{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T05:31:03Z","timestamp":1764221463098,"version":"3.46.0"},"reference-count":45,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NRDI, National Laboratory of Translational Neuroscience","award":["RRF-2.3.1-21-2022-00011"],"award-info":[{"award-number":["RRF-2.3.1-21-2022-00011"]}]},{"DOI":"10.13039\/501100003549","name":"OTKA","doi-asserted-by":"publisher","award":["K139389","PD138454"],"award-info":[{"award-number":["K139389","PD138454"]}],"id":[{"id":"10.13039\/501100003549","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Neonatal hypoxic\u2013ischemic encephalopathy (HIE) remains a major cause of neonatal mortality and long-term disability, despite therapeutic hypothermia (TH) treatment, underscoring the need for further preclinical research. In the present study, we compared the neuroprotection afforded by TH and inhaled molecular hydrogen (H2) treatment in a translational newborn pig HIE model. Following 20 min of asphyxia induced by a hypoxic\/hypercapnic gas mixture, piglets were reoxygenated and monitored for 48 h. Animals were randomly assigned to normothermia, continuous H2 ventilation (2.1%), or TH (33.5 \u00b0C for 37 h followed by slow rewarming) groups. Physiological parameters, electroencephalography (EEG), visual evoked potentials (VEPs), and neuropathology were assessed. TH eliminated post-asphyxia seizures and improved VEP latency, while H2 delayed seizure onset and increased quantitative EEG markers of signal complexity. Neuropathology revealed severe thalamic injury in normothermic controls, which was significantly attenuated by both H2 and TH, while neocortical, hippocampal, and basal ganglia injury was less extensive and not significantly altered by either of the neuroprotective interventions. These findings demonstrate that continuous H2 inhalation provides neuroprotection in HIE comparable to TH, particularly in the thalamus. H2 also exerts distinct electrophysiological effects, suggesting its therapeutic potential as a treatment for neonatal HIE.<\/jats:p>","DOI":"10.3390\/antiox14121405","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T16:31:54Z","timestamp":1764088314000},"page":"1405","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Hydrogen Affords Similar Neuroprotection to Therapeutic Hypothermia in a Porcine Model of Neonatal Hypoxic\u2013Ischemic Encephalopathy"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4703-7658","authenticated-orcid":false,"given":"Emma","family":"Balog","sequence":"first","affiliation":[{"name":"Department of Physiology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"},{"name":"Centre of Excellence for Interdisciplinary Research, Development and Innovation of the University of Szeged (IKIKK), 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3448-3835","authenticated-orcid":false,"given":"G\u00e1bor","family":"Remzs\u0151","sequence":"additional","affiliation":[{"name":"Department of Physiology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2418-4214","authenticated-orcid":false,"given":"Val\u00e9ria","family":"T\u00f3th-Sz\u0171ki","sequence":"additional","affiliation":[{"name":"Department of Physiology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8468-3483","authenticated-orcid":false,"given":"\u00c9va","family":"R\u00f3zsa","sequence":"additional","affiliation":[{"name":"Department of Physiology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"},{"name":"Centre of Excellence for Interdisciplinary Research, Development and Innovation of the University of Szeged (IKIKK), 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7474-7148","authenticated-orcid":false,"given":"Vikt\u00f3ria","family":"Kov\u00e1cs","sequence":"additional","affiliation":[{"name":"Department of Physiology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5581-2167","authenticated-orcid":false,"given":"Ferenc","family":"Domoki","sequence":"additional","affiliation":[{"name":"Department of Physiology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.earlhumdev.2010.05.010","article-title":"Epidemiology of Neonatal Encephalopathy and Hypoxic-Ischaemic Encephalopathy","volume":"86","author":"Kurinczuk","year":"2010","journal-title":"Early Hum. Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1053\/j.nainr.2011.07.004","article-title":"Hypoxic Ischemic Encephalopathy: Pathophysiology and Experimental Treatments","volume":"11","author":"Allen","year":"2011","journal-title":"Newborn Infant Nurs. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1159\/000320332","article-title":"Reducing Global Neonatal Mortality Is Possible","volume":"99","author":"Saugstad","year":"2011","journal-title":"Neonatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1177\/08830738020170111101","article-title":"Cerebrospinal Fluid Levels of Nitric Oxide and Nitrotyrosine in Neonates with Mild Hypoxic-Ischemic Encephalopathy","volume":"17","author":"Ergenekon","year":"2002","journal-title":"J. Child Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S1474-4422(09)70295-9","article-title":"Assessment of Brain Tissue Injury after Moderate Hypothermia in Neonates with Hypoxic-Ischaemic Encephalopathy: A Nested Substudy of a Randomised Controlled Trial","volume":"9","author":"Rutherford","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Jia, W., Lei, X., Dong, W., and Li, Q. (2018). Benefits of Starting Hypothermia Treatment within 6 h vs. 6\u201312 h in Newborns with Moderate Neonatal Hypoxic-Ischemic Encephalopathy. BMC Pediatr., 18.","DOI":"10.1186\/s12887-018-1013-2"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1001\/archpediatrics.2011.1772","article-title":"Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy: An Updated Systematic Review and Meta-Analysis","volume":"166","author":"Tagin","year":"2012","journal-title":"Arch. Pediatr. Adolesc. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1007\/s12035-024-04398-9","article-title":"Hypoxic-Ischemic Encephalopathy: Pathogenesis and Promising Therapies","volume":"62","author":"Yang","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_9","first-page":"677","article-title":"Molecular Hydrogen Affords Neuroprotection in a Translational Piglet Model of Hypoxic-Ischemic Encephalopathy","volume":"67","author":"Nemeth","year":"2016","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1159\/000348445","article-title":"Delayed Neurovascular Dysfunction Is Alleviated by Hydrogen in Asphyxiated Newborn Pigs","volume":"104","author":"Bari","year":"2013","journal-title":"Neonatology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1038\/s41390-024-03041-6","article-title":"Hydrogen Gas Can Ameliorate Seizure Burden during Therapeutic Hypothermia in Asphyxiated Newborn Piglets","volume":"95","author":"Tsuchiya","year":"2024","journal-title":"Pediatr. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.neulet.2008.05.077","article-title":"Hydrogen Therapy Reduces Apoptosis in Neonatal Hypoxia-Ischemia Rat Model","volume":"441","author":"Cai","year":"2008","journal-title":"Neurosci. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1038\/s41390-025-04046-5","article-title":"Sex Dimorphism in Brain Cell Death after Hypoxia-Ischemia in Newborn Piglets","volume":"98","author":"Chillida","year":"2025","journal-title":"Pediatr. Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kov\u00e1cs, V., Remzs\u0151, G., T\u00f3th-Sz\u0171ki, V., Varga, V., N\u00e9meth, J., and Domoki, F. (2020). Inhaled H2 or CO2 Do Not Augment the Neuroprotective Effect of Therapeutic Hypothermia in a Severe Neonatal Hypoxic-Ischemic Encephalopathy Piglet Model. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186801"},{"key":"ref_15","first-page":"387","article-title":"Hydrogen Is Neuroprotective and Preserves Cerebrovascular Reactivity in Asphyxiated Newborn Pigs","volume":"68","author":"Domoki","year":"2010","journal-title":"Pediatr. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/jon.13052","article-title":"Brain Injury Patterns in Hypoxic Ischemic Encephalopathy of Term Neonates","volume":"33","author":"Bobba","year":"2023","journal-title":"J. Neuroimaging"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Htun, Y., Nakamura, S., Nakao, Y., Mitsuie, T., Nakamura, M., Yamato, S., Jinnai, W., Koyano, K., Ohta, K., and Morimoto, A. (2019). Hydrogen Ventilation Combined with Mild Hypothermia Improves Short-Term Neurological Outcomes in a 5-Day Neonatal Hypoxia-Ischaemia Piglet Model. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-40674-8"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Nakamura, S., Nakao, Y., Htun, Y., Mitsuie, T., Koyano, K., Morimoto, A., Konishi, Y., Arioka, M., Kondo, S., and Kato, I. (2023). Impact of Hydrogen Gas Inhalation during Therapeutic Hypothermia on Cerebral Hemodynamics and Oxygenation in the Asphyxiated Piglet. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-28274-z"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Inoue, E., Nakamura, S., Sugiyama, Y., Tsuchiya, T., Nakao, Y., Mitsuie, T., Yokota, T., Sakamoto, K., Inoue, K., and Htun, Y. (2025). Six Hours of Hydrogen Gas Inhalation Has a Neuroprotective Effect Even in Piglets with Delayed Functional Recovery. Dev. Neurosci., 1\u201311.","DOI":"10.1159\/000546831"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1038\/aps.2017.148","article-title":"Molecular Hydrogen Alleviates Asphyxia-Induced Neuronal Cyclooxygenase-2 Expression in Newborn Pigs","volume":"39","author":"Varga","year":"2018","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.brainres.2015.04.038","article-title":"Hydrogen-Rich Water Protects against Ischemic Brain Injury in Rats by Regulating Calcium Buffering Proteins","volume":"1615","author":"Han","year":"2015","journal-title":"Brain Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Abdul-Nasir, S., Chau, C.T., Nguyen, T.T., Bajgai, J., Rahman, M.d.H., Hwang-Un, K., You, I.-S., Kim, C.-S., Seo, B.A., and Lee, K.-J. (2025). Hydrogen Gas Attenuates Toxic Metabolites and Oxidative Stress-Mediated Signaling to Inhibit Neurodegeneration and Enhance Memory in Alzheimer\u2019s Disease Models. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26146922"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1179\/1743132812Y.0000000002","article-title":"Inhalation of Hydrogen Gas Attenuates Cognitive Impairment in Transient Cerebral Ischemia via Inhibition of Oxidative Stress","volume":"34","author":"Ge","year":"2012","journal-title":"Neurol. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/nm1577","article-title":"Hydrogen Acts as a Therapeutic Antioxidant by Selectively Reducing Cytotoxic Oxygen Radicals","volume":"13","author":"Ohsawa","year":"2007","journal-title":"Nat. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pharmthera.2014.04.006","article-title":"Molecular Hydrogen as a Preventive and Therapeutic Medical Gas: Initiation, Development and Potential of Hydrogen Medicine","volume":"144","author":"Ohta","year":"2014","journal-title":"Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13618-015-0035-1","article-title":"Beneficial Biological Effects and the Underlying Mechanisms of Molecular Hydrogen-Comprehensive Review of 321 Original Articles","volume":"5","author":"Ichihara","year":"2015","journal-title":"Med. Gas. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e70194","DOI":"10.1002\/mco2.70194","article-title":"Molecular Hydrogen Therapy: Mechanisms, Delivery Methods, Preventive, and Therapeutic Application","volume":"6","author":"Jin","year":"2025","journal-title":"MedComm"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s12264-020-00597-1","article-title":"Neuroprotective Effects of Molecular Hydrogen: A Critical Review","volume":"37","author":"Chen","year":"2020","journal-title":"Neurosci. Bull."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"115330","DOI":"10.1016\/j.bbr.2024.115330","article-title":"Molecular Hydrogen Inhibits Neuroinflammation and Ameliorates Depressive-like Behaviors and Short-Term Cognitive Impairment in Senescence-Accelerated Mouse Prone 8 Mice","volume":"478","author":"Nakagawa","year":"2025","journal-title":"Behav. Brain Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"444","DOI":"10.3390\/hydrogen2040025","article-title":"Molecular Hydrogen as Medicine: An Assessment of Administration Methods","volume":"2","author":"Russell","year":"2021","journal-title":"Hydrogen"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"687","DOI":"10.2174\/1381612826666201113095720","article-title":"Hydrogen-Induced Neuroprotection in Neonatal Hypoxic-Ischemic Encephalopathy","volume":"27","author":"Domoki","year":"2021","journal-title":"Curr. Pharm. Des."