premature infants are especially vulnerable to reactive oxygen species ( ros)-induced injury1 ) because of their insufficient ability to synthesize antioxidant enzymes and the resulting deficiency of antioxidant enzymes . the imbalance between ros production and antioxidant defense may lead to ros - induced diseases such as bronchopulmonary dysplasia ( bpd ) , periventricular leukomalacia ( pvl ) , or retinopathy of prematurity ( rop)2 ) . free radicals are highly reactive molecules that contain one or more unpaired electrons , and radicals containing oxygen are referred to as ros3 ) . under normal physiological conditions , a balance is maintained between ros production and the antioxidant enzyme system . however , if this balance breaks down , ros oxidize lipids , proteins , and polysaccharides and can damage dna and rna4,5 ) . superoxide dismutase ( sod ) ; catalase ; glutathione peroxidase ( gpx ) ; vitamins a , c , and e ; and glutathione are common antioxidants6 ) . majority of the studies on the antioxidant system in the developing brain have focused on the physiological functions of classical antioxidant enzymes such as manganese - containing sod ( mn - sod ) , copper- and zinc - containing sod ( cuzn - sod ) , gpx , and catalase , under conditions of oxidative stress7 - 9 ) . the recently discovered antioxidant enzyme family , peroxiredoxins ( prdxs ) , was first identified in yeast as a 25-kda enzyme10 ) . the peroxidase activities of prdx1 and 2 in the 2-cys prdx group control the reduction - oxidation status during normal oxidative metabolism and in the presence of oxidative stress11 ) . prdx6 is the only member of the 1-cys prdx group and catalyzes the reduction of phospholipid hydroperoxide12,13 ) . in this article , we review oxidative stress and the antioxidant enzyme system in the fetus and preterm infant . the three most common ros are superoxide ( o2 ) , hydroxyl radical ( oh ) , and hydrogen peroxide ( h2o2 ) . o2 is produced when molecular oxygen gains an additional electron . mitochondria can also produce antioxidant enzymes such as sod , gpx , and glutathione reductase16 ) . sod leads to the generation of h2o2 from o2 , which is then dissociated by catalase or gpx into water and molecular oxygen17 ) . h2o2 is also produced in response to extracellular responses such as cytokines , neurotransmitters , peptide growth factors , and hormones18,19 ) . h2o2 affects the functions of proteins , including those of transcription factors , phospholipases , and protein kinases19,20 ) . h2o2 is considered an important intracellular messenger under physiological concentrations , but under pathological conditions , h2o2 can react with fe via fenton reaction to produce the highly reactive oh1 ) . nitric oxide ( no ) is a relatively weak oxygen free radical produced by nitric oxide synthase ( nos ) . however , a reaction between no and o2 leads to the formation of peroxynitrite , a potent free radical causing lipid peroxidation15,21 ) . . there are three forms of sod : cuzn - sod , which is mainly located in the cytoplasm , mn - sod , which is mainly located in the mitochondria , and extracellular sod ( ec - sod ) , which is located in the intracellular spaces in neonates but in the extracellular space thereafter . catalase and gpx catalyze the conversion of h2o2 into oxygen and water7 - 9,17 ) . the developing human brain needs protective antioxidant enzymes against the oxidative stress that suddenly occurs at birth , due to the hyperoxia caused by transfer from an anaerobic in utero environment to an oxygen - rich environment . the expressions of sod , catalase , and gpx are known to increase by 150% during the last 15% of the gestation period22 ) . development of the antioxidant enzyme system during the fetal period is associated with redox signaling for the maintenance of pregnancy through utero - placental - fetal interactions22,23 ) . in addition , the regulation of antioxidant enzymes associated with local no generation via nos and downstream no - dependent signaling in the placenta are important for normal vascular development22,24 ) . the exact timing of the acquisition of adult levels of these antioxidant enzymes is obscure . mn - sod seems to be important for the protection of oligodendroglial ( ol ) cells in the presence of high levels of iron , which can lead to generation of oh25 ) . previous studies showed that the expression of cuzn - sod dramatically increases during the highly metabolic period of myelin sheath synthesis and that the quantity of catalase - containing peroxisomes increases during active myelin sheath formation in the postnatal rat26,27 ) . prdx was initially discovered in yeast as a 25-kda enzyme that protects against oxidative damage . prdx is a widely distributed superfamily of nonselenium gpx , which directly reduce h2o2 and alkyl hydroperoxides . there are six mammalian prdx isoforms : 2-cys prdx group ( prdx1 - 4 ) , atypical 2-cys prdx group ( prdx5 ) , and 1-cys prdx group ( prdx6)10,11 ) . group members prdx1 and 2 play roles as scavengers of h2o2 and effectors of signaling cascades , in which h2o2 acts as a second messenger to regulate cellular responses10,11 ) . on the other hand , prdx6 , the only member of the 1-cys prdx group , has been suggested to use glutathione as an electron donor . its localization to both cytoplasm and lysosomes and its