{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T01:50:36Z","timestamp":1783734636030,"version":"3.55.0"},"reference-count":129,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T00:00:00Z","timestamp":1715904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["1R01NS117428-01A1"],"award-info":[{"award-number":["1R01NS117428-01A1"]}]},{"name":"NIH","award":["ANR-21-CE17-0019-01"],"award-info":[{"award-number":["ANR-21-CE17-0019-01"]}]},{"name":"ANR","award":["1R01NS117428-01A1"],"award-info":[{"award-number":["1R01NS117428-01A1"]}]},{"name":"ANR","award":["ANR-21-CE17-0019-01"],"award-info":[{"award-number":["ANR-21-CE17-0019-01"]}]},{"name":"Biorender","award":["1R01NS117428-01A1"],"award-info":[{"award-number":["1R01NS117428-01A1"]}]},{"name":"Biorender","award":["ANR-21-CE17-0019-01"],"award-info":[{"award-number":["ANR-21-CE17-0019-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hypoxic-ischemic encephalopathy (HIE) is a major cause of newborn brain damage stemming from a lack of oxygenated blood flow in the neonatal period. Twenty-five to fifty percent of asphyxiated infants who develop HIE die in the neonatal period, and about sixty percent of survivors develop long-term neurological disabilities. From the first minutes to months after the injury, a cascade of events occurs, leading to blood-brain barrier (BBB) opening, neuronal death and inflammation. To date, the only approach proposed in some cases is therapeutic hypothermia (TH). Unfortunately, TH is only partially protective and is not applicable to all neonates. This review synthesizes current knowledge on the basic molecular mechanisms of brain damage in hypoxia-ischemia (HI) and on the different therapeutic strategies in HI that have been used and explores a major limitation of unsuccessful therapeutic approaches.<\/jats:p>","DOI":"10.3390\/ijms25105449","type":"journal-article","created":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T04:26:29Z","timestamp":1715919989000},"page":"5449","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Targeting the Multiple Complex Processes of Hypoxia-Ischemia to Achieve Neuroprotection"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2442-7601","authenticated-orcid":false,"given":"Auriane","family":"Ma\u00efza","sequence":"first","affiliation":[{"name":"CEA, DMTS, SPI, Neurovascular Unit Research & Therapeutic Innovation Laboratory, Paris-Saclay University, CEDEX 91191 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1402-0868","authenticated-orcid":false,"given":"Rifat","family":"Hamoudi","sequence":"additional","affiliation":[{"name":"Center of Excellence of Precision Medicine, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Division of Surgery and Interventional Science, University College London, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0627-8949","authenticated-orcid":false,"given":"Alo\u00efse","family":"Mabondzo","sequence":"additional","affiliation":[{"name":"CEA, DMTS, SPI, Neurovascular Unit Research & Therapeutic Innovation Laboratory, Paris-Saclay University, CEDEX 91191 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1001\/jamapediatrics.2014.3269","article-title":"Hypoxic-ischemic encephalopathy: A review for the clinician","volume":"169","author":"Weiss","year":"2015","journal-title":"JAMA Pediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/s41372-019-0531-6","article-title":"Antenatal and intrapartum risk factors for neonatal hypoxic ischemic encephalopathy","volume":"40","author":"Peebles","year":"2020","journal-title":"J. Perinatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1186\/s12884-020-02876-1","article-title":"Is perinatal asphyxia predictable?","volume":"20","author":"Locatelli","year":"2020","journal-title":"BMC Pregnancy Childbirth"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/B978-0-444-64029-1.00015-1","article-title":"Neuroprotection of the preterm brain","volume":"162","author":"Fleiss","year":"2019","journal-title":"Handb. Clin. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/j.clp.2009.07.011","article-title":"Hypoxic-Ischemic Encephalopathy in the Term Infant","volume":"36","author":"Fatemi","year":"2009","journal-title":"Clin. Perinatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1080\/02699050802403565","article-title":"Working memory performance following paediatric traumatic brain injury","volume":"22","author":"Conklin","year":"2008","journal-title":"Brain Inj."