{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:40:06Z","timestamp":1792172406086,"version":"4.4.0"},"reference-count":86,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T00:00:00Z","timestamp":1698192000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"BIOSTIME Foundation, Geneva, Switzerland"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neonatal hypoxic-ischemic (HI) encephalopathy (HIE) in term newborns is a leading cause of mortality and chronic disability. Hypothermia (HT) is the only clinically available therapeutic intervention; however, its neuroprotective effects are limited. Lactoferrin (LF) is the major whey protein in milk presenting iron-binding, anti-inflammatory and anti-apoptotic properties and has been shown to protect very immature brains against HI damage. We hypothesized that combining early oral administration of LF with whole body hypothermia could enhance neuroprotection in a HIE rat model. Pregnant Wistar rats were fed an LF-supplemented diet (1 mg\/kg) or a control diet from (P6). At P7, the male and female pups had the right common carotid artery occluded followed by hypoxia (8% O2 for 60\u2032) (HI). Immediately after hypoxia, hypothermia (target temperature of 32.5\u201333.5 \u00b0C) was performed (5 h duration) using Criticool\u00ae. The animals were divided according to diet, injury and thermal condition. At P8 (24 h after HI), the brain neurochemical profile was assessed using magnetic resonance spectroscopy (1H-MRS) and a hyperintense T2W signal was used to measure the brain lesions. The mRNA levels of the genes related to glutamatergic excitotoxicity, energy metabolism and inflammation were assessed in the right hippocampus. The cell markers and apoptosis expression were assessed using immunofluorescence in the right hippocampus. HI decreased the energy metabolites and increased lactate. The neuronal\u2013astrocytic coupling impairments observed in the HI groups were reversed mainly by HT. LF had an important effect on astrocyte function, decreasing the levels of the genes related to glutamatergic excitotoxicity and restoring the mRNA levels of the genes related to metabolic support. When combined, LF and HT presented a synergistic effect and prevented lactate accumulation, decreased inflammation and reduced brain damage, pointing out the benefits of combining these therapies. Overall, we showed that through distinct mechanisms lactoferrin can enhance neuroprotection induced by HT following neonatal brain hypoxia-ischemia.<\/jats:p>","DOI":"10.3390\/ijms242115583","type":"journal-article","created":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T09:54:08Z","timestamp":1698227648000},"page":"15583","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Early Neuroprotective Effects of Bovine Lactoferrin Associated with Hypothermia after Neonatal Brain Hypoxia-Ischemia in Rats"],"prefix":"10.3390","volume":"24","author":[{"given":"Eduardo","family":"Sanches","sequence":"first","affiliation":[{"name":"Division of Child Development and Growth, Department of Pediatrics, School of Medicine, University of Geneva, 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohan","family":"van de Looij","sequence":"additional","affiliation":[{"name":"Division of Child Development and Growth, Department of Pediatrics, School of Medicine, University of Geneva, 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3990-7331","authenticated-orcid":false,"given":"Dini","family":"Ho","sequence":"additional","affiliation":[{"name":"Division of Child Development and Growth, Department of Pediatrics, School of Medicine, University of Geneva, 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9772-9345","authenticated-orcid":false,"given":"Laura","family":"Modernell","sequence":"additional","affiliation":[{"name":"Division of Child Development and Growth, Department of Pediatrics, School of Medicine, University of Geneva, 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Analina","family":"da Silva","sequence":"additional","affiliation":[{"name":"Center for Biomedical Imaging (CIBM), Animal Imaging and Technology Section, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL), 1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0093-8747","authenticated-orcid":false,"given":"St\u00e9phane","family":"Sizonenko","sequence":"additional","affiliation":[{"name":"Division