{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:58:32Z","timestamp":1792789112912,"version":"4.5.0"},"reference-count":112,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T00:00:00Z","timestamp":1748649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"#NEXTGENERATIONEU (NGEU)","award":["PE0000006"],"award-info":[{"award-number":["PE0000006"]}]},{"name":"Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP)","award":["PE0000006"],"award-info":[{"award-number":["PE0000006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Physiological oxidative stress plays a pivotal role in supporting proper growth and development. While moderate oxidative stress is essential for activating key metabolic pathways and maintaining normal cellular signaling, excessive production of reactive oxygen species (ROSs) can overwhelm the immature antioxidant systems of newborns, potentially leading to cellular damage and impaired physiological function. This vulnerability is particularly pronounced in the central nervous system, where limited detoxification capacity exacerbates the risk of oxidative damage, following hypoxic\u2013ischemic events. Antioxidants agents\u2014such as melatonin, erythropoietin, allopurinol, N-acetylcisteine, selenium, iminobiotin, taurine, and acetyl-L-carnitine\u2014have demonstrated significant neuroprotective effects in preclinical experimental studies, reducing markers of oxidative injury and improving neurological outcomes. These neuroprotective agents have also been evaluated in clinical trials, demonstrating antioxidant effects. A major issue lies in the complexity of neurological damage, which is not associated with a single pathological pathway. Additionally, the inability of these agents to reach effective concentrations within the central nervous system, along with inconsistencies across clinical trials in terms of dosage and administration methods, hinders the ability to obtain robust results. Future efforts should therefore focus on the development of delivery systems capable of crossing the blood\u2013brain barrier and on establishing standardized clinical trial protocols and study designs. This educational review aims to provide a comprehensive overview of emerging protective strategies, including antioxidant bioactive agents and nutritional interventions. It also explores the underlying mechanisms of oxidative stress and its impact on neonatal brain injury.<\/jats:p>","DOI":"10.3390\/cells14110818","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T12:27:09Z","timestamp":1748867229000},"page":"818","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Antioxidant Bioactive Agents for Neuroprotection Against Perinatal Brain Injury"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6669-2439","authenticated-orcid":false,"given":"Virginia","family":"Beretta","sequence":"first","affiliation":[{"name":"Neonatology Unit, Department of Medicine and Surgery, University of Parma, Pietro Barilla Children\u2019s Hospital, 43121 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2252-0592","authenticated-orcid":false,"given":"Elena","family":"Scarpa","sequence":"additional","affiliation":[{"name":"Neonatology Unit, Department of Medicine and Surgery, University of Parma, Pietro Barilla Children\u2019s Hospital, 43121 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3634-3454","authenticated-orcid":false,"given":"Silvia","family":"Carloni","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3042-0367","authenticated-orcid":false,"given":"Chiara","family":"Petrolini","sequence":"additional","affiliation":[{"name":"Neonatology Unit, Department of Medicine and Surgery, University of Parma, Pietro Barilla Children\u2019s Hospital, 43121 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Dell\u2019Orto","sequence":"additional","affiliation":[{"name":"Neonatology Unit, Department of Medicine and Surgery, University of Parma, Pietro Barilla Children\u2019s Hospital, 43121 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiano","family":"Ravenda","sequence":"additional","affiliation":[{"name":"Stress Physiology Lab, Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Viale delle Scienze 11, 43125 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5478-5657","authenticated-orcid":false,"given":"Serafina","family":"Perrone","sequence":"additional","affiliation":[{"name":"Neonatology Unit, Department