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1542\/peds.2014-1566","article-title":"Cognitive Outcomes After Neonatal Encephalopathy","volume":"135","author":"Pappas","year":"2015","journal-title":"Pediatrics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1111\/dmcn.13215","article-title":"Seizure burden and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy","volume":"58","author":"Kharoshankaya","year":"2016","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3364","DOI":"10.1161\/STROKEAHA.112.674481","article-title":"Immediate Hypothermia Is Not Neuroprotective After Severe Hypoxia-Ischemia and Is Deleterious When Delayed by 12 Hours in Neonatal Rats","volume":"43","author":"Sabir","year":"2012","journal-title":"Stroke"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1056\/NEJMoa1112066","article-title":"Childhood outcomes after hypothermia for neonatal encephalopathy","volume":"366","author":"Shankaran","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/S0140-6736(05)71048-5","article-title":"4 million neonatal deaths: When? Where? Why?","volume":"365","author":"Lawn","year":"2005","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.pediatrneurol.2020.08.014","article-title":"Sarnat Grading Scale for Neonatal Encephalopathy after 45 Years: An Update Proposal","volume":"113","author":"Sarnat","year":"2020","journal-title":"Pediatr. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1542\/peds.100.6.1004","article-title":"Interventions for perinatal hypoxic-ischemic encephalopathy","volume":"100","author":"Vannucci","year":"1997","journal-title":"Pediatrics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"78","DOI":"10.3389\/fncel.2017.00078","article-title":"Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges","volume":"11","author":"Millar","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.clp.2021.05.014","article-title":"The Term Newborn: Evaluation for Hypoxic-Ischemic Encephalopathy","volume":"48","author":"Bonifacio","year":"2021","journal-title":"Clin. Perinatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.jped.2015.07.004","article-title":"Hypothermia therapy for newborns with hypoxic ischemic encephalopathy","volume":"91","author":"Silveira","year":"2015","journal-title":"J. Pediatr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s11910-019-0916-0","article-title":"Therapeutic Hypothermia in Neonatal Hypoxic-Ischemic Encephalopathy","volume":"19","author":"Wassink","year":"2019","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_18","first-page":"398","article-title":"Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy","volume":"97","author":"Shankaran","year":"2012","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1055\/s-0042-1755235","article-title":"Neonatal Hypoxic-Ischemic Encephalopathy: Perspectives of Neuroprotective and Neuroregenerative Treatments","volume":"53","author":"Quintanar","year":"2022","journal-title":"Neuropediatrics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1136\/archdischild-2015-309639","article-title":"Management and investigation of neonatal encephalopathy: 2017 update","volume":"102","author":"Martinello","year":"2017","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_21","first-page":"4901014","article-title":"Plasticity in the Neonatal Brain following Hypoxic-Ischaemic Injury","volume":"2016","author":"Hristova","year":"2016","journal-title":"Neural Plast."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3149","DOI":"10.1242\/jeb.01064","article-title":"Hypoxia-ischemia in the immature brain","volume":"207","author":"Vannucci","year":"2004","journal-title":"J. Exp. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e76451","DOI":"10.7554\/eLife.76451","article-title":"Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia","volume":"11","author":"Kennedy","year":"2022","journal-title":"Elife"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/0166-2236(88)90200-7","article-title":"Calcium-mediated neurotoxicity: Relationship to specific channel types and role in ischemic damage","volume":"11","author":"Choi","year":"1988","journal-title":"Trends Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.clp.2013.10.005","article-title":"Mechanisms of hypothermic neuroprotection","volume":"41","author":"Drury","year":"2014","journal-title":"Clin. Perinatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"22368","DOI":"10.3390\/ijms160922368","article-title":"Neuroprotective Strategies after Neonatal Hypoxic Ischemic Encephalopathy","volume":"16","author":"Dixon","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1203\/01.PDR.0000144819.45689.BB","article-title":"Neonatal encephalopathy: Association of cytokines with MR spectroscopy and outcome","volume":"56","author":"Bartha","year":"2004","journal-title":"Pediatr. Res."},{"key":"ref_28","first-page":"144","article-title":"Neuroinflammation and neuroimmune dysregulation after acute hypoxic-ischemic injury of developing brain","volume":"2","author":"Bhalala","year":"2014","journal-title":"Front. Pediatr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/nrneurol.2015.13","article-title":"The role of inflammation in perinatal brain injury","volume":"11","author":"Hagberg","year":"2015","journal-title":"Nat. Rev. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1038\/aps.2013.89","article-title":"Inflammatory responses in hypoxic ischemic encephalopathy","volume":"34","author":"Liu","year":"2013","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/jcbfm.2013.3","article-title":"The endogenous regenerative capacity of the damaged newborn brain: Boosting neurogenesis with mesenchymal stem cell treatment","volume":"33","author":"Donega","year":"2013","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.neubiorev.2014.01.004","article-title":"Inflammation and the developing brain: Consequences for hippocampal neurogenesis and behavior","volume":"40","author":"Green","year":"2014","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1002\/ana.22620","article-title":"Inflammation during fetal and neonatal life: Implications for neurologic and neuropsychiatric disease in children and adults","volume":"71","author":"Hagberg","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1002\/jnr.24590","article-title":"Hypoxic-ischemic-related cerebrovascular changes and potential therapeutic strategies in the neonatal brain","volume":"98","author":"Disdier","year":"2020","journal-title":"J. Neurosci. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.nbd.2009.07.030","article-title":"Structure and function of the blood-brain barrier","volume":"37","author":"Abbott","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1002\/cne.20885","article-title":"Functional effectiveness of the blood brain barrier to small water-soluble molecules in developing and adult opossum (Monodelphis domestica)","volume":"496","author":"Ek","year":"2006","journal-title":"J. Comp. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.neuro.2011.12.009","article-title":"Barriers in the developing brain and Neurotoxicology","volume":"33","author":"Ek","year":"2012","journal-title":"Neurotoxicology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3389\/fnins.2015.00040","article-title":"Blood-brain barrier dysfunction in disorders of the developing brain","volume":"9","author":"Moretti","year":"2015","journal-title":"Front. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Jithoo, A., Penny, T.R., Pham, Y., Sutherland, A.E., Smith, M.J., Petraki, M., Fahey, M.C., Jenkin, G., Malhotra, A., and Miller, S.L. (2024). The Temporal Relationship between Blood-Brain Barrier Integrity and Microglial Response following Neonatal Hypoxia Ischemia. Cells, 13.","DOI":"10.3390\/cells13080660"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.neuroscience.2012.08.043","article-title":"Ischemia-reperfusion impairs blood-brain barrier fucntion and alters tight junction protein expression in the ovine fetus","volume":"226","author":"Chen","year":"2012","journal-title":"Neuroscience"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.nbd.2014.09.007","article-title":"Neutralizing anti-interleuldn-1 beta antibodies modulate fetal blood-brain barrier function after ischemia","volume":"73","author":"Chen","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.expneurol.2014.12.020","article-title":"G-CSF attenuates neuroinflammation and stabilizes the blood-brain barrier via the PI3K\/Akt\/GSK-3 beta signaling pathway following neonatal hypoxia-ischemia in rats","volume":"272","author":"Li","year":"2015","journal-title":"Exp. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1038\/jcbfm.2014.255","article-title":"Brain barrier properties and cerebral blood flow in neonatal mice exposed to cerebral hypoxia-ischemia","volume":"35","author":"Ek","year":"2015","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1016\/j.neuroscience.2008.08.028","article-title":"Inflammation and the neurovascular unit in the setting of focal cerebral ischemia","volume":"158","year":"2009","journal-title":"Neuroscience"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1203\/01.PDR.0000081297.53793.C6","article-title":"Effects of allopurinol and deferoxamine on reperfusion injury of the brain in newborn piglets after neonatal hypoxia-ischemia","volume":"54","author":"Braun","year":"2003","journal-title":"Pediatr. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1203\/00006450-199705000-00002","article-title":"The role of neutrophils in the production of hypoxic-ischemic brain injury in the neonatal rat","volume":"41","author":"Hudome","year":"1997","journal-title":"Pediatr. Res."},{"key":"ref_47","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_48","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1177\/1933719113493516","article-title":"Antenatal allopurinol reduces hippocampal brain damage after acute birth asphyxia in late gestation fetal sheep","volume":"21","author":"Kaandorp","year":"2014","journal-title":"Reprod. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1136\/adc.2005.086652","article-title":"Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia","volume":"91","author":"Benders","year":"2006","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"247","DOI":"10.3389\/fneur.2018.00247","article-title":"Fetal Neuroprotection by Magnesium Sulfate: From Translational Research to Clinical Application","volume":"9","author":"Chollat","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1177\/1933719107305864","article-title":"Neuroprotective effect of long-term MgSO4 administration after cerebral hypoxia-ischemia in newborn rats is related to the severity of brain damage","volume":"14","author":"Spandou","year":"2007","journal-title":"Reprod. Sci."},{"key":"ref_52","first-page":"e16826","article-title":"The Neuroprotective Efficacy of Postnatal Magnesium Sulfate in Term or Near-Term Infants with Moderate-to-Severe Birth Asphyxia","volume":"13","author":"Iqbal","year":"2021","journal-title":"Cureus"},{"key":"ref_53","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_54","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_55","doi-asserted-by":"crossref","first-page":"71","DOI":"10.2174\/156720208783565645","article-title":"Blood brain barrier in hypoxic-ischemic conditions","volume":"5","author":"Kaur","year":"2008","journal-title":"Curr. Neurovasc. Res."},{"key":"ref_56","first-page":"1233","article-title":"Role of melatonin in management of hypoxic ischaemic encephalopathy in newborns: A randomized control trial","volume":"68","author":"Ahmad","year":"2018","journal-title":"J. Pak. Med. Assoc."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"125","DOI":"10.2174\/156720208784310231","article-title":"Erythropoietin and oxidative stress","volume":"5","author":"Maiese","year":"2008","journal-title":"Curr. Neurovasc. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"153","DOI":"10.4161\/21623945.2014.978654","article-title":"Erythropoietin and obesity-induced white adipose tissue inflammation: Redefining the boundaries of the immunometabolism territory","volume":"4","author":"Alnaeeli","year":"2015","journal-title":"Adipocyte"},{"key":"ref_59","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_60","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.braindev.2010.10.014","article-title":"Erythropoietin in neonatal brain protection: The past, the present and the future","volume":"33","author":"Kumral","year":"2011","journal-title":"Brain Dev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/35088074","article-title":"Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades","volume":"412","author":"Digicaylioglu","year":"2001","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0304-3940(00)01361-6","article-title":"Erythropoietin protects cultured cortical neurons, but not astroglia, from hypoxia and AMPA toxicity","volume":"290","author":"Sinor","year":"2000","journal-title":"Neurosci. Lett."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"218","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_64","doi-asserted-by":"crossref","unstructured":"Oorschot, D.E., Sizemore, R.J., and Amer, A.R. (2020). Treatment of Neonatal Hypoxic-Ischemic Encephalopathy with Erythropoietin Alone, and Erythropoietin Combined with Hypothermia: History, Current Status, and Future Research. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041487"},{"key":"ref_65","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_66","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1111\/j.1399-6576.2009.02177.x","article-title":"Dexmedetomidine provides cortical neuroprotection: Impact on anaesthetic-induced neuroapoptosis in the rat developing brain","volume":"54","author":"Sanders","year":"2010","journal-title":"Acta Anaesthesiol. Scand."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1093\/abbs\/gmab092","article-title":"Dexmedetomidine maintains blood-brain barrier integrity by inhibiting Drp1-related endothelial mitochondrial dysfunction in ischemic stroke","volume":"53","author":"Zhou","year":"2021","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"770511","DOI":"10.3389\/fpain.2021.770511","article-title":"Dexmedetomidine Use in Infants Undergoing Cooling Due to Neonatal Encephalopathy (DICE Trial): A Randomized Controlled Trial: Background, Aims and Study Protocol","volume":"2","author":"Baserga","year":"2021","journal-title":"Front. Pain Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.expneurol.2004.01.025","article-title":"Therapeutic doses of topiramate are not toxic to the developing rat brain","volume":"187","author":"Glier","year":"2004","journal-title":"Exp. Neurol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/1471-2431-12-144","article-title":"Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI)","volume":"12","author":"Filippi","year":"2012","journal-title":"BMC Pediatr."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1097\/00000542-199706000-00007","article-title":"Xenon provides faster emergence from anesthesia than does nitrous oxide-sevoflurane or nitrous oxide-isoflurane","volume":"86","author":"Goto","year":"1997","journal-title":"Anesthesiology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1093\/bja\/aei080","article-title":"Xenon reduces glutamate-, AMPA-, and kainate-induced membrane currents in cortical neurones","volume":"94","author":"Dinse","year":"2005","journal-title":"Br. J. Anaesth."