ability to catalyze the reduction of phospholipid hydroperoxide suggest that prdx6 has functional roles in phospholipid metabolism in a variety of biological systems12,13 ) . in our recent perinatal rat brain study , the expressions of both prdx1 and 6 were deficient during the early gestational period and were elevated in the late gestational period . prdx1 and 6 expressions might be increased against oxidative stress that suddenly occurs at birth . it is likely that the observed increase in the expressions of prdx1 and 6 is in response to the sudden oxidative stress that occurs at birth . prdx1 protein expression reached peak level after birth , and then , it gradually decreased to the adult level . in contrast , prdx2 was largely expressed during the gestational period and was constitutive during the perinatal period . we also observed these expression patterns in our perinatal rat lung studies28 - 30 ) . prdx1 expression can be induced by specific stimulations occurring at birth , and it is predominantly expressed in ol cells32 ) . because immature ol cells are vulnerable to free radicals , prdx1 might have an important role to play in the protection of the brain from perinatal oxidative stress . . there are three forms of sod : cuzn - sod , which is mainly located in the cytoplasm , mn - sod , which is mainly located in the mitochondria , and extracellular sod ( ec - sod ) , which is located in the intracellular spaces in neonates but in the extracellular space thereafter . catalase and gpx catalyze the conversion of h2o2 into oxygen and water7 - 9,17 ) . the developing human brain needs protective antioxidant enzymes against the oxidative stress that suddenly occurs at birth , due to the hyperoxia caused by transfer from an anaerobic in utero environment to an oxygen - rich environment . the expressions of sod , catalase , and gpx are known to increase by 150% during the last 15% of the gestation period22 ) . development of the antioxidant enzyme system during the fetal period is associated with redox signaling for the maintenance of pregnancy through utero - placental - fetal interactions22,23 ) . in addition , the regulation of antioxidant enzymes associated with local no generation via nos and downstream no - dependent signaling in the placenta are important for normal vascular development22,24 ) . the exact timing of the acquisition of adult levels of these antioxidant enzymes is obscure . mn - sod seems to be important for the protection of oligodendroglial ( ol ) cells in the presence of high levels of iron , which can lead to generation of oh25 ) . previous studies showed that the expression of cuzn - sod dramatically increases during the highly metabolic period of myelin sheath synthesis and that the quantity of catalase - containing peroxisomes increases during active myelin sheath formation in the postnatal rat26,27 ) . prdx was initially discovered in yeast as a 25-kda enzyme that protects against oxidative damage . prdx is a widely distributed superfamily of nonselenium gpx , which directly reduce h2o2 and alkyl hydroperoxides . there are six mammalian prdx isoforms : 2-cys prdx group ( prdx1 - 4 ) , atypical 2-cys prdx group ( prdx5 ) , and 1-cys prdx group ( prdx6)10,11 ) . group members prdx1 and 2 play roles as scavengers of h2o2 and effectors of signaling cascades , in which h2o2 acts as a second messenger to regulate cellular responses10,11 ) . on the other hand , prdx6 , the only member of the 1-cys prdx group , has been suggested to use glutathione as an electron donor . its localization to both cytoplasm and lysosomes and its ability to catalyze the reduction of phospholipid hydroperoxide suggest that prdx6 has functional roles in phospholipid metabolism in a variety of biological systems12,13 ) . in our recent perinatal rat brain study , the expressions of both prdx1 and 6 were deficient during the early gestational period and were elevated in the late gestational period . prdx1 and 6 expressions might be increased against oxidative stress that suddenly occurs at birth . it is likely that the observed increase in the expressions of prdx1 and 6 is in response to the sudden oxidative stress that occurs at birth . prdx1 protein expression reached peak level after birth , and then , it gradually decreased to the adult level . in contrast , prdx2 was largely expressed during the gestational period and was constitutive during the perinatal period . we also observed these expression patterns in our perinatal rat lung studies28 - 30 ) . prdx1 expression can be induced by specific stimulations occurring at birth , and it is predominantly expressed in ol cells32 ) . because immature ol cells are vulnerable to free radicals , prdx1 might have an important role to play in the protection of the brain from perinatal oxidative stress . preterm infants are vulnerable to perinatal insults such as pvl , because of vascular immaturity , impaired cerebrovascular autoregulation , and maturation - dependent vulnerability of ol precursor cells1 ) . there are two types of pvl : a focal type induced by localized necrosis that is expressed as cystic formation in ultrasonography , and the diffuse type that is more common and is induced by diffuse ol precursor cell apoptosis1 ) . the diffuse type pvl can be detected by diffusion - weighted magnetic resonance imaging ( mri ) . it was reported that free