of Medicine and Surgery, University of Parma, Pietro Barilla Children\u2019s Hospital, 43121 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Pizzino, G., Irrera, N., Cucinotta, M., Pallio, G., Mannino, F., Arcoraci, V., Squadrito, F., Altavilla, D., and Bitto, A. (2017). Oxidative Stress: Harms and Benefits for Human Health. Oxidative Med. Cell. Longev., 2017.","DOI":"10.1155\/2017\/8416763"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1007\/s00204-023-03562-9","article-title":"Reactive oxygen species, toxicity, oxidative stress, and antioxidants: Chronic diseases and aging","volume":"97","author":"Jomova","year":"2023","journal-title":"Arch. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.siny.2010.04.003","article-title":"Oxygen toxicity: Chemistry and biology of reactive oxygen species","volume":"15","author":"Buonocore","year":"2010","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"472","DOI":"10.3390\/biom5020472","article-title":"Biological Activities of Reactive Oxygen and Nitrogen Species: Oxidative Stress versus Signal Transduction","volume":"5","author":"Weidinger","year":"2015","journal-title":"Biomolecules"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.abb.2012.08.002","article-title":"The role of redox environment in neurogenic development","volume":"534","author":"Ostrakhovitch","year":"2013","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1111\/aji.12454","article-title":"Oxidative Stress: Placenta Function and Dysfunction","volume":"76","author":"Wu","year":"2016","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.jneuroim.2005.06.031","article-title":"Expression of nitric oxide synthase isoforms and nitrotyrosine formation after hypoxia-ischemia in the neonatal rat brain","volume":"167","author":"Nijboer","year":"2005","journal-title":"J. Neuroimmunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.siny.2007.01.020","article-title":"Anti-oxidant strategies","volume":"12","author":"Buonocore","year":"2007","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Perrone, S., Santacroce, A., Longini, M., Proietti, F., Bazzini, F., and Buonocore, G. (2018). The Free Radical Diseases of Prematurity: From Cellular Mechanisms to Bedside. Oxidative Med. Cell. Longev., 2018.","DOI":"10.1155\/2018\/7483062"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1111\/apa.13039","article-title":"Resuscitating preterm infants with 100% oxygen is associated with higher oxidative stress than room air","volume":"104","author":"Tataranno","year":"2015","journal-title":"Acta Paediatr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1089\/152308604771978453","article-title":"Role of redox in fetal development and neonatal diseases","volume":"6","author":"Dennery","year":"2004","journal-title":"Antioxid. Redox Signal"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Andreescu, S., Henkel, R., and Khelfi, A. (2024). Oxidative Stress in Preeclampsia and Preterm Newborn. Biomarkers of Oxidative Stress, Springer.","DOI":"10.1007\/978-3-031-69962-7"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.3109\/14767058.2013.796170","article-title":"Brain susceptibility to oxidative stress in the perinatal period","volume":"28","author":"Perrone","year":"2015","journal-title":"J. Matern. Neonatal Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Juan, C.A., P\u00e9rez de la Lastra, J.M., Plou, F.J., and P\u00e9rez-Lebe\u00f1a, E. (2021). The Chemistry of Reactive Oxygen Species (ROS) Revisited: Outlining Their Role in Biological Macromolecules (DNA, Lipids and Proteins) and Induced Pathologies. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094642"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Chaudhary, P., Janmeda, P., Docea, A.O., Yeskaliyeva, B., Abdull Razis, A.F., Modu, B., Calina, D., and Sharifi-Rad, J. (2023). Oxidative stress, free radicals and antioxidants: Potential crosstalk in the pathophysiology of human diseases. Front. Chem., 11.","DOI":"10.3389\/fchem.2023.1158198"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1093\/brain\/awg116","article-title":"Non protein bound iron as early predictive marker of neonatal brain damage","volume":"126","author":"Buonocore","year":"2003","journal-title":"Brain"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/S0891-5849(98)00126-9","article-title":"Intraerythrocyte nonprotein-bound iron and plasma malondialdehyde in the hypoxic newborn","volume":"25","author":"Buonocore","year":"1998","journal-title":"Free Radic. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1124\/jpet.116.237503","article-title":"Oxidative Stress and the Central Nervous System","volume":"360","author":"Salim","year":"2017","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.jagp.2022.01.009","article-title":"Polyunsaturated Fatty Acid Intake and Brain Health: Balance is the Key","volume":"30","author":"Rebello","year":"2022","journal-title":"Am. J. Geriatr. Psychiatry Off. J. Am. Assoc. Geriatr. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/0163-7827(85)90011-6","article-title":"Lipids of nervous tissue: Composition and metabolism","volume":"24","author":"Sastry","year":"1985","journal-title":"Prog. Lipid Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1194\/jlr.M700503-JLR200","article-title":"F2-dihomo-isoprostanes arise from free radical attack on adrenic acid","volume":"49","author":"VanRollins","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1523\/JNEUROSCI.3989-03.2004","article-title":"Glutathione peroxidase-catalase cooperativity is required for resistance to hydrogen peroxide by mature rat oligodendrocytes","volume":"24","author":"Baud","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Arteaga, O., Revuelta, M., Urig\u00fcen, L., \u00c1lvarez, A., Montalvo, H., and Hilario, E. (2015). Pretreatment with Resveratrol Prevents Neuronal Injury and Cognitive Deficits Induced by Perinatal Hypoxia-Ischemia in Rats. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0142424"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1093\/jnen\/63.9.990","article-title":"Developmental lag in superoxide dismutases relative to other antioxidant enzymes in premyelinated human telencephalic white matter","volume":"63","author":"Folkerth","year":"2004","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhao, M., Zhu, P., Fujino, M., Zhuang, J., Guo, H., Sheikh, I., Zhao, L., and Li, X.K. (2016). Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17122078"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Menzel, A., Samouda, H., Dohet, F., Loap, S., Ellulu, M.S., and Bohn, T. (2021). Common and Novel Markers for Measuring Inflammation and Oxidative Stress Ex Vivo in Research and Clinical Practice-Which to Use Regarding Disease Outcomes?. Antioxidants, 10.","DOI":"10.3390\/antiox10030414"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Martini, S., Castellini, L., Parladori, R., Paoletti, V., Aceti, A., and Corvaglia, L. (2021). Free Radicals and Neonatal Brain Injury: From Underlying Pathophysiology to Antioxidant Treatment Perspectives. Antioxidants, 10.","DOI":"10.3390\/antiox10122012"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.siny.2010.05.005","article-title":"Mechanisms of hypothermic neuroprotection","volume":"15","author":"Drury","year":"2010","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.pediatrneurol.2010.05.009","article-title":"Whole body hypothermia and oxidative stress in babies with hypoxic-ischemic brain injury","volume":"43","author":"Perrone","year":"2010","journal-title":"Pediatr. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Jacobs, S.E., Berg, M., Hunt, R., Tarnow-Mordi, W.O., Inder, T.E., and Davis, P.G. (2013). Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst. Rev., 2013.","DOI":"10.1002\/14651858.CD003311.pub3"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1159\/000360646","article-title":"Oxygen supplementation in the neonatal period: Changing the paradigm","volume":"105","author":"Vento","year":"2014","journal-title":"Neonatology"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Perrone, S., Manti, S., Petrolini, C., Dell\u2019Orto, V.G., Boscarino, G., Ceccotti, C., Bertini, M., Buonocore, G., Esposito, S.M.R., and Gitto, E. (2023). Oxygen for the Newborn: Friend or Foe?. Children, 10.","DOI":"10.3390\/children10030579"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S185","DOI":"10.1161\/CIR.0000000000000895","article-title":"Neonatal Life Support Collaborators Neonatal Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations","volume":"142","author":"Wyckoff","year":"2020","journal-title":"Circulation"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Tataranno, M.L., Perrone, S., Longini, M., and Buonocore, G. (2015). New antioxidant drugs for neonatal brain