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Advanced Neurology Ferroptosis in neonatal HIBI

Another key process in ferroptosis is iron-dependent underlying excitotoxic cell death and demonstrated the
lipid peroxidation, which occurs through two mechanisms: therapeutic potential of ferroptosis inhibitors in treating
fenton-like reactions, where ferrous iron (Fe ) catalyzes neurological diseases. Such excitotoxic cell death is a well-
2+
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the production of hydroxyl radicals ( OH) from hydrogen established mechanism in neonatal HIBI. 16,71,72 The role of
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peroxide (H O ), and iron-dependent lipoxygenase iron-catalyzed ROS production in the pathophysiology
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(LOX) enzyme activity. Therefore, proteins involved in of neonatal HIBI has also been described for decades.
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iron metabolism help regulate ferroptosis. These include Early work revealed that neonatal animals experience iron
transferrin (TF), which acts through the transferrin overload in response to HIBI, the degree of which positively
receptor (TFR), to transport inactive ferric iron (Fe ) into correlates with susceptibility to damage, and that iron
3+
the cell, where it is modified into Fe , the active form. chelators counteract this. 10,11,13 Further supporting these
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Ferritin, which stores excess iron, and ferroportin, which findings, a study in human neonates identified a positive
facilitates iron efflux, are also important proteins. 35,60,61 correlation between the level of non-protein-bound iron
In addition, mitochondrial and nicotinamide adenine (NPBI) in the plasma of newborns with asphyxia at birth
dinucleotide phosphate oxidase (NOX) enzyme activity is and the severity of their neurodevelopmental deficits at
important for ROS production in ferroptosis. Mitochondria 1 year of age. The levels of thiobarbituric acid reactive
also play a key role in iron metabolism. 27,31 Voltage-gated species, a marker of lipid peroxidation, were also elevated
anion channels (VDACs) are mediators of erastin-induced in infants with asphyxia compared to controls; although
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mitochondrial dysfunction. Both VDAC and NOX this effect was not statistically significant. Another
inhibitors attenuate ferroptosis. 31,34,35 Other agents that study found that NPBI is detectable in the cerebrospinal
indirectly modulate mitochondrial and NOX activity have fluid (CSF) of neonates with HIE but not in unaffected
also shown promise in regulating ferroptosis. 37,62,63 The controls. The levels of ortho- and meta-tyrosine, markers
details of these mechanisms are beyond the scope of this of ROS-mediated protein oxidation, were also notably
review. elevated in the CSF of affected neonates compared to
healthy controls. Other studies have demonstrated
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The activities of acyl-coenzyme a synthetase long-chain that the neonatal brain is hypersensitive to the effects of
family member 4 (ACSL4) and lysophosphatidylcholine iron overload. This can be explained by increased iron
acyltransferase 3 (LPCAT3) are also important because concentrations, which are highest at the time of birth due
they promote ferroptosis by acylating polyunsaturated fatty to iron’s key role in developmental processes, coupled
acids, such as arachidonic acid, and incorporating them with incomplete development of iron processing and
into the cell membrane, respectively, thereby increasing antioxidant mechanisms. 75-78 Ferroptosis may, therefore,
the quantity of membrane lipids available for peroxidation. play an even more important role in neonatal HIBI than
Deletion of these enzymes suppresses ferroptosis. 64,65 in adult conditions of neurological ischemia-reperfusion.
Additional aspects of ferroptosis signaling have been
reviewed by Feng et al. and Peeples et al. Further To the best of our knowledge, the first study that
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research is required to establish the complex interactions directly investigated the role of ferroptosis, since it was
between these diverse mechanisms. described by name, in neonatal HIBI was performed by
Wang et al. in 2016. They found that anemia, induced
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3. Establishing the role of ferroptosis in by controlled blood loss, attenuates signs of brain
neonatal HIBI and HIE damage after subsequent HIBI in neonatal rats. HIBI was
modeled via bilateral carotid artery ligation, followed by
Several studies, dating back to before ferroptosis was exposure to hypoxic conditions. This result suggests that
described by name, have supported its putative role in anemia may be neuroprotective against HIBI in neonatal
neonatal HIBI (Table 1). As the Stockwell group. stated, rats. The authors then treated a subset of the anemic rats
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excitotoxic neuronal death has long been established to with iron, starting at 2 time points. Early iron treatment
be oxidative and iron-dependent. Prior studies revealed (beginning 1 day after HIBI) increased signs of brain
that excessive glutamatergic NMDA receptor activation damage, while late treatment (beginning 7 days post-
promotes iron accumulation in the brain and that this iron HIBI) reduced them. The latter may be explained by the
catalyzes free radical production, resulting in oxidative essential role of iron in neurodevelopment. Although
stress. 68-70 Consistent with this, the group showed that Fer- these findings do not suggest high therapeutic potential of
1, an iron chelator, and a positive control NMDA receptor anemia in neonatal HIBI, the study supports involvement
antagonist all inhibit excitotoxic cell death to the same of ferroptosis in the pathophysiology of neonatal HIBI.
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degree in organotypic hippocampal slice cultures. This Another group provided more direct evidence of this
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finding further implicated ferroptosis as a mechanism role by measuring characteristic features and mediators

Volume 4 Issue 1 (2025) 29 doi: 10.36922/an.4575