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Advanced Neurology Ferroptosis in neonatal HIBI

Table 1. (Continued)
Paper Models Key findings Contribution to establishing the role
of ferroptosis in neonatal HIBI
Dorrepaal et al. 73 Newborn human infants • Plasma NPBI levels were elevated in moderate Shows that neonatal asphyxia is
(healthy, moderate and severe asphyxia groups, with more notable associated with increased NPBI levels
asphyxia, and severe elevations in the severe asphyxia group and oxidative stress, suggesting that the
asphyxia groups) compared to healthy controls. two may be related
• Increased NPBI concentrations 0 and 8 h
after birth were strongly correlated with
neurodevelopmental deficits at 1 year of age.
• TBARS levels were higher in the moderate and
severe asphyxia groups than healthy controls.
Ogihara et al. 74 Newborn human infants • NPBI was detected in the CSF of infants with Demonstrates that neonatal HIE is
with HIE, healthy controls HIE, with its concentrations significantly associated with detectable NPBI and
correlating with the infants’ Sarnat’s clinical oxidative stress, providing additional
stages, but not in that of healthy controls. support for a potential link
• Levels of ortho- and meta-tyrosine were
also elevated in the CSF of infants with HIE,
indicating oxidative stress.
Lin et al. 79 7-day-old rats with R–V • Signs of mitochondrial damage characteristic Provides strong evidence for the role of
method-induced HIBI of ferroptosis, but not of other cell death types, ferroptosis in neonatal HIBI
were identified post-HIBI.
• HIBI was associated with decreases in GSH,
GPX4, and SLC7A11 levels and increases in
ROS, TF, TFR, FLC, and FHC.
Abbreviations: CSF: Cerebrospinal fluid; DFO: Deferoxamine mesylate; FHC: Ferritin heavy chain; FLC: Ferritin light chain; GSH: Glutathione;
GPX4: Glutathione peroxidase-4; HIBI: Hypoxic-ischemic brain injury; HIE: Hypoxic-ischemic encephalopathy; MDA: Malondialdehyde;
MDA: N-methyl-D-aspartate; nNOS: Neuronal nitric oxide synthase; NPBI: Non-protein-bound iron; OHSC: Organotypic hippocampal slice culture;
ROS: Reactive oxygen species; R-V: Rice-Vannucci; SLC7A11: Solute carrier family 7 member 11; TBARS: Thiobarbituric acid reactive species;
TF: Transferrin; TFR: Transferrin receptor.

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of ferroptosis in neonatal rats subjected to the Rice- malondialdehyde (MDA), a marker of lipid peroxidation.
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Vannucci (R-V) method. This is a well-established Iron overload, induced by treatment with iron dextran,
technique for modeling neonatal HIBI in rodents, which potentiated the increase in MDA, while treatment with
involves subjecting them to unilateral common carotid deferoxamine mesylate (DFO), an iron chelator, attenuated
artery ligation on post-natal day 7, followed by hypoxia. the increases in MDA, indicating that the observed
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Using electron microscopy, the authors detected signs MDA elevation was iron-dependent. Iron dextran also
of mitochondrial damage, namely, atrophy and cristae exacerbated the observed HIBI-mediated decrease in
loss, which are hallmarks of ferroptosis but not of SLC7A11. Furthermore, inhibition of ferroptosis through
other types of cell death. Furthermore, morphological administration of either DFO or Fer-1 reduced observable
changes consistent with these other types of cell death brain damage on 2,3,5-triphenyltetrazolium chloride and
were absent. The authors also found that GSH, GPX4, Nissl staining, while iron dextran treatment increased
and SLC7A11 levels were considerably reduced 72 h it. These results were corroborated in vitro. Oxygen and
post-HIBI, while ROS levels were notably elevated. In glucose deprivation (OGD) reduced survival of cultured
addition, they noted HIBI-mediated elevation in TF, cells and increased MDA and ROS levels while decreasing
TFR, ferritin light chain (FLC), and ferritin heavy chain levels of SLC7A11, GSH, and GPX4. All these effects were
(FHC) protein expression. Overall, their study provides exacerbated by ferric ammonium citrate but inhibited by
strong evidence for the role of ferroptosis in mediating DFO or Fer-1. In addition, overexpression of SLC7A11,
HIBI in neonatal rats. 79 induced through plasmid transfection, suppressed ROS
Recently, an additional study helped establish this role. production and increased cell survival under OGD
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The R-V method was again used to induce HIBI in neonatal conditions, indicating inhibition of ferroptosis. Overall,
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rats. This substantially increased brain iron content, this literature strongly suggests an essential role of
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which was associated with observable characteristics of ferroptosis in neonatal HIBI, directly and indirectly. This
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ferroptosis, including mitochondrial atrophy, decreased role has also been discussed in reviews by Feng et al.,
SLC7A11 and GPX4 expression, and increased levels of Peeples et al., and Huo et al. Thus, there is significant
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Volume 4 Issue 1 (2025) 31 doi: 10.36922/an.4575