{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:12:20Z","timestamp":1790208740418,"version":"4.1.0"},"reference-count":113,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2018,6,7]],"date-time":"2018-06-07T00:00:00Z","timestamp":1528329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01-HD-057100"],"award-info":[{"award-number":["1R01-HD-057100"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Perinatal brain injury is a major cause of morbidity and long-standing disability in newborns. Hypothermia is the only therapy approved to attenuate brain injury in the newborn. However, this treatment is unfortunately only partially neuroprotective and can only be used to treat hypoxic-ischemic encephalopathy in full term infants. Therefore, there is an urgent need for adjunctive therapeutic strategies. Post-ischemic neuro-inflammation is a crucial contributor to the evolution of brain injury in neonates and constitutes a promising therapeutic target. Recently, we demonstrated encouraging neuroprotective capacities of anti-cytokine monoclonal antibodies (mAbs) in an ischemic-reperfusion (I\/R) model of brain injury in the ovine fetus. The purpose of this review is to summarize the current knowledge regarding the inflammatory response in the perinatal sheep brain after I\/R injury and to review our recent findings regarding the beneficial effects of treatment with anti-cytokine mAbs.<\/jats:p>","DOI":"10.3390\/brainsci8060101","type":"journal-article","created":{"date-parts":[[2018,6,8]],"date-time":"2018-06-08T03:13:18Z","timestamp":1528427598000},"page":"101","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Anti-Cytokine Therapy to Attenuate Ischemic-Reperfusion Associated Brain Injury in the Perinatal Period"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3107-3459","authenticated-orcid":false,"given":"Cl\u00e9mence","family":"Disdier","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Women &amp; Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Women &amp; Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong-Eun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Women &amp; Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven W.","family":"Threlkeld","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Regis College, Weston, MA 02493, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara S.","family":"Stonestreet","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Women &amp; Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,6,7]]},"reference":[{"key":"ref_1","unstructured":"Volpe, J. (2001). Hypoxic-ischemic encephalopathy. Neurology of the Newborn, W.B. Saunders Company. [4th ed.]."},{"key":"ref_2","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_3","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_4","doi-asserted-by":"crossref","first-page":"E624","DOI":"10.1542\/peds.2014-1566","article-title":"Cognitive outcomes after neonatal encephalopathy","volume":"135","author":"Pappas","year":"2015","journal-title":"Pediatrics"},{"key":"ref_5","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_6","doi-asserted-by":"crossref","unstructured":"Jacobs, S.E., Berg, M., Hunt, R., Tarnow-Mordi, W.O., Inder, T.E., and Davis, P.G. (2013). Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst. Rev.","DOI":"10.1002\/14651858.CD003311.pub3"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1053\/j.semperi.2016.09.007","article-title":"Outcomes in childhood following therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy (HIE)","volume":"40","author":"Natarajan","year":"2016","journal-title":"Semin. Perinatol."},{"key":"ref_8","first-page":"1073","article-title":"Childhood outcomes after hypothermia for neonatal encephalopathy (vol 366, pg 2085, 2012)","volume":"367","author":"Shankaran","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1056\/NEJMc053092","article-title":"Hypothermia for neonates with hypoxic-ischemic encephalopathy","volume":"354","author":"Gluckman","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_10","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_11","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1056\/NEJMra041996","article-title":"Medical progress\u2014Neonatal brain injury","volume":"351","author":"Ferriero","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Bhalala, U.S., Koehler, R.C., and Kannan, S. (2014). Neuroinflammation and neuroimmune dysregulation after acute hypoxic-ischemic injury of developing brain. Front. Pediatr., 2.","DOI":"10.3389\/fped.2014.00144"},{"key":"ref_13","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_14","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_15","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/mrdd.20107","article-title":"Perinatal white matter injury: The changing spectrum of pathology and emerging insights into pathogenetic mechanisms","volume":"12","author":"Back","year":"2006","journal-title":"Ment. Retard. Dev. Disabil. Res. Rev."},{"key":"ref_16","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_17","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_18","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_19","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.ijdevneu.2008.02.005","article-title":"Post-insult minocycline treatment attenuates hypoxia-ischemia-induced neuroinflammation and white matter injury in the neonatal rat: A comparison of two different dose regimens","volume":"26","author":"Carty","year":"2008","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/mrdd.20102","article-title":"Microglia and inflammation: Impact on developmental brain injuries","volume":"12","author":"Chew","year":"2006","journal-title":"Ment. Retard. Dev. Disabil. Res. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/jcbfm.2009.194","article-title":"Minocycline reduces neuronal death and attenuates microglial response after pediatric asphyxial cardiac arrest","volume":"30","author":"Tang","year":"2010","journal-title":"J. Cereb. Blood Flow Metabol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"McAdams, R.M., and Juul, S.E. (2012). The role of cytokines and inflammatory cells in perinatal brain injury. Neurol. Res. Int., 2012.","DOI":"10.1155\/2012\/561494"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1111\/j.1471-4159.2005.03227.x","article-title":"Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice: Possible involvement of stat3 activation in the protection of neurons","volume":"94","author":"Yamashita","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1016\/j.neuroscience.2008.09.009","article-title":"Neuro-immune crosstalk in cns diseases","volume":"158","author":"Kerschensteiner","year":"2009","journal-title":"Neuroscience"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.neuroscience.2014.04.036","article-title":"The role of the immune system in central nervous system plasticity after acute injury","volume":"283","author":"Donega","year":"2014","journal-title":"Neuroscience"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1093\/humrep\/15.9.2011","article-title":"Circulating cytokines and cd30 in normal human pregnancy and recurrent spontaneous abortions","volume":"15","author":"Makhseed","year":"2000","journal-title":"Hum. Reprod."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/j.1600-0897.2005.00342.x","article-title":"Evidence for interleukin-10-mediated inhibition of cyclo-oxygenase-2 expression and prostaglandin production in preterm human placenta","volume":"55","author":"Hanna","year":"2006","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5721","DOI":"10.4049\/jimmunol.164.11.5721","article-title":"Gestational age-dependent expression of IL-10 and its receptor in human placental tissues and isolated cytotrophoblasts","volume":"164","author":"Hanna","year":"2000","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1111\/j.1600-0897.2010.00810.x","article-title":"Interleukin-10: A multi-faceted agent of pregnancy","volume":"63","author":"Thaxton","year":"2010","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1111\/j.1600-0897.1992.tb00772.x","article-title":"Cytokines considered critical in pregnancy","volume":"28","author":"Hill","year":"1992","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/0167-5699(93)90235-D","article-title":"Bidirectional cytokine interactions in the maternal-fetal relationship: Is successful pregnancy a TH2 phenomenon?","volume":"14","author":"Wegmann","year":"1993","journal-title":"Immunol. Today"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1172\/JCI119153","article-title":"Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs","volume":"99","author":"Gunn","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3045","DOI":"10.1523\/JNEUROSCI.5200-05.2006","article-title":"Spatial heterogeneity in oligodendrocyte lineage maturation and not cerebral blood flow predicts fetal ovine periventricular white matter injury","volume":"26","author":"Riddle","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"R468","DOI":"10.1152\/ajpregu.2000.279.2.R468","article-title":"Exogenous and endogenous corticosteroids modulate blood-brain barrier development in the ovine fetus","volume":"279","author":"Stonestreet","year":"2000","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_35","first-page":"R283","article-title":"Antenatal steroids decrease blood-brain barrier permeability in the ovine fetus","volume":"276","author":"Stonestreet","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1002\/cne.901350302","article-title":"The foetal sheep: Morphogenesis of the nervous system and histochemical aspects of myelination","volume":"135","author":"Barlow","year":"1969","journal-title":"J. Comp. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/S0079-6123(08)61419-3","article-title":"On the prenatal development of function and structure in the somesthetic cortex of the sheep","volume":"26","author":"Bernhard","year":"1967","journal-title":"Prog. Brain Res."},{"key":"ref_38","first-page":"441","article-title":"The development of the somatosensory evoked potential in the unanaesthetized fetal sheep","volume":"9","author":"Cook","year":"1987","journal-title":"J. Dev. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1177\/08830738060210070101","article-title":"Role of instrumented fetal sheep preparations in defining the pathogenesis of human periventricular white-matter injury","volume":"21","author":"Back","year":"2006","journal-title":"J. Child Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1203\/00006450-200206000-00019","article-title":"White matter injury after cerebral ischemia in ovine fetuses","volume":"51","author":"Petersson","year":"2002","journal-title":"Pediatr. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0165-2427(99)00158-0","article-title":"Characterisation of monoclonal antibodies to ovine interleukin-6 and the development of a sensitive capture elisa","volume":"73","author":"McWaters","year":"2000","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/S0165-2427(96)05754-6","article-title":"Analysis of ovine IL-1 beta production in vivo and in vitro by enzyme immunoassay and immunohistochemistry","volume":"57","author":"Rothel","year":"1997","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.jcpa.2012.06.001","article-title":"In-vitro validation of cytokine neutralizing antibodies by testing with ovine mononuclear splenocytes","volume":"148","author":"Chen","year":"2013","journal-title":"J. Comp. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1093\/jnen\/nlx046","article-title":"Insights into the neuroinflammatory responses after neonatal hypoxia-ischemia","volume":"76","author":"Jaworska","year":"2017","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1042\/BST0351122","article-title":"Interleukin-1 and inflammatory neurodegeneration","volume":"35","author":"Simi","year":"2007","journal-title":"Biochem. Soc. Trans."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/nri1664","article-title":"Interleukin-1 and neuronal injury","volume":"5","author":"Allan","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.ijdevneu.2012.06.001","article-title":"Ontogeny and the effects of in utero brain ischemia on interleukin-1 beta and interleukin-6 protein expression in ovine cerebral cortex and white matter","volume":"30","author":"Sadowska","year":"2012","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1093\/jnen\/nlw030","article-title":"HMGB1 translocation after ischemia in the ovine fetal brain","volume":"75","author":"Zhang","year":"2016","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1096\/fj.14-258822","article-title":"Anti-IL-6 neutralizing antibody modulates blood-brain barrier function in the ovine fetus","volume":"29","author":"Zhang","year":"2015","journal-title":"FASEB J."},{"key":"ref_50","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_51","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_52","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1038\/jcbfm.2015.134","article-title":"Interleukin-1 beta transfer across the blood-brain barrier in the ovine fetus","volume":"35","author":"Sadowska","year":"2015","journal-title":"J. Cereb. Blood Flow Metabol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1038\/sj.jcbfm.9600582","article-title":"Early release of HMGB-1 from neurons after the onset of brain ischemia","volume":"28","author":"Qiu","year":"2008","journal-title":"J. Cereb. Blood Flow Metabol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1161\/STROKEAHA.110.598334","article-title":"Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats","volume":"42","author":"Zhang","year":"2011","journal-title":"Stroke"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Prout, A.P., Frasch, M.G., Veldhuizen, R.A.W., Hammond, R., Ross, M.G., and Richardson, B.S. (2010). Systemic and cerebral inflammatory response to umbilical cord occlusions with worsening acidosis in the ovine fetus. Am. J. Obstet. Gynecol., 202.","DOI":"10.1016\/j.ajog.2009.08.020"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Jellema, R.K., Passos, V.L., Zwanenburg, A., Ophelders, D., De Munter, S., Vanderlocht, J., Germeraad, W.T.V., Kuypers, E., Collins, J.J.P., and Cleutjens, J.P.M. (2013). Cerebral inflammation and mobilization of the peripheral immune system following global hypoxia-ischemia in preterm sheep. J. Neuroinflamm., 10.","DOI":"10.1186\/1742-2094-10-13"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Yawno, T., Mahen, M., Li, J.G., Fahey, M.C., Jenkin, G., and Miller, S.L. (2017). The beneficial effects of melatonin administration following hypoxia-ischemia in preterm fetal sheep. Front. Cell. Neurosci., 11.","DOI":"10.3389\/fncel.2017.00296"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.expneurol.2016.06.017","article-title":"Preterm white matter brain injury is prevented by early administration of umbilical cord blood cells","volume":"283","author":"Li","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Jellema, R.K., Ophelders, D., Zwanenburg, A., Nikiforou, M., Delhaas, T., Andriessen, P., Mays, R.W., Deans, R., Germeraad, W.T.V., and Wolfs, T. (2015). Multipotent adult progenitor cells for hypoxic-ischemic injury in the preterm brain. J. Neuroinflamm., 12.","DOI":"10.1186\/s12974-015-0459-5"},{"key":"ref_60","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_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1528-1167.2012.03696.x","article-title":"Overview and introduction: The blood-brain barrier in health and disease","volume":"53","author":"Abbott","year":"2012","journal-title":"Epilepsia"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.neuroscience.2015.09.062","article-title":"Ontogeny of tight junction protein expression in the ovine cerebral cortex during development","volume":"310","author":"Sadowska","year":"2015","journal-title":"Neuroscience"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"H1485","DOI":"10.1152\/ajpheart.00645.2001","article-title":"Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation","volume":"282","author":"Mark","year":"2002","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_64","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_65","doi-asserted-by":"crossref","first-page":"S533","DOI":"10.33549\/physiolres.933541","article-title":"Pathophysiology of perinatal hypoxic-ischemic encephalopathy\u2014Biomarkers, animal models and treatment perspectives","volume":"65","author":"Riljak","year":"2016","journal-title":"Physiol. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"R1594","DOI":"10.1152\/ajpregu.1996.271.6.R1594","article-title":"Ontogeny of blood-brain barrier function in ovine fetuses, lambs, and adults","volume":"271","author":"Stonestreet","year":"1996","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1097\/NEN.0000000000000071","article-title":"Ischemia\/reperfusion-induced neovascularization in the cerebral cortex of the ovine fetus","volume":"73","author":"Virgintino","year":"2014","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1046\/j.1469-7580.2002.00064.x","article-title":"Astrocyte-endothelial interactions and blood-brain barrier permeability","volume":"200","author":"Abbott","year":"2002","journal-title":"J. Anat."