injury. Oxidative Med. Cell. Longev., 2015.","DOI":"10.1155\/2015\/108251"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1055\/s-0031-1295480","article-title":"Total antioxidant capacity and total oxidant status in perinatal asphyxia in relation to neurological outcome","volume":"42","author":"Aydemir","year":"2011","journal-title":"Neuropediatrics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e722","DOI":"10.1542\/peds.2008-0269","article-title":"Free radical injury and blood-brain barrier permeability in hypoxic-ischemic encephalopathy","volume":"122","author":"Kumar","year":"2008","journal-title":"Pediatrics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1159\/000355460","article-title":"Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia","volume":"35","author":"Traudt","year":"2013","journal-title":"Dev. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1161\/01.STR.0000132196.49028.a4","article-title":"Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats","volume":"35","author":"Wang","year":"2004","journal-title":"Stroke"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1159\/000472710","article-title":"Erythropoietin Treatment Exacerbates Moderate Injury after Hypoxia-Ischemia in Neonatal Superoxide Dismutase Transgenic Mice","volume":"39","author":"Sheldon","year":"2017","journal-title":"Dev. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1159\/000085993","article-title":"Melatonin provides neuroprotection in the late-gestation fetal sheep brain in response to umbilical cord occlusion","volume":"27","author":"Miller","year":"2005","journal-title":"Dev. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1203\/01.pdr.0000252546.20451.1a","article-title":"Melatonin reduces inflammation and cell death in white matter in the mid-gestation fetal sheep following umbilical cord occlusion","volume":"61","author":"Welin","year":"2007","journal-title":"Pediatr. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1111\/j.1600-079X.2007.00503.x","article-title":"Melatonin protects from the long-term consequences of a neonatal hypoxic-ischemic brain injury in rats","volume":"44","author":"Carloni","year":"2008","journal-title":"J. Pineal Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1159\/000232562","article-title":"Neuroprotective properties of melatonin in a model of birth asphyxia in the spiny mouse (Acomys cahirinus)","volume":"31","author":"Hutton","year":"2009","journal-title":"Dev. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1111\/j.1600-079X.2008.00639.x","article-title":"Free iron, total F-isoprostanes and total F-neuroprostanes in a model of neonatal hypoxic-ischemic encephalopathy: Neuroprotective effect of melatonin","volume":"46","author":"Signorini","year":"2009","journal-title":"J. Pineal Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/978-3-7091-0693-8_34","article-title":"Neuroprotection by melatonin after germinal matrix hemorrhage in neonatal rats","volume":"111","author":"Lekic","year":"2011","journal-title":"Acta Neurochir. Suppl."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"119","DOI":"10.3109\/14767058.2012.663232","article-title":"The use of melatonin in hypoxic-ischemic brain damage: An experimental study","volume":"25","author":"Balduini","year":"2012","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1093\/brain\/aws285","article-title":"Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model","volume":"136","author":"Robertson","year":"2013","journal-title":"Brain"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1007\/s12031-023-02155-6","article-title":"MiR-126 and miR-146a as Melatonin-Responsive Biomarkers for Neonatal Brain Ischemia","volume":"73","author":"Albertini","year":"2023","journal-title":"J. Mol. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1203\/00006450-199004000-00003","article-title":"Reduction of perinatal hypoxic-ischemic brain damage with allopurinol","volume":"27","author":"Palmer","year":"1990","journal-title":"Pediatr. Res."},{"key":"ref_50","first-page":"405","article-title":"Allopurinol administered after inducing hypoxia-ischemia reduces brain injury in 7-day-old rats","volume":"33","author":"Palmer","year":"1993","journal-title":"Pediatr. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1002\/mrm.25537","article-title":"In vivo longitudinal proton magnetic resonance spectroscopy on neonatal hypoxic-ischemic rat brain injury: Neuroprotective effects of acetyl-L-carnitine","volume":"74","author":"Xu","year":"2015","journal-title":"Magn. Reson. Med."