radicals are more toxic to ol precursor cells than to mature ol cells by using cell culture under cystine - deprived medium , which results in glutathione depletion , thereby leading to a condition of free radical attack33 ) . intraventricular hemorrhage ( ivh ) provides a source of free iron , which can generate oh by fenton reaction34 ) . accumulation of intracellular ca due to activation of n - methyl - d - aspartate receptors can lead to free radical generation , cell apoptosis , and necrosis by various mechanisms . activated protease induces the conversion of xanthine dehydrogenase to xanthine oxidase , resulting in increased free radical generation . in addition , nos is more activated and easily generates no , which can react with o2 to form peroxynitrite , a potent free radical35 ) . neuronal membranes in preterm infants are rich in polyunsaturated fatty acids , which provide a source of peroxidation16 ) . ol precursor cells , which are mainly present in the immature nervous system in preterm infants , are vulnerable to free radical attack . furthermore , ol precursor cells tend to accumulate iron for maturation purposes , and ivh also provides a source of free iron , which facilitates the fenton reaction . the conversion of h2o2 to oh by fenton reaction increases cytotoxicity in the immature nervous system1,16,34 ) . in fact , free radicals and ol precursor cells are the primary players in the pathogenesis of brain injury in preterm infants . in conclusion , preterm infants are sensitive to ros because of an antioxidant enzyme deficiency and a tendency to produce large amounts of ros . several substances are considered as therapeutic candidates for oxidative stress ; however , further preclinical and clinical studies are required before clinical application of these substances . melatonin ( 5-methoxy - n - acetyltryptamine ) is secreted predominantly in the pineal gland and has potent antioxidant and anti - inflammatory activities . melatonin acts as a direct antioxidant by scavenging free radicals , including oh , o2 , h2o2 , and peroxynitrite . melatonin acts as an indirect antioxidant by increasing the levels of antioxidant enzymes such as gpx , glutathione reductase , sod , and catalase36,37 ) . currently , melatonin is not available as a formulation for neonates , but it seems likely that in the near future , it will be available for the treatment of ros - induced neonatal diseases . allopurinol , the xanthine oxidase inhibitor , can reduce free radical formation and works as a free radical scavenger or iron chelator at high dosages38,39 ) . although clinical data about the use of allopurinol are insufficient to determine its efficacy in neonates under oxidative stress , animal studies have provided evidence of its neuroprotective capabilities14 ) . vitamins c ( ascorbic acid ) and e ( tocopherols and tocotrienols ) are also considered important antioxidants . vitamin c works as a free radical scavenger and can regenerate reduced tocopherol41 ) . in one study , cotreatment with vitamins c and e was found to exhibit a synergistic antioxidant effect42 ) . however , the study failed to show that these antioxidant vitamins significantly reduce ros - associated injury . in fact , it can reduce bpd incidence but does not affect long - term outcome43 ) . recombinant human sod ( rhsod ) was tested for the prevention of bpd or rop in preterm infants44,45 ) . the balance between ros production and the antioxidant system is of particular importance in fetuses and newborns . in particular , ol precursor cells , which are mainly present in the immature nervous system in preterm infants , are vulnerable to oxidative stress . classical antioxidant enzymes such as sod , gpx , and catalase are deficient in the early gestational period , but their expressions are upregulated during the late gestational period as a response to ros exposure at birth , which is due to relative hyperoxia upon air exposure . currently , several potential antioxidants are being studied for clinical applications , and it is hoped that these efforts will result in suitable antioxidant therapies for preterm infants in the near future .
preterm infants are vulnerable to the oxidative stress due to the production of large amounts of free radicals , antioxidant system insufficiency , and immature oligodendroglial cells . 
 reactive oxygen species ( ros ) play a pivotal role in the development of periventricular leukomalacia . 
 the three most common ros are superoxide ( o2- ) , hydroxyl radical ( oh ) , and hydrogen peroxide ( h2o2 ) . under normal physiological conditions 
 , a balance is maintained between the production of ros and the capacity of the antioxidant enzyme system . 
 however , if this balance breaks down , ros can exert toxic effects . 
 superoxide dismutase , glutathione peroxidase , and catalase are considered the classical antioxidant enzymes . 
 a recently discovered antioxidant enzyme family , peroxiredoxin ( prdx ) , is also an important scavenger of free radicals . 
 prdx1 expression is induced at birth , whereas prdx2 is constitutively expressed , and prdx6 expression is consistent with the classical antioxidant enzymes . 
 several antioxidant substances have been studied as potential therapeutic agents ; however , further preclinical and clinical studies are required before allowing clinical application .