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Advanced Neurology Ferroptosis in neonatal HIBI

and neurodevelopmental disability, with many survivors Ca -dependent enzymes that promote production of free
2+
experiencing developmental delays, sensorimotor and radicals, including reactive oxygen species (ROS) and nitric
memory impairments, learning disabilities, epilepsy, and oxide (NO). ROS and NO exert cytotoxic effects during
cerebral palsy. HIE’s burden is also massive in terms of the secondary neuronal injury phase. Mitochondrial
1-3
healthcare and social costs, accumulated through acute dysfunction follows, exacerbating ATP loss and free radical
treatment and lifelong supportive care. Therapeutic production. 15,20 Primary neuronal injury is also associated
4-6
hypothermia (TH) has been widely implemented as the with excessive glutamate release. Although glutamate is
standard of care for neonatal HIBI and HIE. It involves the primary excitatory neurotransmitter in physiological
7
reducing the brain’s temperature through localized signaling, its aberrant release overactivates N-methyl-
or systemic cooling to combat excessive membrane D-aspartate (NMDA) receptors, promoting further Ca
2+
excitability and induce molecular changes that prevent influx and excitotoxicity. 16,20 This is exacerbated by anoxic
further neuronal injury and promote recovery. TH has depolarization because it enables passive NMDA receptor
7,8
remarkably reduced overall HIBI-associated mortality activation. The neonatal brain is more susceptible to the
16
and disability; however, the number of neonates affected effects of excitotoxicity than the adult one due to higher
by both remains striking. According to a meta-analysis NMDA receptor expression and activity. 21,22 In addition, the
7-9
by the Canadian Pediatric Society, TH protects against byproducts of primary neuronal injury, such as ROS and
mortality and moderate-to-severe disability at the age of 18 NO, activate microglia, leading them to adopt phagocytic
– 24 months, with an overall relative risk (RR) of 0.75 and capabilities and release proinflammatory cytokines and
an RR of 0.68 and 0.82 in moderate and severe HIBI groups, chemokines. This disrupts blood-brain barrier integrity,
respectively. The insufficient success of TH is partially allowing for migration of peripheral immune cells into the
7
explained by limited eligibility for this treatment because it brain, which enhances delayed inflammatory signaling for
requires initiation within 6 h of HIBI onset and fulfillment secondary injury. 17,23 In addition to directly killing cells,
of specific gestational age, weight, and umbilical pH these primary neuronal injury mechanisms supply effector
criteria. Furthermore, incomplete efficacy is a contributing molecules, which mediate large-scale cell death in the
factor, considering that TH potentially fails to target all key secondary neuronal injury phase of neonatal HIBI. 24
pathophysiological processes. 1,7-9 Consequently, there is a
major need for alternative therapeutic strategies to prevent Three forms of secondary cell death occur due to
neonatal HIBI and HIE. Significant research has aimed at primary neuronal injury-induced oxidative stress,
addressing the gaps in understanding of their mechanistic excitotoxicity, and inflammation: apoptosis, necrosis, and
15,17
underpinnings and identifying unique strategies to exploit autophagy. Apoptosis involves chromatin condensation,
them. 10-14 However, there is still much work to be done in DNA fragmentation, and cytoskeletal structure loss,
this regard. followed by the collection of disassembled cellular contents
in vesicles known as apoptotic bodies. Apoptosis is
A series of complex, interacting mechanisms contribute mediated by the proteolytic activity of caspases; therefore,
to neonatal HIBI and consequential HIE (Figure 1). These caspase activation is another characteristic feature. 15,25-27
occur in two phases: primary neuronal injury, which Necrosis, often observed in severe HIBI, involves nuclear
consists of acute cellular consequences of blood and degradation and swelling of organelles and whole
oxygen loss, and secondary neuronal injury, which involves cells, leading to membrane damage and consequential
8,14
higher-volume cell death, beginning 6 – 24 h later. The lysis. 15,27-29 Autophagy involves the formation of vesicles –
hallmarks of primary neuronal injury are intracellular autophagosomes – in which disassembled cellular contents
ATP depletion, anoxic depolarization, excessive glutamate are collected before they are broken down via fusion with
release, and microglial activation. 15-17 Blood and oxygen large vacuoles. These vacuoles are the primary observable
deprivation necessitates cellular reliance on anaerobic feature of autophagy. 27,29,30 Essential involvement of an
metabolism, which significantly reduces ATP production additional form of cell death – ferroptosis – in neonatal
and triggers the release of lactic acid and hydrogen ions HIBI has been suggested, which is the focus of our review.
(H ). This promotes extracellular, and consequently,
+
intracellular, acidosis, impairing cell signaling. 2. Ferroptosis
15
Moreover, this decline in cellular energy leads to anoxic
depolarization – the dysregulation of ion gradients across 2.1. Overview
neuronal membranes – resulting in excessive accumulation Ferroptosis is a unique form of cell death, first described by
of calcium (Ca ), sodium (Na ), and chloride (Cl ) Dr. Brent Stockwell’s group in 2012, which involves iron-
31
2+
+
–
intracellularly and potassium (K ) extracellularly. 15,18,19 dependent lipid peroxidation, leading to a fatal buildup of
+
The ion buildup stimulates cell swelling and activation of ROS. Ferroptosis is induced by Ras-selective lethal (RSL)
Volume 4 Issue 1 (2025) 26 doi: 10.36922/an.4575