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Mehta, S.L., Kumari, S., Mendelev, N., and Li, P.A. (2012). Selenium preserves mitochondrial function, stimulates mitochondrial biogenesis, and reduces infarct volume after focal cerebral ischemia. BMC Neurosci., 13.","DOI":"10.1186\/1471-2202-13-79"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.ejphar.2014.01.025","article-title":"Modes of direct modulation by taurine of the glutamate NMDA receptor in rat cortex","volume":"728","author":"Chan","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/sj.jcbfm.9600342","article-title":"Gender-specific neuroprotection by 2-iminobiotin after hypoxia-ischemia in the neonatal rat via a nitric oxide independent pathway","volume":"27","author":"Nijboer","year":"2007","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1161\/STROKEAHA.112.677922","article-title":"Short-term dose-response characteristics of 2-iminobiotin immediately postinsult in the neonatal piglet after hypoxia-ischemia","volume":"44","author":"Bjorkman","year":"2013","journal-title":"Stroke"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e218","DOI":"10.1542\/peds.2008-3553","article-title":"Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy","volume":"124","author":"Zhu","year":"2009","journal-title":"Pediatrics"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1542\/peds.2012-0498","article-title":"Erythropoietin for neuroprotection in neonatal encephalopathy: Safety and pharmacokinetics","volume":"130","author":"Wu","year":"2012","journal-title":"Pediatrics"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1111\/ped.12121","article-title":"High-dose phenobarbital or erythropoietin for the treatment of perinatal asphyxia in term newborns","volume":"55","author":"Avasiloaiei","year":"2013","journal-title":"Pediatr. Int."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.3109\/14767058.2013.855894","article-title":"Single dose recombinant erythropoietin versus moderate hypothermia for neonatal hypoxic ischemic encephalopathy in low resource settings","volume":"27","author":"Awad","year":"2014","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.pediatrneurol.2014.08.010","article-title":"Erythropoietin and hypothermia for hypoxic-ischemic encephalopathy","volume":"51","author":"Rogers","year":"2014","journal-title":"Pediatr. Neurol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1038\/jp.2017.17","article-title":"Erythropoietin monotherapy in perinatal asphyxia with moderate to severe encephalopathy: A randomized placebo-controlled trial","volume":"37","author":"Malla","year":"2017","journal-title":"J. Perinatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.jpeds.2017.03.053","article-title":"Erythropoietin and Brain Magnetic Resonance Imaging Findings in Hypoxic-Ischemic Encephalopathy: Volume of Acute Brain Injury and 1-Year Neurodevelopmental Outcome","volume":"186","author":"Mulkey","year":"2017","journal-title":"J. Pediatr."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.4103\/1673-5374.217338","article-title":"Effect of erythropoietin combined with hypothermia on serum tau protein levels and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy","volume":"12","author":"Lv","year":"2017","journal-title":"Neural Regen. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1056\/NEJMoa1907423","article-title":"A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants","volume":"382","author":"Juul","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/jp.2014.186","article-title":"Melatonin use for neuroprotection in perinatal asphyxia: A randomized controlled pilot study","volume":"35","author":"Aly","year":"2015","journal-title":"J. Perinatol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Marseglia, L., Gitto, E., Laschi, E., Giordano, M., Romeo, C., Cannav\u00f2, L., Toni, A.L., Buonocore, G., and Perrone, S. (2021). Antioxidant Effect of Melatonin in Preterm Newborns. Oxidative Med. Cell. Longev., 2021.","DOI":"10.1155\/2021\/6308255"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"F27","DOI":"10.1136\/fn.73.1.F27","article-title":"Randomised controlled trial of allopurinol prophylaxis in very preterm