of Child Development and Growth, Department of Pediatrics, School of Medicine, University of Geneva, 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,25]]},"reference":[{"key":"ref_1","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_2","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_3","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_4","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.1016\/j.ijgo.2009.07.016","article-title":"Two Million Intrapartum-Related Stillbirths and Neonatal Deaths: Where, Why, and What Can Be Done?","volume":"107","author":"Lawn","year":"2009","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s12975-017-0534-6","article-title":"Translational Stroke Research Guideline Projections: The 20\/20 Standards","volume":"9","author":"Lapchak","year":"2018","journal-title":"Transl. Stroke Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jpeds.2017.08.031","article-title":"Neuroprotective Strategies in Neonatal Brain Injury","volume":"192","author":"Parikh","year":"2018","journal-title":"J. Pediatr."},{"key":"ref_7","unstructured":"American College of Obstetricians and Gynecologists (2017). Guidelines for Perinatal Care, American College of Obstetricians and Gynecologists."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1089\/ars.2019.7779","article-title":"The Role of Mitochondrial and Endoplasmic Reticulum Reactive Oxygen Species Production in Models of Perinatal Brain Injury","volume":"31","author":"Nair","year":"2019","journal-title":"Antioxid. Redox Signal."},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1136\/archdischild-2020-320902","article-title":"Trends in the Incidence and Management of Hypoxic-Ischaemic Encephalopathy in the Therapeutic Hypothermia Era: A National Population Study","volume":"106","author":"Shipley","year":"2021","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.pediatrneurol.2003.10.001","article-title":"Selective Vulnerability in the Developing Central Nervous System","volume":"30","author":"McQuillen","year":"2004","journal-title":"Pediatr. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"F153","DOI":"10.1136\/adc.2006.108837","article-title":"Pathogenesis of Cerebral White Matter Injury of Prematurity","volume":"93","author":"Khwaja","year":"2008","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.ijdevneu.2007.08.014","article-title":"Glial Responses to Neonatal Hypoxic-Ischemic Injury in the Rat Cerebral Cortex","volume":"26","author":"Sizonenko","year":"2008","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/S1701-2163(16)30325-5","article-title":"Proinflammatory Cytokines: A Link between Chorioamnionitis and Fetal Brain Injury","volume":"24","author":"Patrick","year":"2002","journal-title":"J. Obstet. Gynaecol. Can."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1002\/ana.21466","article-title":"Neonatal Encephalitis and White Matter Injury: More than Just Inflammation?","volume":"64","author":"Volpe","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Azevedo, P.N., Zanirati, G., Venturin, G.T., Schu, G.G., Dur\u00e1n-Carabali, L.E., Odorcyk, F.K., Soares, A.V., Laguna, G.d.O., Netto, C.A., and Zimmer, E.R. (2020). Long-Term Changes in Metabolic Brain Network Drive Memory Impairments in Rats Following Neonatal Hypoxia-Ischemia. Neurobiol. Learn. Mem., 171.","DOI":"10.1016\/j.nlm.2020.107207"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3389\/fneur.2016.00057","article-title":"Rodent Hypoxia-Ischemia Models for Cerebral Palsy Research: A Systematic Review","volume":"7","author":"Rumajogee","year":"2016","journal-title":"Front. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1002\/ana.22419","article-title":"Neuronal Cell Death in Neonatal Hypoxia-Ischemia","volume":"69","author":"Northington","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1007\/s11940-012-0200-y","article-title":"Therapeutic Hypothermia for Neonatal Encephalopathy","volume":"14","author":"Shankaran","year":"2012","journal-title":"Curr. Treat. Options Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1042\/BST20130247","article-title":"Neonatal Encephalopathy: Pre-Clinical Studies in Neuroprotection","volume":"42","author":"Patel","year":"2014","journal-title":"Biochem. Soc. Trans."