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Advanced Neurology Ferroptosis in neonatal HIBI

contribution of inflammatory signaling to ferroptosis. In addition, the effects of Lip-1 as a ferroptosis
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The authors assessed the impact of TAK-242, a specific inhibitor in neonatal HIBI were recently further evaluated
antagonist of Toll-like receptor 4 (TLR4). TLR4 plays a key in an R-V neonatal rat model. 80,89 Lip-1 stimulated signs
role in activating proinflammatory signaling in the nervous of healing against HIBI-induced brain damage and
system and is, thus, activated in response to hypoxic- counteracted the HIBI-related decreases in SLC7A11,
ischemic insult. The authors had previously identified GSH, and GPX4 and the increase in ROS. Moreover, it
TLR4 as a promising therapeutic target for neonatal HIBI prevented the reductions in HIF-1α and NRF2 and the
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and demonstrated the efficacy of TAK-242 in treating it. elevations in TFR, FHC, and FLC. These findings suggest
In this study, they established a link between this effect and that multiple mechanisms may be responsible for the
ferroptosis. Consistent with other groups, they used an antiferroptotic effects of Lip-1. 89
R-V rat model and an OGD cell model. In the rat model,
80
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TAK-242 resisted HIBI-induced increases in TLR4, MDA, – Taken together, these studies suggest that NRF2, system
proinflammatory signaling molecules, and tumor protein x , and members of their signaling cascades, along with
c
p53 (a transcription factor that downregulates SLC7A11 regulators of lipid peroxidation and iron metabolism,
expression). TAK-242, also, counteracted decreases in are key mediators of ferroptosis in neonatal HIBI and,
SLC7A11, GSH, GPX4, and SOD expression. Furthermore, therefore, therapeutically relevant targets. The potential
it reduced signs of mitochondrial damage and mRNA mechanisms of action of the novel ferroptosis inhibitors
expression of ferroptosis-related genes. It also improved in neonatal HIBI models are summarized in Figure 2.
performance on the MWM, indicating improvement of Research is still required to establish these mechanisms
neurobehavioral outcomes. These results were verified in and determine the efficacy and safety of the relevant agents
vitro as similar protective effects were observed with TAK- in treating HIBI in human neonates. However, these
242 treatment before OGD in cells. SB203580, an inhibitor preliminary in vivo and in vitro experiments show that
of the proinflammatory molecule p38 mitogen-activated ferroptosis inhibitors may represent the necessary class of
protein kinase (MAPK), also demonstrated antiferroptotic mechanistically distinct therapeutic alternatives to TH.
effects in vitro by counteracting OGD-mediated decreases
in SLC7A11 and GPX4 expression. This supports the 5. Future directions
authors’ proposed mechanism that TAK-242 antagonizes These preliminary findings open up numerous avenues for
TLR4, inhibiting p38 MAPK, which then suppresses p53, future research. First, the agents studied and mechanistically
leading to SLC7A11 activation. 14,85-87 TAK-242 and other related ones should be investigated in vitro and in vivo to
agents that inhibit inflammatory signaling and activate gain greater insight into their therapeutic potential. Ideally,
system x should be further investigated in this regard. 14 they may then be progressed to clinical trials to help address
–
c
A recent study explored the utility of modulating the the gap in available therapeutics. Challenges in therapeutic
lipid peroxidation component of ferroptosis. The authors development may include off-target effects, blood-brain
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studied the effects of 7-dehydrocholesterol (7-DHC), a barrier impermeability, and plasma instability. However,
Vitamin D precursor, in primary neurons subjected to the diverse nature of agents already tested creates hope
OGD and in neonatal mice with R-V method-induced that some may overcome these challenges. In addition,
HIBI. 80,88 Of all lipids, 7-DHC is most susceptible to ferroptosis inhibitors currently in clinical trials for the
oxidation; therefore, introducing it was intended to treatment of other conditions should be considered for
conserve the much less reactive membrane lipids. The preliminary testing in neonatal HIBI models. These include
authors used cariprazine (CAR), an agent that increases bardoxolone methyl, an NRF2 activator being studied in
7-DHC levels by inhibiting 7-DHC reductase (DHCR7), patients with diabetes-associated chronic kidney disease,
as it promoted cell survival with the highest potency and mTORC1 inhibitors INK128 and AZD8055, which are
among three such agents tested. CAR administration 48 h being tested for pancreatic cancer and glioma, respectively.
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before or 30 min after OGD initiation enhanced primary Such agents were reviewed by Scarpellini et al. There may
neuron survival. In vivo, pre- and post-HIBI treatment also be utility in testing antiferroptotic agents which have
with CAR increased brain levels of 7-DHC and reduced shown early-stage efficacy against other conditions. For
those of MDA. CAR treatment also prevented the HIBI- example, in preliminary experiments, a Tat-conjugated
mediated decrease in viable brain tissue, but interestingly, selenocysteine peptide, an inhibitor of 15-LOX, and a
this effect was only statistically significant with post-HIBI spiroquinoxalinamine derivative protect against stroke,
administration. These findings implicate CAR and other myocardial ischemia-reperfusion, and hepatic ischemia-
agents that inhibit lipid peroxidation by elevating 7-DHC reperfusion, respectively, all of which have been linked to
as potential therapeutic candidates. 88 ferroptosis inhibition. 39,41,91

Volume 4 Issue 1 (2025) 33 doi: 10.36922/an.4575