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.brainres.2014.09.030","article-title":"Inhalation of Hydrogen Gas Attenuates Brain Injury in Mice with Cecal Ligation and Puncture via Inhibiting Neuroinflammation, Oxidative Stress and Neuronal Apoptosis","volume":"1589","author":"Liu","year":"2014","journal-title":"Brain Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Park, H.J., Gonzalez-Islas, C.E., Kang, Y., Li, J.M., and Choi, I. (2019). Deletion of the Na\/HCO3 Transporter NBCn1 Protects Hippocampal Neurons from NMDA-Induced Seizures and Neurotoxicity in Mice. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-52413-0"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1111\/apa.12784","article-title":"Cooling Neonates Who Do Not Fulfil the Standard Cooling Criteria\u2013Short- and Long-Term Outcomes","volume":"104","author":"Smit","year":"2015","journal-title":"Acta Paediatr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1093\/pch\/pxy028","article-title":"Hypothermia for Newborns with Hypoxic-Ischemic Encephalopathy","volume":"23","author":"Lemyre","year":"2018","journal-title":"Paediatr. Child Health"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"S186","DOI":"10.1097\/CCM.0b013e3181aa5241","article-title":"Mechanisms of Action, Physiological Effects, and Complications of Hypothermia","volume":"37","author":"Polderman","year":"2009","journal-title":"Crit. Care Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.brainres.2015.12.034","article-title":"Therapeutic Hypothermia and Targeted Temperature Management in Traumatic Brain Injury: Clinical Challenges for Successful Translation","volume":"1640","author":"Dietrich","year":"2016","journal-title":"Brain Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000489737","article-title":"Hydrogen Therapy in Cardiovascular and Metabolic Diseases: From Bench to Bedside","volume":"47","author":"Zhang","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.2174\/138161211797052664","article-title":"Recent Progress Toward Hydrogen Medicine: Potential of Molecular Hydrogen for Preventive and Therapeutic Applications","volume":"17","author":"Ohta","year":"2011","journal-title":"Curr. Pharm. Des."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"277","DOI":"10.2165\/11319360-000000000-00000","article-title":"Effects of Hypothermia on Pharmacokinetics and Pharmacodynamics","volume":"49","author":"Groenendaal","year":"2010","journal-title":"Clin. Pharmacokinet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s40119-022-00292-4","article-title":"Targeted Temperature Management in Cardiac Arrest: An Updated Narrative Review","volume":"12","author":"Belur","year":"2023","journal-title":"Cardiol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.neuroimage.2009.11.058","article-title":"Dynamic Control for Synchronization of Separated Cortical Areas through Thalamic Relay","volume":"52","author":"Gollo","year":"2010","journal-title":"Neuroimage"},{"key":"ref_43","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_44","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_45","doi-asserted-by":"crossref","first-page":"105925","DOI":"10.1016\/j.neuint.2024.105925","article-title":"Hydrogen Inhalation Exerts Anti-Seizure Effects by Preventing Oxidative Stress and Inflammation in the Hippocampus in a Rat Model of Kainic Acid-Induced Seizures","volume":"183","author":"Lin","year":"2025","journal-title":"Neurochem. Int."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/14\/12\/1405\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T05:29:02Z","timestamp":1764221342000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/14\/12\/1405"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,25]]},"references-count":45,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["antiox14121405"],"URL":"https:\/\/doi.org\/10.3390\/antiox14121405","relation":{},"ISSN":["2076-3921"],"issn-type":[{"type":"electronic","value":"2076-3921"}],"subject":[],"published":{"date-parts":[[2025,11,25]]}}}