infants","volume":"73","author":"Russell","year":"1995","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"F216","DOI":"10.1136\/archdischild-2014-306769","article-title":"Maternal allopurinol administration during suspected fetal hypoxia: A novel neuroprotective intervention? A multicentre randomised placebo controlled trial","volume":"100","author":"Kaandorp","year":"2015","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s40262-021-01068-0","article-title":"Pharmacokinetic\/Pharmacodynamic Modelling of Allopurinol, its Active Metabolite Oxypurinol, and Biomarkers Hypoxanthine, Xanthine and Uric Acid in Hypoxic-Ischemic Encephalopathy Neonates","volume":"61","author":"Chu","year":"2022","journal-title":"Clin. Pharmacokinet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1177\/0271678X18765828","article-title":"N-Acetylcysteine rapidly replenishes central nervous system glutathione measured via magnetic resonance spectroscopy in human neonates with hypoxic-ischemic encephalopathy","volume":"38","author":"Wiest","year":"2018","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s13052-015-0185-8","article-title":"Correlations between maternal and neonatal serum selenium levels in full term neonates with hypoxic ischemic encephalopathy","volume":"41","author":"Mahmoud","year":"2015","journal-title":"Ital. J. Pediatr."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S0303-8467(99)00035-9","article-title":"Excitatory amino acids and taurine levels in cerebrospinal fluid of hypoxic ischemic encephalopathy in newborn","volume":"101","author":"Atalay","year":"1999","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s40272-019-00373-3","article-title":"A Phase IIa Clinical Trial of 2-Iminobiotin for the Treatment of Birth Asphyxia in DR Congo, a Low-Income Country","volume":"22","author":"Biselele","year":"2020","journal-title":"Paediatr. Drugs"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Rey, F., Balsari, A., Giallongo, T., Ottolenghi, S., Di Giulio, A.M., Samaja, M., and Carelli, S. (2019). Erythropoietin as a Neuroprotective Molecule: An Overview of Its Therapeutic Potential in Neurodegenerative Diseases. ASN Neuro, 11.","DOI":"10.1177\/1759091419871420"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Perrone, S., Lembo, C., Gironi, F., Petrolini, C., Catalucci, T., Corbo, G., Buonocore, G., Gitto, E., and Esposito, S.M.R. (2022). Erythropoietin as a Neuroprotective Drug for Newborn Infants: Ten Years after the First Use. Antioxidants, 11.","DOI":"10.3390\/antiox11040652"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"803","DOI":"10.2119\/molmed.2015.00192","article-title":"Widespread Expression of Erythropoietin Receptor in Brain and Its Induction by Injury","volume":"21","author":"Ott","year":"2015","journal-title":"Mol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1159\/000472709","article-title":"Neuroprotective Treatments after Perinatal Hypoxic-Ischemic Brain Injury Evaluated with Magnetic Resonance Spectroscopy","volume":"39","author":"Berger","year":"2017","journal-title":"Dev. Neurosci."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Wu, Y.W., Mathur, A.M., Chang, T., McKinstry, R.C., Mulkey, S.B., Mayock, D.E., Van Meurs, K.P., Rogers, E.E., Gonzalez, F.F., and Comstock, B.A. (2016). High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial. Pediatrics, 137.","DOI":"10.1542\/peds.2016-0191"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1007\/BF02253360","article-title":"Actions of melatonin in the reduction of oxidative stress. A review","volume":"7","author":"Reiter","year":"2000","journal-title":"J. Biomed. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Pluta, R., Furmaga-Jab\u0142o\u0144ska, W., Januszewski, S., and Tarkowska, A. (2023). Melatonin: A Potential Candidate for the Treatment of Experimental and Clinical Perinatal Asphyxia. Molecules, 28.","DOI":"10.3390\/molecules28031105"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1034\/j.1600-079X.2001.310409.x","article-title":"Increased levels of malondialdehyde and nitrite\/nitrate in the blood of asphyxiated newborns: Reduction by melatonin","volume":"31","author":"Fulia","year":"2001","journal-title":"J. Pineal Res."