![]() ![]() In Harlequin (Hq) mice, which have an 80% reduction in AIF expression, enhanced oxidative stress is seen in dying neurons. Oxidative stress results from an imbalance between pro-oxidants and antioxidants in living cells, and many lines of evidence have suggested that oxidative stress is one of the major contributors to perinatal HI injury in newborns. Under normal physiological conditions, AIF is a flavoprotein oxidoreductase located at the inner mitochondrial membrane where it functions as a reactive oxygen species (ROS) scavenger targeting H 2O 2 and in redox cycling with nicotinamide adenine dinucleotide phosphate. Our previous studies have shown that apoptotic cell death accounts for a large portion of neuronal cell loss in neonatal HI injury and that AIF, a principal component of the caspase-independent apoptotic cell death pathway, is a significant contributor to neuron loss induced by neonatal cerebral HI. Thus, the immature brain is likely to be more susceptible to activation of apoptotic cell death pathways than the adult brain. During the normal development of the mammalian nervous system, apoptosis occurs extensively and has been observed in populations of developing neural precursor cells, differentiated neurons, and glial cells, or depression of apoptotic cell death may lead to neuroanatomic abnormalities and possibly to developmental disabilities. Multiple mechanisms are involved in this process, including energy depletion, oxidative stress, excitotoxicity, and inflammatory responses, all of which lead to the activation of several distinct cell death pathways, including apoptosis, necrosis, necroptosis, ferroptosis, and autophagy. The immature brain is particularly susceptible to HI injury. Therefore, more in-depth research into neuronal cell death and the mechanisms of brain injury after HI is warranted in order to develop more effective therapies for preventing and treating neonatal brain injury. Although erythropoietin treatment has demonstrated remarkable neuroprotection in infants, the window of opportunity and optimal dosage is still controversial. ![]() ![]() Therapeutic hypothermia within 6 h of hypoxia–ischemia (HI) onset has been clinically shown to be a promising therapeutic intervention, but it only reduces the risk of death and disability by about 11%, meaning that up to 40% of the treated infants still develop neurological deficits. HIE is a global problem with an estimated incidence ranging from 1 to live births in developed countries to live births in underdeveloped countries. It is a major cause of mortality in neonates and can result in profound and devastating lifelong mental and physical disabilities, including cerebral palsy, seizures, and cognitive impairments in both term and preterm neonates. Hypoxic–ischemic encephalopathy (HIE) is a severe central nervous system injury caused by oxygen deprivation and limited blood flow in the neonatal brain. Altogether, these findings corroborate earlier studies and further demonstrate that AIF is involved in oxidative stress, which contributes to the sex-specific differences observed in neonatal HI brain injury. We also found that AIF stimulated carbohydrate metabolism in young males. Under physiological conditions (without HI), the doublecortin-positive area in the dentate gyrus of females was 1.15 times larger than in males, indicating that AIF upregulation effectively promoted neurogenesis in females in the long term. As compared to females, male mice exhibited more severe brain injury, correlating with reduced antioxidant capacities, more pronounced protein carbonylation and nitration, and increased neuronal cell death. We found that the male sex significantly aggravated AIF-driven brain damage, as indicated by the injury volume in the gray matter (2.25 times greater in males) and by the lost volume of subcortical white matter (1.71 greater in males) after HI. Based on previous findings that AIF overexpression aggravates neonatal HI brain injury, we further investigated potential sex differences in the severity and molecular mechanisms underlying the injury using mice that overexpress AIF from homozygous transgenes. There are sex differences in the severity, mechanisms, and outcomes of neonatal hypoxia–ischemia (HI) brain injury, and apoptosis-inducing factor (AIF) may play a critical role in this discrepancy.
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