostanes, neurofurans), protein oxidation markers (protein carbonyls, advanced oxidation protein products), and a DNA peroxidation marker (8-hydroxydeoxyguanosine).”

    From Umbilical cord pH, blood gases, and lactate at birth: normal values, interpretation, and clinical utility. (2023) · cites this paper as [112]

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Authors
Martini, S., Austin, T., Aceti, A., Faldella, G., & Corvaglia, L.
Affiliations
  • IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
  • Cambridge University Hospitals NHS Foundation Trust (GB)
Corresponding author
Martini, Silvia
ORCID
Venue
Pediatric Research
Publisher
Springer Science and Business Media LLC
Published
2019-10-26
Volume
87
Issue
5
Pages
823-833
ISSN
  • 0031-3998 (ISSN-L)
  • 1530-0447
DOI
10.1038/s41390-019-0639-6
OpenAlex
W2982026083
Cited by
50
References
157
Citations by year
2026: 4 · 2025: 4 · 2024: 10 · 2023: 16 · 2022: 6 · 2021: 8 · 2020: 2
FWCI
0.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Pediatric Research (publishedVersion)
  • PubMed (publishedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal Health and Biochemistry
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Neonatal and Maternal Infections
Keywords
neonatal encephalopathy, free radicals, oxidative stress, perinatal asphyxia, oxidative stress biomarkers, antioxidant treatment, neuroprotection, melatonin, erythropoietin, allopurinol, N-acetylcysteine, uric acid, malondialdehyde, nitric oxide, non-protein-bound iron, antioxidant enzymes
MeSH terms
Acetylcysteine, Allopurinol, Animals, Antioxidants, Asphyxia Neonatorum, Brain Injuries, Clinical Trials as Topic, DNA, Erythropoietin, Free Radicals, Humans, Hypothermia, Induced, Infant, Newborn, Malondialdehyde, Melatonin, Nitric Oxide, Prostaglandins, Proteins, Uric Acid, Biomarkers, Oxidative Stress, Hypoxia-Ischemia, Brain

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