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Weiss, M.D., Carloni, S., Vanzolini, T., Coppari, S., Balduini, W., Buonocore, G., Longini, M., Perrone, S., Sura, L., and Mohammadi, A. (2022). Human-rat integrated microRNAs profiling identified a new neonatal cerebral hypoxic-ischemic pathway melatonin-sensitive. J. Pineal Res., 73.","DOI":"10.1111\/jpi.12818"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Arteaga, O., \u00c1lvarez, A., Revuelta, M., Santaolalla, F., Urtasun, A., and Hilario, E. (2017). Role of Antioxidants in Neonatal Hypoxic-Ischemic Brain Injury: New Therapeutic Approaches. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020265"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Engel, C., R\u00fcdiger, M., Benders, M.J.N.L., van Bel, F., Allegaert, K., Naulaers, G., Bassler, D., Kleberma\u00df-Schrehof, K., Vento, M., and Vilan, A. (2024). Detailed statistical analysis plan for ALBINO: Effect of Allopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome\u2014A blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III). Trials, 25.","DOI":"10.1186\/s13063-024-08031-x"},{"key":"ref_85","first-page":"199","article-title":"N-acetylcysteine alleviates H2O2-induced damage via regulating the redox status of intracellular antioxidants in H9c2 cells","volume":"43","author":"Liu","year":"2019","journal-title":"Int. J. Mol. Med."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Sahasrabudhe, S.A., Terluk, M.R., and Kartha, R.V. (2023). N-acetylcysteine Pharmacology and Applications in Rare Diseases-Repurposing an Old Antioxidant. Antioxidants, 12.","DOI":"10.3390\/antiox12071316"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1159\/000252972","article-title":"Cerebral amino acid profiles after hypoxia-reoxygenation and N-acetylcysteine treatment in the newborn piglet","volume":"97","author":"Jantzie","year":"2010","journal-title":"Neonatology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.earlhumdev.2019.03.006","article-title":"Postnatal N-acetylcysteine does not provide neuroprotection in extremely low birth weight infants: A follow-up of a randomized controlled trial","volume":"132","author":"Kiuru","year":"2019","journal-title":"Early Hum. Dev."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Virmani, M.A., and Cirulli, M. (2022). The Role of l-Carnitine in Mitochondria, Prevention of Metabolic Inflexibility and Disease Initiation. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052717"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1586\/14737175.2013.814930","article-title":"Acetyl-L-carnitine: From a biological curiosity to a drug for the peripheral nervous system and beyond","volume":"13","author":"Onofrj","year":"2013","journal-title":"Expert. Rev. Neurother."},{"key":"ref_91","first-page":"197","article-title":"Selenium: Implications for outcomes in extremely preterm infants","volume":"38","author":"Tindell","year":"2018","journal-title":"J. Perinatol. Off. J. Calif. Perinat. Assoc."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Zhang, F., Li, X., and Wei, Y. (2023). Selenium and Selenoproteins in Health. Biomolecules, 13.","DOI":"10.3390\/biom13050799"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Zoidis, E., Seremelis, I., Kontopoulos, N., and Danezis, G.P. (2018). Selenium-Dependent Antioxidant Enzymes: Actions and Properties of Selenoproteins. Antioxidants, 7.","DOI":"10.3390\/antiox7050066"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Bj\u00f8rklund, G., Shanaida, M., Lysiuk, R., Antonyak, H., Klishch, I., Shanaida, V., and Peana, M. (2022). Selenium: An Antioxidant with a Critical Role in Anti-Aging. Molecules, 27.","DOI":"10.3390\/molecules27196613"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.freeradbiomed.2023.11.041","article-title":"Selenite ameliorates the ATP hydrolysis of mitochondrial F1FO-ATPase by changing the redox state of thiol groups and impairs the ADP phosphorylation","volume":"210","author":"Algieri","year":"2024","journal-title":"Free Radic. Biol. Med."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Jakaria, M., Azam, S., Haque, M.E., Jo, S.H., Uddin, M.S., Kim, I.S., and Choi, D.K. (2019). Taurine and its analogs in neurological disorders: Focus on therapeutic potential and molecular mechanisms. Redox Biol., 24.","DOI":"10.1016\/j.redox.2019.101223"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Rafiee, Z., Garc\u00eda-Serrano, A.M., and Duarte, J.M.N. (2022). Taurine Supplementation as a Neuroprotective Strategy upon Brain Dysfunction in Metabolic Syndrome and Diabetes. Nutrients, 14.","DOI":"10.3390\/nu14061292"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1023\/B:NERE.0000010453.96832.97","article-title":"Content and concentration of taurine, hypotaurine, and zinc in the retina, the hippocampus, and the dentate gyrus of the rat at various postnatal days","volume":"29","author":"Lima","year":"2004","journal-title":"Neurochem. Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1111\/j.1651-2227.1999.tb01002.x","article-title":"Glycine and other neurotransmitter amino acids in cerebrospinal fluid in perinatal asphyxia and neonatal hypoxic-ischaemic encephalopathy","volume":"88","author":"Deulofeu","year":"1999","journal-title":"Acta Paediatr."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1002\/jnr.10027","article-title":"Role of taurine in regulation of intracellular calcium level and neuroprotective function in cultured neurons","volume":"66","author":"Chen","year":"2001","journal-title":"J. Neurosci. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.brainres.2005.01.058","article-title":"Mode of action of taurine as a neuroprotector","volume":"1038","author":"Wu","year":"2005","journal-title":"Brain Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1111\/j.1471-4159.2010.07051.x","article-title":"Neurochemical profile of the developing mouse cortex determined by in vivo 1H NMR spectroscopy at 14.1 T and the effect of recurrent anaesthesia","volume":"115","author":"Kulak","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1517\/21678707.2013.853614","article-title":"2-Iminobiotin for the treatment of perinatal asphyxia","volume":"1","author":"Perrone","year":"2013","journal-title":"Expert Opin. Orphan Drugs"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.ccc.2019.12.009","article-title":"Nitric Oxide and Endothelial Dysfunction","volume":"36","author":"Cyr","year":"2020","journal-title":"Crit. Care Clin."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1006\/bbrc.1994.2554","article-title":"2-Iminobiotin is an inhibitor of nitric oxide synthases","volume":"204","author":"Sup","year":"1994","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.4236\/abb.2012.327127","article-title":"Oxidative stress and free radicals related diseases of the newborn","volume":"3","author":"Perrone","year":"2012","journal-title":"Adv. Biosci. Biotechnol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.niox.2010.06.001","article-title":"Nitric oxide and neuronal death","volume":"23","author":"Brown","year":"2010","journal-title":"Nitric Oxide"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/S0891-5849(98)00092-6","article-title":"Chemical biology of nitric oxide: Insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide","volume":"25","author":"Wink","year":"1998","journal-title":"Free Radic. Biol. Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1111\/j.1471-4159.2004.02500.x","article-title":"Nitrosylation precedes caspase-3 activation and translocation of apoptosis-inducing factor in neonatal rat cerebral hypoxia-ischaemia","volume":"90","author":"Zhu","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/s41390-019-0587-1","article-title":"Pharmacokinetics and short-term safety of the selective NOS inhibitor 2-iminobiotin in asphyxiated neonates treated with therapeutic hypothermia","volume":"87","author":"Bakker","year":"2020","journal-title":"Pediatr. Res."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Fernandes, L.F., Bruch, G.E., Massensini, A.R., and Fr\u00e9zard, F. (2018). Recent Advances in the Therapeutic and Diagnostic Use of Liposomes and Carbon Nanomaterials in Ischemic Stroke. Front. Neurosci., 12.","DOI":"10.3389\/fnins.2018.00453"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Lin, Y.A., Kim, S.Y., Su, L., Liu, J., Kannan, R.M., and Kannan, S. (2020). Systemic dendrimer-drug nanomedicines for long-term treatment of mild-moderate cerebral palsy in a rabbit model. J. Neuroinflamm., 17.","DOI":"10.1186\/s12974-020-01984-1"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/11\/818\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:44:48Z","timestamp":1760031888000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/11\/818"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,31]]},"references-count":112,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["cells14110818"],"URL":"https:\/\/doi.org\/10.3390\/cells14110818","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,31]]}}}