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1161\/01.STR.0000198867.31134.ac","article-title":"Xenon provides short-term neuroprotection in neonatal rats when administered after hypoxia-ischemia","volume":"37","author":"Dingley","year":"2006","journal-title":"Stroke"},{"key":"ref_74","first-page":"ePAS20111660-7","article-title":"First human use of 50% xenon inhalation during hypothermia for neonatal hypoxic ischemic encephalopathy: The \u201cCoolxenon\u201d Feasibility Study","volume":"2011","author":"Thoresen","year":"2011","journal-title":"Pediatr. Acad. Soc."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/jnr.10403","article-title":"Citicoline mechanisms and clinical efficacy in cerebral ischemia","volume":"70","author":"Adibhatla","year":"2002","journal-title":"J. Neurosci. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1385\/JMN:20:1:53","article-title":"CDP-choline prevents glutamate-mediated cell death in cerebellar granule neurons","volume":"20","author":"Mir","year":"2003","journal-title":"J. Mol. Neurosci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"448","DOI":"10.3171\/jns.2000.92.3.0448","article-title":"Neuroprotective effects of citicoline on brain edema and blood-brain barrier breakdown after traumatic brain injury","volume":"92","author":"Rao","year":"2000","journal-title":"J. Neurosurg."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.29271\/jcpsp.2021.12.1511","article-title":"Role of Citicoline in Treatment of Moderate to Severe Birth Asphyxia: A Pilot Project","volume":"31","author":"Khushdil","year":"2021","journal-title":"J. Coll. Physicians Surg. Pak."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.neuroscience.2014.01.018","article-title":"Effects of intravenous administration of umbilical cord blood CD34(+) cells in a mouse model of neonatal stroke","volume":"263","author":"Tsuji","year":"2014","journal-title":"Neuroscience"},{"key":"ref_80","first-page":"147","article-title":"Stem cell therapy for neonatal hypoxic-ischemic encephalopathy","volume":"5","author":"Reyes","year":"2014","journal-title":"Front. Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Serrenho, I., Rosado, M., Dinis, A., Cardoso, M.C., Gr\u00e3os, M., Manadas, B., and Baltazar, G. (2021). Stem Cell Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Systematic Review of Preclinical Studies. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063142"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/pr.2017.260","article-title":"Future perspectives of cell therapy for neonatal hypoxic-ischemic encephalopathy","volume":"83","author":"Nabetani","year":"2018","journal-title":"Pediatr. Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4080","DOI":"10.1073\/pnas.94.8.4080","article-title":"Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice","volume":"94","author":"Eglitis","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1159\/000368396","article-title":"Administration of umbilical cord blood cells transiently decreased hypoxic-ischemic brain injury in neonatal rats","volume":"37","author":"Hattori","year":"2015","journal-title":"Dev. Neurosci."},{"key":"ref_85","unstructured":"Emira, S. (2014). Cerebral Palsy, IntechOpen. Chapter 5."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"27","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_87","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.siny.2007.04.001","article-title":"Antenatal magnesium sulphate neuroprotection in the preterm infant","volume":"12","author":"Marret","year":"2007","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1038\/jcbfm.2014.253","article-title":"Therapeutic hypothermia achieves neuroprotection via a decrease in acetylcholine with a concurrent increase in carnitine in the neonatal hypoxia-ischemia","volume":"35","author":"Takenouchi","year":"2015","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1080\/1071576021000038504","article-title":"Melatonin, longevity and health in the aged: An assessment","volume":"36","author":"Reiter","year":"2002","journal-title":"Free Radic. Res."},{"key":"ref_90","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_91","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1111\/jog.13568","article-title":"Pretreatment with magnesium sulfate attenuates white matter damage by preventing cell death of developing oligodendrocytes","volume":"44","author":"Seyama","year":"2018","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1084\/jem.20021067","article-title":"Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis","volume":"198","author":"Villa","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Yamaguchi, M., Okamoto, K., Kusano, T., Matsuda, Y., Suzuki, G., Fuse, A., and Yokota, H. (2015). The Effects of Xanthine Oxidoreductase Inhibitors on Oxidative Stress Markers following Global Brain Ischemia Reperfusion Injury in C57BL\/6 Mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0133980"},{"key":"ref_94","first-page":"16","article-title":"Magnesium and the blood-brain barrier in vitro: Effects on permeability and magnesium transport","volume":"32","author":"Romeo","year":"2019","journal-title":"Magnes. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.expneurol.2006.04.038","article-title":"Neuroprotective effect of topiramate on hypoxic ischemic brain injury in neonatal rats","volume":"201","author":"Noh","year":"2006","journal-title":"Exp. Neurol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1093\/jnen\/61.7.605","article-title":"Cerebral vasculature is the major target of oxidative protein alterations in bacterial meningitis","volume":"61","author":"Schaper","year":"2002","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/pr.2011.59","article-title":"Umbilical cord blood mononuclear cell transplantation for neonatal hypoxic-ischemic encephalopathy","volume":"71","year":"2012","journal-title":"Pediatr. Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1161\/STROKEAHA.112.654806","article-title":"Citicoline enhances neuroregenerative processes after experimental stroke in rats","volume":"43","author":"Diederich","year":"2012","journal-title":"Stroke"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/24525","article-title":"How does xenon produce anaesthesia?","volume":"396","author":"Franks","year":"1998","journal-title":"Nature"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1097\/01.anes.0000264762.48920.80","article-title":"Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain","volume":"106","author":"Ma","year":"2007","journal-title":"Anesthesiology"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1016\/j.neuropharm.2004.02.010","article-title":"Topiramate selectively protects against seizures induced by ATPA, a GluR5 kainate receptor agonist","volume":"46","author":"Kaminski","year":"2004","journal-title":"Neuropharmacology"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0304-3940(97)00543-0","article-title":"Topiramate attenuates voltage-gated sodium currents in rat cerebellar granule cells","volume":"231","author":"Zona","year":"1997","journal-title":"Neurosci. Lett."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/j.1528-1157.2000.tb02169.x","article-title":"Topiramate as an inhibitor of carbonic anhydrase isoenzymes","volume":"41","author":"Dodgson","year":"2000","journal-title":"Epilepsia"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1111\/j.0013-9580.2004.13504.x","article-title":"The mechanism of neuroprotection by topiramate in an animal model of epilepsy","volume":"45","author":"Kudin","year":"2004","journal-title":"Epilepsia"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"109","DOI":"10.4161\/cbt.9.2.10583","article-title":"N-acetylcysteine, reactive oxygen species and beyond","volume":"9","author":"Sun","year":"2010","journal-title":"Cancer Biol. Ther."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.pharmthera.2013.09.006","article-title":"Existing and potential therapeutic uses for N-acetylcysteine: The need for conversion to intracellular glutathione for antioxidant benefits","volume":"141","author":"Rushworth","year":"2014","journal-title":"Pharmacol. Ther."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1006\/niox.2001.0356","article-title":"N-acetylcysteine inhibits in vivo nitric oxide production by inducible nitric oxide synthase","volume":"5","author":"Bergamini","year":"2001","journal-title":"Nitric Oxide"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.bbi.2009.10.017","article-title":"Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration","volume":"24","author":"Kavelaars","year":"2010","journal-title":"Brain Behav. Immun."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2939","DOI":"10.1002\/mrm.28646","article-title":"Measuring (129) Xe transfer across the blood-brain barrier using MR spectroscopy","volume":"85","author":"Rao","year":"2021","journal-title":"Magn. Reson. Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"3626","DOI":"10.1007\/s12325-023-02586-y","article-title":"Narrative Review of Topiramate: Clinical Uses and Pharmacological Considerations","volume":"40","author":"Pearl","year":"2023","journal-title":"Adv. Ther."},{"key":"ref_111","first-page":"1","article-title":"Citicoline: Pharmacological and clinical review, 2006 update","volume":"28","author":"Secades","year":"2006","journal-title":"Methods Find. Exp. Clin. Pharmacol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1203\/00006450-199903000-00005","article-title":"Possible protective role of growth hormone in hypoxia-ischemia in neonatal rats","volume":"45","author":"Gustafson","year":"1999","journal-title":"Pediatr. Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"bqab008","DOI":"10.1210\/endocr\/bqab008","article-title":"Recombinant Human Growth Hormone Activates Neuroprotective Growth Factors in Hypoxic Brain Injury in Neonatal Mice","volume":"162","author":"Jung","year":"2021","journal-title":"Endocrinology"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1179\/174313208X338133","article-title":"Delayed IGF-1 treatment reduced long-term hypoxia-ischemia-induced brain damage and improved behavior recovery of immature rats","volume":"31","author":"Zhong","year":"2009","journal-title":"Neurol. Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.pneurobio.2003.08.002","article-title":"Insulin-like growth factor-1 and post-ischemic brain injury","volume":"70","author":"Guan","year":"2003","journal-title":"Prog. Neurobiol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"7629","DOI":"10.1523\/JNEUROSCI.14-12-07629.1994","article-title":"Cell death of spinal motoneurons in the chick embryo following deafferentation: Rescue effects of tissue extracts, soluble proteins, and neurotrophic agents","volume":"14","author":"Yin","year":"1994","journal-title":"J. Neurosci."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"9833","DOI":"10.1073\/pnas.0400337101","article-title":"Insulin-like growth factor I is required for vessel remodeling in the adult brain","volume":"101","author":"LeRoith","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1159\/000054584","article-title":"Interactions of IGF-1 with the blood-brain barrier in vivo and in situ","volume":"72","author":"Pan","year":"2000","journal-title":"Neuroendocrinology"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1172\/JCI118416","article-title":"Insulin-like growth factor-1 is a potent neuronal rescue agent after hypoxic-ischemic injury in fetal lambs","volume":"97","author":"Johnston","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/nrn3379","article-title":"Neurotrophin regulation of neural circuit development and function","volume":"14","author":"Park","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Colucci-D\u2019Amato, L., Speranza, L., and Volpicelli, F. (2020). Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21207777"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.4103\/1673-5374.303033","article-title":"Brain-derived neurotrophic factor and its related enzymes and receptors play important roles after hypoxic-ischemic brain damage","volume":"16","author":"Xiong","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1002\/ana.410410416","article-title":"Marked age-dependent neuroprotection by brain-derived neurotrophic factor against neonatal hypoxic-ischemic brain injury","volume":"41","author":"Cheng","year":"1997","journal-title":"Ann. Neurol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/S0306-4522(03)00066-6","article-title":"Continuous low-dose treatment with brain-derived neurotrophic factor or neurotrophin-3 protects striatal medium spiny neurons from mild neonatal hypoxia\/ischemia: A stereological study","volume":"118","author":"Galvin","year":"2003","journal-title":"Neuroscience"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1006\/exnr.1998.6836","article-title":"Co-infusion with a TrkB-Fc receptor body carrier enhances BDNF distribution in the adult rat brain","volume":"152","author":"Croll","year":"1998","journal-title":"Exp. Neurol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/BF02740746","article-title":"Neurotrophin-3 as an essential signal for the developing nervous system","volume":"12","author":"Chalazonitis","year":"1996","journal-title":"Mol. Neurobiol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1016\/j.neuroimage.2003.11.025","article-title":"Resting fluctuations in arterial carbon dioxide induce significant low frequency variations in BOLD signal","volume":"21","author":"Wise","year":"2004","journal-title":"Neuroimage"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/nature07525","article-title":"Brain metabolism dictates the polarity of astrocyte control over arterioles","volume":"456","author":"Gordon","year":"2008","journal-title":"Nature"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"8940","DOI":"10.1523\/JNEUROSCI.3065-04.2004","article-title":"Cortical GABA interneurons in neurovascular coupling: Relays for subcortical vasoactive pathways","volume":"24","author":"Cauli","year":"2004","journal-title":"J. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/10\/5449\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:43:44Z","timestamp":1760107424000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/10\/5449"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,17]]},"references-count":129,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["ijms25105449"],"URL":"https:\/\/doi.org\/10.3390\/ijms25105449","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,17]]}}}