# Balance of Antioxidants vs. Oxidants in Perinatal Asphyxia
## 7 Therapeutic Strategies
### Reduction in Free Radical Production Initiators and Scavengers  
Allopurinol is a specific inhibitor of XO, competing with this enzyme to reduce the production of ROS during reperfusion [128; 129]. Allopurinol, by blocking the activity of XO, also reduces the production of NO from nitrites, while acting as a chelator for non-protein-bound iron and a direct scavenger for free radicals [128; 129]. These characteristics position it as a potential candidate in the treatment of hypoxic/ischemic encephalopathy. Maternal administration of allopurinol to fetuses experiencing hypoxia resulted in a decrease in the levels of the S-100B protein, an indicator of brain injury, in the infant's cord blood [130]. Previous evidence has shown that allopurinol reduced oxidative stress and improved blood flow and brain activity in newborns without causing toxicity [131]. However, a later study found no benefits in newborns given allopurinol within the first four hours after birth compared to those given a placebo, likely due to the delay in its administration [132]. Erythropoietin, essential for brain development, is a promising agent in treating NE by increasing the expression of genes that prevent cell death, reducing inflammation, lowering levels of oxygen free radicals, decreasing the activation of caspases, lessening the effects of glutamate excitotoxicity, and enhancing signaling pathways [133; 134]. Under conditions of hypoxia, the expression of erythropoietin receptors and the secretion of erythropoietin increase, making it a particularly effective option for treatment [135]. Melatonin, a powerful natural compound, has multiple beneficial effects including antioxidant, anti-inflammatory, and anti-apoptotic properties. It can easily cross the blood-brain barrier, making it an attractive option for treating hypoxic/ischemic encephalopathy [136; 137]. N-acetylcysteine (NAC), a precursor of cysteine, possesses antioxidant effects, including the neutralization of ROS and the replenishment of glutathione in cells [138]. These attributes, along with its ability to dissolve in fat and its low toxicity [139], have positioned NAC as a promising candidate for neuroprotection in NE. NAC reduces the severity of hypoxic/ischemic damage in newborn rats [140] and can be used in conjunction with hypothermia to lessen brain damage [141; 142]. Administering NAC to rats alongside hypothermia has been shown to enhance myelin production [141], improve brain function [141], and lead to better long-term motor outcomes [142]. DHA is known for its ability to neutralize free radicals and its role in reducing glutamate excitotoxicity and decreasing NO levels. Evidence of enhanced antioxidant enzyme activities in cultures of neurons enriched with DHA has suggested a potential neuroprotective function for DHA [143]. Edaravone acts as a neutralizer of free radicals and has been investigated for its multiple antioxidant effects across various experimental models, including those involving animal models of NE [144]. Phenobarbital administered within the first two hours of life in term newborns with perinatal asphyxia has been associated with lower levels of lipid peroxides and antioxidant enzymes in the cerebrospinal fluid [145]. Molecular hydrogen, a compound recently recognized for its antioxidant properties, has shown neuroprotective effects and maintains the reactivity of blood vessels in newborn pigs exposed to asphyxia [146]. Deferoxamine is an iron-binding antioxidant that crosses the blood-brain barrier and helps remove excess iron due to its capacity to bind free iron in the brain. Deferoxamine has been shown to lessen brain edema and injury in animal models of hypoxia/ischemia, lower the levels of excitatory amino acids, and improve the histological condition of the hippocampus in newborn rats following hypoxia/ischemia [127; 147]. Following birth asphyxia, iron is released from ferritin, hemosiderin, or transferrin [148; 149], leading to the production of free radicals [150].