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Advanced Neurology Ferroptosis in neonatal HIBI

therapeutic potential for antiferroptotic agents to treat of ferroptosis. This study provides support for a potential
HIBI and HIE in neonates. role of FA and other agents that promote NRF2/HO-1
signaling in preventing neonatal HIBI. The third study
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4. Modulating activity of mechanistic assessed the effects of Vitamin D on ferroptosis in rats with
targets of ferroptosis in neonatal HIBI R-V method-induced HIBI. The authors showed that
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Several groups have investigated the utility of putative Vitamin D reduces HIBI-associated edema, neuron loss
antiferroptotic agents in combatting neonatal HIBI in vivo and damage, and mitochondrial damage. It also prevents the
and in vitro. NRF2 signaling has been a target of interest post-HIBI increase in MDA and decreases in SOD, GSH,
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in three studies to date. One study assessed the effects of NRF2, and HO-1. These results were supported in cultured
resveratrol (Res), an agonist of silent information regulator cells under OGD conditions as Vitamin D increased
factor 2–related enzyme 1 (SIRT1), in neonatal HIBI based GSH expression and SOD activity, while preventing an
on a previous report that SIRT1 upregulates NRF2 to protect increase in ROS. The authors used quantitative reverse
against traumatic brain injury. Consistent with other transcription polymerase chain reaction on cells subjected
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studies, the authors noted a decrease in GPX4 expression to OGD to further investigate their hypothesis that Vitamin
and an increase in iron and MDA levels in rats 24 h after D upregulates NRF2/HO-1 signaling. They detected
HIBI was induced using the R-V method. They also increased NRF2, HO-1, and GPX4 messenger RNA
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observed detrimental structural changes and characteristic (mRNA) expression in Vitamin D-treated cells. Vitamin
signs of ferroptosis-related mitochondrial damage in D also decreased the release of proinflammatory cytokines
hippocampal CA1 neurons. Functional impairments under OGD conditions. Overall, the authors concluded
on the Morris water maze (MWM) were detected in that Vitamin D inhibits ferroptosis in HIBI by activating
association. As expected, all these consequences were NRF2/HO-1 signaling. It is noteworthy that although the
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attenuated by intracerebroventricular (ICV) injection of focus of the study was neonatal HIBI, the rats used were
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Fer-1 30 min before HIBI. ICV injection of Res conferred 10 – 12 weeks old. Further investigation is, therefore,
similar neuroprotective effects: it increased SIRT1 and necessary to determine the relevance of these findings in
NRF2 levels, counteracted the HIBI-mediated decrease the neonatal setting. Overall, these studies highlight NRF2
in GPX4, and reduced iron accumulation in response as a promising target for therapeutic development.
to HIBI. Furthermore, Res-treated animals showed Another study’s findings centered on system x –
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reduced brain atrophy and structural damage, along signaling. The authors compared the effects of ginsenoside
with improved MWM performance. These findings Rb1 (GsRb1), an active ingredient in ginseng, to those of
suggest that Res inhibits ferroptosis by activating liproxstatin-1 (Lip-1), a known ferroptosis inhibitor, in
SIRT1/NRF2/GPX4 signaling. Overall, the study highlights neonatal rats with R-V method-induced HIBI. 47,80 Both
the potential efficacy of this indirect NRF2 activator as a agents decreased brain atrophy, liquefaction, cerebral
neuroprotectant against neonatal HIBI. There may also infarct volume, and pathological structural changes
be utility in investigating other agents that upregulate 72 h later. They also similarly attenuated HIBI-induced
SIRT1/NRF2/GPX4 signaling. Another study investigated increases in ionized calcium-binding adaptor molecule
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the impact of farrerol (FA), an anti-inflammatory and 1 and glial fibrillary acidic protein, markers of microglia
antioxidant agent used in traditional Chinese medicine, and astrocytes, respectively; and reduced signs of
alone and in combination with ML385, a specific NRF2 mitochondrial damage. Furthermore, they counteracted
inhibitor, on HIBI in neonatal rats. The neonatal HIBI decreases in SLC7A11, SLC3A2, glutathione synthetase
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was again modeled using the R-V method. FA decreased (GSS, which helps catalyze GSH production), GSH, and
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post-HIBI infarct volumes, as well as brain edema, neuron GPX4, indicating protection against system x inhibition.
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–
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death, nucleus atrophy, and cytoplasmic abnormalities. It GsRb1 and Lip-1 also counteracted the decrease in HIF-1α,
also reduced iron buildup and ROS and MDA levels, while implicating HIF-1α activation as a potential starting point
increasing GSH-Px and superoxide dismutase (SOD) for these effects, due to the role of HIF-1α in upregulating
antioxidant enzyme levels. Furthermore, FA counteracted system x expression. 47,58,59 The authors reproduced these
–
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the HIBI-mediated decreases in SLC7A11 and GPX4 and results in vitro using cells subjected to OGD. Overall, the
increased levels of NRF2 and heme oxygenase-1 (HO-1), study illustrates the potential therapeutic utility of GsRb1 in
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which exerts antioxidant effects on NRF2 activation. FA protecting against ferroptosis-induced oxidative stress and
also reduced behavioral signs of neurological deficits. inflammation in neonatal HIBI. Its antioxidant effects focus
The protective effects of FA were attenuated, and in some on the system x signaling pathway and may commence
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cases eliminated, by ML385, suggesting that they are with HIF-1α activation. Another study also implicated
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mediated by NRF2/HO-1 signaling-induced suppression system x as a therapeutic target, while emphasizing the
–
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Volume 4 Issue 1 (2025) 32 doi: 10.36922/an.4575