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.clp.2013.09.004","article-title":"Pharmacologic Neuroprotective Strategies in Neonatal Brain Injury","volume":"41","author":"Juul","year":"2014","journal-title":"Clin. Perinatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"198","DOI":"10.3389\/fneur.2015.00198","article-title":"Therapeutic Hypothermia for Neonatal Hypoxic\u2013Ischemic Encephalopathy\u2014Where to from Here?","volume":"6","author":"Davidson","year":"2015","journal-title":"Front. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/dmcn.12730","article-title":"Erythropoietin: A Novel Therapy for Hypoxic-Ischaemic Encephalopathy?","volume":"57","author":"Wu","year":"2015","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Chang, H.-Y., Sung, Y.-H., Wang, S.-M., Lung, H.-L., Chang, J.-H., Hsu, C.-H., Jim, W.-T., Lee, C.-H., and Hung, H.-F. (2015). Short- and Long-Term Outcomes in Very Low Birth Weight Infants with Admission Hypothermia. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0131976"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1089\/ther.2022.0021","article-title":"Is Selective Head Cooling Combined with Whole-Body Cooling the Most Effective Hypothermia Method for Neonatal Hypoxic-Ischemic Encephalopathy?","volume":"13","author":"Celik","year":"2023","journal-title":"Ther. Hypothermia Temp. Manag."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1213\/ANE.0b013e31825d3600","article-title":"Early Antioxidant Treatment and Delayed Hypothermia after Hypoxia-Ischemia Have No Additive Neuroprotection in Newborn Pigs","volume":"115","author":"Ni","year":"2012","journal-title":"Anesth. Analg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1159\/000430862","article-title":"Effects of Neonatal Hypoxic-Ischemic Injury and Hypothermic Neuroprotection on Neural Progenitor Cells in the Mouse Hippocampus","volume":"37","author":"Kwak","year":"2015","journal-title":"Dev. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.4103\/1673-5374.143417","article-title":"Mild Hypothermia Combined with Neural Stem Cell Transplantation for Hypoxic-Ischemic Encephalopathy: Neuroprotective Effects of Combined Therapy","volume":"9","author":"Wang","year":"2014","journal-title":"Neural Regen. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1111\/dmcn.14610","article-title":"Combination Treatments with Therapeutic Hypothermia for Hypoxic-Ischemic Neuroprotection","volume":"62","author":"Zhou","year":"2020","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ijdevneu.2018.06.004","article-title":"Pregnancy as a Valuable Period for Preventing Hypoxia-Ischemia Brain Damage","volume":"70","author":"Netto","year":"2018","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_31","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_32","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3389\/fnsyn.2019.00034","article-title":"An Assessment of Melatonin\u2019s Therapeutic Value in the Hypoxic-Ischemic Encephalopathy of the Newborn","volume":"11","author":"Cardinali","year":"2019","journal-title":"Front. Synaptic Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1203\/01.PDR.0000157722.07810.15","article-title":"Maternal Dietary Supplementation with Pomegranate Juice Is Neuroprotective in an Animal Model of Neonatal Hypoxic-Ischemic Brain Injury","volume":"57","author":"Loren","year":"2005","journal-title":"Pediatr. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1097\/01.aoa.0000389604.63510.21","article-title":"Docosahexaenoic Acid Pretreatment Confers Neuroprotection in a Rat Model of Perinatal Cerebral Hypoxia-Ischemia","volume":"30","author":"Berman","year":"2010","journal-title":"Obstet. Anesth. Dig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"469.e1","DOI":"10.1016\/j.ajog.2010.01.076","article-title":"Docosahexaenoic Acid Confers Neuroprotection in a Rat Model of Perinatal Hypoxia-Ischemia Potentiated by Escherichia Coli Lipopolysaccharide-Induced Systemic Inflammation","volume":"202","author":"Berman","year":"2010","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Schirmbeck, G.H., Sizonenko, S., and Sanches, E.F. (2022). Neuroprotective Role of Lactoferrin during Early Brain Development and Injury through Lifespan. Nutrients, 14.","DOI":"10.3390\/nu14142923"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.bbagen.2011.06.018","article-title":"Lactoferrin a Multiple Bioactive Protein: An