# Balance of Antioxidants vs. Oxidants in Perinatal Asphyxia
## 3 Pathophysiology
### Hypoxia Referfusion Injury  
In conditions of ischemia and decreased oxygen supply followed by reperfusion, free radicals containing oxygen (ROS) or nitrogen (reactive nitrogen species, RNS) can be generated. Free radicals are extremely reactive and unstable due to an unpaired electron that they contain in their external membrane [34]. When the number of RFRs surpasses the capacity of the body's endogenous ADS to neutralize them, it can lead to oxidative damage. This damage may affect DNA, polysaccharides, proteins, and lipids, compromising cellular function and potentially causing cell death through either apoptosis or necrosis [35]. The developing brain is characterized by a high oxygen requirement, a low antioxidant defense of polyunsaturated fatty acids which are the main component of phospholipids, a high concentration of metals that catalyze ROS production, and a large number of immature cells; thus, it is particularly vulnerable to ROS/RNS-induced injury [36]. The progression of NE can be segmented into three stages, though in actuality, these stages overlap, with events often occurring simultaneously (Figure 2). The initial stage lasts 6 h and is marked by a decrease in blood flow to the fetus, resulting in systemic and cerebral hypoperfusion. Cerebral hypoperfusion leads to brain ischemia, hypoxia, acidosis, and cellular damage due to energy depletion. During hypoxia/ischemia, the brain areas with the highest metabolic activity and numerous excitatory glutamatergic synapses are primarily affected [37]. A key factor in hypoxic/ischemic-related brain damage is the overstimulation of postsynaptic receptors due to the excitotoxicity of glutamate neurotransmission, leading to cell death [38]. During prolonged hypoxia/ischemia, neurons may face a depletion of high-energy metabolites, an increase in cytotoxic edema, and an extracellular accumulation of excitatory amino acids [39]. Some neurons may die immediately or shortly after the injury, while others might initially recover at different stages, eventually leading to cell death [40]. Cerebral hypoxia triggers anaerobic metabolism, which results in an intracellular increase in lactic acid, sodium, calcium, and water; a decrease in ATP levels; and the reuptake of neurotransmitters, leading to secondary excitotoxicity. Intracellular calcium triggers the release of lipases, nitric oxide synthase (NOS), and substances that promote cell death; enhances the production of free radicals; and causes direct damage to the mitochondria. The second stage, which can last from 6 to 48 h, is characterized by ongoing excitotoxicity, a decrease in mitochondrial function and oxidative stress due to alterations in the membrane potential, a decrease in ATP production, and an alkaline environment despite sufficient oxygen supply. Immediately after a severe injury, there is a recovery of  
Figure 2: The progression of hypoxemic/ischemic/reperfusion injury. (**A**). Phase of hypoxia/ischemia. (**B**). Phase of reperfusion. (**C**). Phase of chronic inflammation. ATP, adenosine triphosphate; NMDA, N-methyl-D-aspartate; NOS, nitric oxide synthase; NADPH, nicotinamide adenine dinucleotide; RNS, reactive nitrogen species; ROS, reactive oxygen species; XD, xanthine dehydrogenase; XO, xanthine oxidase, IL, interleukin; TNF, tumor necrosis factor, IF-\(\gamma\), interferon-\(\gamma\). The Figures of the graphical abstract were partly generated using Servier Medical Art, provided by Servier (Creative Commons, Mountain View, CA, USA), licensed under a Creative Commons Attribution 3.0 unported license. blood flow to the brain, which is vital for survival but paradoxically leads to reperfusion injury due to an overproduction of radicals [41]. This causes not just an initial burst of oxidative stress but also a gradual breakdown of the mitochondrial electron transport chain, a depletion in ATP levels, and further damage to brain cells [8]. During reperfusion, reactive molecules are mainly generated by the mitochondrial respiratory chain complex and the xanthine oxidase (XO) system.