Overview","volume":"1820","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1023\/B:BIOM.0000027694.40260.70","article-title":"Lactoferrin and Iron: Structural and Dynamic Aspects of Binding and Release","volume":"17","author":"Baker","year":"2004","journal-title":"Biometals"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1080\/07315724.2000.10718933","article-title":"Lactoferrin Levels in Term and Preterm Milk","volume":"19","author":"Baroni","year":"2000","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1002\/acn3.138","article-title":"Lactoferrin during Lactation Protects the Immature Hypoxic-Ischemic Rat Brain","volume":"1","author":"Ginet","year":"2014","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1002\/biof.1278","article-title":"Lactoferrin during Lactation Reduces Lipopolysaccharide-Induced Brain Injury","volume":"42","author":"Ginet","year":"2016","journal-title":"Biofactors"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"46","DOI":"10.3389\/fendo.2019.00046","article-title":"Nutritional Intervention for Developmental Brain Damage: Effects of Lactoferrin Supplementation in Hypocaloric Induced Intrauterine Growth Restriction Rat Pups","volume":"10","author":"Larpin","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/pr.2013.199","article-title":"Protective Effects of Maternal Nutritional Supplementation with Lactoferrin on Growth and Brain Metabolism","volume":"75","author":"Somm","year":"2013","journal-title":"Pediatr. Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Sanches, E., van de Looij, Y., Sow, S., Toulotte, A., da Silva, A., Modernell, L., and Sizonenko, S. (2021). Dose-Dependent Neuroprotective Effects of Bovine Lactoferrin Following Neonatal Hypoxia-Ischemia in the Immature Rat Brain. Nutrients, 13.","DOI":"10.3390\/nu13113880"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.neuroscience.2014.12.074","article-title":"Sexual Dimorphism and Brain Lateralization Impact Behavioral and Histological Outcomes Following Hypoxia\u2013Ischemia in P3 and P7 Rats","volume":"290","author":"Sanches","year":"2015","journal-title":"Neuroscience"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"480","DOI":"10.3389\/fneur.2018.00480","article-title":"Brain Metabolism Alterations Induced by Pregnancy Swimming Decreases Neurological Impairments Following Neonatal Hypoxia-Ischemia in Very Immature Rats","volume":"9","author":"Sanches","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/(SICI)1098-1136(199909)27:3<239::AID-GLIA5>3.0.CO;2-K","article-title":"Rapid Uptake and Degradationof Glycine by Astroglial Cells in Culture:Synthesis and Releaseof Serine and Lactate","volume":"27","author":"Verleysdonk","year":"1999","journal-title":"Glia"},{"key":"ref_48","unstructured":"Patri, M. (2019). Neurochemical Basis of Brain Function and Dysfunction, IntechOpen."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"753092","DOI":"10.3389\/fimmu.2021.753092","article-title":"Aspartate Metabolism Facilitates IL-1\u03b2 Production in Inflammatory Macrophages","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1042\/EBC20220080","article-title":"Astrocytes as Metabolic Suppliers to Support Neuronal Activity and Brain Functions","volume":"67","author":"Roumes","year":"2023","journal-title":"Essays Biochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1203\/01.PDR.0000157673.36848.67","article-title":"Distinctive Neuropathologic Alterations in the Deep Layers of the Parietal Cortex after Moderate Ischemic-Hypoxic Injury in the P3 Immature Rat Brain","volume":"57","author":"Sizonenko","year":"2005","journal-title":"Pediatr. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/jdn.10244","article-title":"Short-Term Effects of Therapeutic Hypothermia Following Hypoxia-Ischemia in Neonatal Male and Female Rats","volume":"83","author":"Zang","year":"2023","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1002\/jdn.10235","article-title":"Early Neurodevelopmental Reflex Impairments in a Rodent Model of Cerebral Palsy","volume":"82","author":"Ho","year":"2022","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1159\/000454949","article-title":"Therapeutic Hypothermia Provides Variable Protection against Behavioral Deficits after Neonatal Hypoxia-Ischemia: A Potential Role for Brain-Derived Neurotrophic Factor","volume":"39","author":"Diaz","year":"2017","journal-title":"Dev. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.bbr.2015.03.005","article-title":"Sex-Related Differences in Effects of Progesterone Following Neonatal Hypoxic Brain Injury","volume":"286","author":"Peterson","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.neuroscience.2020.09.006","article-title":"Lactate Administration Reduces Brain Injury and Ameliorates Behavioral Outcomes Following Neonatal Hypoxia\u2013Ischemia","volume":"448","author":"Tassinari","year":"2020","journal-title":"Neuroscience"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.jff.2011.08.001","article-title":"Metabolic Effects of Lactoferrin during Energy Restriction and Weight Regain in Diet-Induced Obese Mice","volume":"4","author":"Shi","year":"2012","journal-title":"J. Funct. Foods"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4036","DOI":"10.1210\/jc.2009-0215","article-title":"Decreased Circulating Lactoferrin in Insulin Resistance and Altered Glucose Tolerance as a Possible Marker of Neutrophil Dysfunction in Type 2 Diabetes","volume":"94","author":"Ortega","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"585833","DOI":"10.3389\/fncel.2020.585833","article-title":"An Overview on the Differential Interplay among Neurons-Astrocytes-Microglia in CA1 and CA3 Hippocampus in Hypoxia\/Ischemia","volume":"14","author":"Lana","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41580-022-00541-3","article-title":"Reassessing the Relationship between MRNA Levels and Protein Abundance in Exercised Skeletal Muscles","volume":"23","author":"Bishop","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1002\/mrm.22617","article-title":"Longitudinal MR Assessment of Hypoxic Ischemic Injury in the Immature Rat Brain","volume":"65","author":"Chatagner","year":"2011","journal-title":"Magn. Reson. Med."},{"key":"ref_62","first-page":"1546","article-title":"Proton MR Spectroscopy in Neonates with Perinatal Cerebral Hypoxic-Ischemic Injury: Metabolite Peak-Area Ratios, Relaxation Times, and Absolute Concentrations","volume":"27","author":"Cheong","year":"2006","journal-title":"Am. J. Neuroradiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S1474-4422(13)70261-8","article-title":"Mitochondria: Hub of Injury Responses in the Developing Brain","volume":"13","author":"Hagberg","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1053\/j.semperi.2004.10.005","article-title":"Mechanisms of Hypoxic-Ischemic Injury in the Term Infant","volume":"28","author":"McLean","year":"2004","journal-title":"Semin. Perinatol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.ijdevneu.2015.03.009","article-title":"Advanced Magnetic Resonance Spectroscopy and Imaging Techniques Applied to Brain Development and Animal Models of Perinatal Injury","volume":"45","author":"Dean","year":"2015","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.brainres.2010.06.024","article-title":"Cerebral and Functional Adaptation with Chronic Hypoxia Exposure: A Multi-Modal MRI Study","volume":"1348","author":"Yan","year":"2010","journal-title":"Brain Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1203\/00006450-200103000-00009","article-title":"Value Of1H-MRS Using Different Echo Times in Neonates with Cerebral Hypoxia-Ischemia","volume":"49","author":"Groenendaal","year":"2001","journal-title":"Pediatr. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"108719","DOI":"10.1016\/j.neuropharm.2021.108719","article-title":"Glutamate Metabolism and Recycling at the Excitatory Synapse in Health and Neurodegeneration","volume":"196","author":"Andersen","year":"2021","journal-title":"Neuropharmacology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"245","DOI":"10.3233\/JAD-191181","article-title":"Dietary Lactoferrin Supplementation Prevents Memory Impairment and Reduces Amyloid-\u03b2 Generation in J20 Mice","volume":"74","author":"Abdelhamid","year":"2020","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1002\/glia.24259","article-title":"Astrocyte-Specific Loss of Lactoferrin Influences Neuronal Structure and Function by Interfering with Cholesterol Synthesis","volume":"70","author":"Xu","year":"2022","journal-title":"Glia"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2048","DOI":"10.1038\/s41386-020-0760-6","article-title":"Glutamine-to-Glutamate Ratio in the Nucleus Accumbens Predicts Effort-Based Motivated Performance in Humans","volume":"45","author":"Strasser","year":"2020","journal-title":"Neuropsychopharmacology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s00424-009-0750-3","article-title":"Hypoxia Stimulates Lactate Release and Modulates Monocarboxylate Transporter (MCT1, MCT2, and MCT4) Expression in Human Adipocytes","volume":"459","author":"Wood","year":"2010","journal-title":"Pflug. Arch."},{"key":"ref_73","first-page":"195","article-title":"Interleukin-1\u03b2 in Central Nervous System Injury and Repair","volume":"1","author":"Hewett","year":"2012","journal-title":"Eur. J. Neurodegener. Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"6734","DOI":"10.1523\/JNEUROSCI.1510-05.2005","article-title":"Modulator Effects of Interleukin-1beta and Tumor Necrosis Factor-Alpha on AMPA-Induced Excitotoxicity in Mouse Organotypic Hippocampal Slice Cultures","volume":"25","author":"Bernardino","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3963","DOI":"10.4049\/jimmunol.163.7.3963","article-title":"Inflammatory Cytokines IL-1 Alpha, IL-1 Beta, IL-6, and TNF-Alpha Impart Neuroprotection to an Excitotoxin through Distinct Pathways","volume":"163","author":"Carlson","year":"1999","journal-title":"J. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3468","DOI":"10.1523\/JNEUROSCI.15-05-03468.1995","article-title":"Interleukin-1 Beta Attenuates Excitatory Amino Acid-Induced Neurodegeneration in Vitro: Involvement of Nerve Growth Factor","volume":"15","author":"Strijbos","year":"1995","journal-title":"J. Neurosci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.brainres.2003.10.013","article-title":"Post-Ischemic Hypothermia-Induced Tissue Protection and Diminished Apoptosis after Neonatal Cerebral Hypoxia-Ischemia","volume":"996","author":"Zhu","year":"2004","journal-title":"Brain Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2016.03.014","article-title":"On the Dependency of Cellular Protein Levels on MRNA Abundance","volume":"165","author":"Liu","year":"2016","journal-title":"Cell"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1038\/s41593-021-00905-6","article-title":"Neuroinflammatory Astrocyte Subtypes in the Mouse Brain","volume":"24","author":"Hasel","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"113317","DOI":"10.1016\/j.expneurol.2020.113317","article-title":"Differential Glucose and Beta-Hydroxybutyrate Metabolism Confers an Intrinsic Neuroprotection to the Immature Brain in a Rat Model of Neonatal Hypoxia Ischemia","volume":"330","author":"Odorcyk","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_81","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_82","doi-asserted-by":"crossref","first-page":"23430","DOI":"10.1038\/srep23430","article-title":"Treatment Temperature and Insult Severity Influence the Neuroprotective Effects of Therapeutic Hypothermia","volume":"6","author":"Wood","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1002\/mrm.21043","article-title":"Localized Short-Echo-Time Proton MR Spectroscopy with Full Signal-Intensity Acquisition","volume":"56","author":"Gambarota","year":"2006","journal-title":"Magn. Reson. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1002\/(SICI)1522-2594(200002)43:2<319::AID-MRM22>3.0.CO;2-1","article-title":"Field Mapping without Reference Scan Using Asymmetric Echo-Planar Techniques","volume":"43","author":"Gruetter","year":"2000","journal-title":"Magn. Reson. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1002\/mrm.1910300604","article-title":"Estimation of Metabolite Concentrations from Localized in Vivo Proton NMR Spectra","volume":"30","author":"Provencher","year":"1993","journal-title":"Magn. Reson. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"161","DOI":"10.3389\/fnana.2015.00161","article-title":"Atlas of the Postnatal Rat Brain in Stereotaxic Coordinates","volume":"9","author":"Khazipov","year":"2015","journal-title":"Front. Neuroanat."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15583\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:11:40Z","timestamp":1760130700000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15583"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,25]]},"references-count":86,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242115583"],"URL":"https:\/\/doi.org\/10.3390\/ijms242115583","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,25]]}}}