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrn1824","article-title":"Astrocyte-endothelial interactions at the blood-brain barrier","volume":"7","author":"Abbott","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3729","DOI":"10.2174\/138161211798220918","article-title":"Cytokine signaling modulates blood-brain barrier function","volume":"17","author":"Pan","year":"2011","journal-title":"Curr. Pharm. Des."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1042\/BST20140319","article-title":"The blood-brain barrier endothelium: A target for pro-inflammatory cytokines","volume":"43","author":"Rochfort","year":"2015","journal-title":"Biochem. Soc. Trans."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1159\/000350470","article-title":"Effects of interleukin-6 on the expression of tight junction proteins in isolated cerebral microvessels from yearling and adult sheep","volume":"20","author":"Cohen","year":"2013","journal-title":"Neuroimmunomodulation"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1159\/000288265","article-title":"Ovine proinflammatory cytokines cross the murine blood-brain barrier by a common saturable transport mechanism","volume":"17","author":"Threlkeld","year":"2010","journal-title":"Neuroimmunomodulation"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0304-3940(94)90933-4","article-title":"Penetration of interleukin-6 across the murine blood-brain-barrier","volume":"179","author":"Banks","year":"1994","journal-title":"Neurosci. Lett."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0165-5728(93)90027-V","article-title":"Murine tumor-necrosis-factor-alpha is transported from blood to brain in the mouse","volume":"47","author":"Gutierrez","year":"1993","journal-title":"J. Neuroimmunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1159\/000097202","article-title":"Passage of cytokines across the blood-brain barrier","volume":"2","author":"Banks","year":"1995","journal-title":"Neuroimmunomodulation"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1203\/00006450-199707000-00001","article-title":"Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn","volume":"42","author":"Dammann","year":"1997","journal-title":"Pediatr. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/j.jpeds.2010.11.059","article-title":"The relationship between early concentrations of 25 blood proteins and cerebral white matter injury in preterm newborns: The elgan study","volume":"158","author":"Leviton","year":"2011","journal-title":"J. Pediatr."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.1001\/jama.292.19.2357","article-title":"Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection","volume":"292","author":"Stoll","year":"2004","journal-title":"JAMA"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/j.jpeds.2005.01.047","article-title":"Extremely low birthweight neonates with protracted ventilation: Mortality and 18-month neurodevelopmental outcomes","volume":"146","author":"Walsh","year":"2005","journal-title":"J Pediatr."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.cyto.2012.10.014","article-title":"Systemic inflammation associated with mechanical ventilation among extremely preterm infants","volume":"61","author":"Bose","year":"2013","journal-title":"Cytokine"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1097\/00004647-199609000-00017","article-title":"Neuroprotective effects of human recombinant interleukin-1 receptor antagonist in focal cerebral ischaemia in the rat","volume":"16","author":"Loddick","year":"1996","journal-title":"J. Cereb. Blood Flow Metabol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/0361-9230(92)90033-T","article-title":"Interleukin-1 receptor antagonist inhibits ischemic and excitotoxic neuronal damage in the rat","volume":"29","author":"Relton","year":"1992","journal-title":"Brain Res. Bull."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/j.bbi.2012.09.001","article-title":"Postnatal administration of il-1ra exerts neuroprotective effects following perinatal inflammation and\/or hypoxic-ischemic injuries","volume":"26","author":"Girard","year":"2012","journal-title":"Brain Behav. Immun."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.expneurol.2006.10.013","article-title":"Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration","volume":"204","author":"Bye","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00702-008-0145-1","article-title":"The genomic profile of the cerebral cortex after closed head injury in mice: Effects of minocycline","volume":"116","author":"Crack","year":"2009","journal-title":"J. Neural Trans."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1097\/00006123-200106000-00051","article-title":"Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction","volume":"48","author":"Mejia","year":"2001","journal-title":"Neurosurgery"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1248\/yakushi.13-00255-2","article-title":"Anti-high mobility group box-1 antibody therapy for traumatic brain injury","volume":"134","author":"Okuma","year":"2014","journal-title":"Yakugaku Zasshi-J. Pharm. Soc. Jpn."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"525","DOI":"10.2147\/NDT.S154809","article-title":"Anti-TNF-alpha antibody attenuates subarachnoid hemorrhage-induced apoptosis in the hypothalamus by inhibiting the activation of ERK","volume":"14","author":"Ma","year":"2018","journal-title":"Neuropsychiatric Dis. Treat."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.immuni.2005.09.010","article-title":"IL-6-STAT3 controls intracellular MHC class II alpha beta dimer level through cathepsin s activity in dendritic cells","volume":"23","author":"Kitamura","year":"2005","journal-title":"Immunity"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1016\/j.cellsig.2007.04.007","article-title":"Activation of NF-kappa b by IL-1 beta blocks IL-6-induced sustained STAT3 activation and STAT3-dependent gene expression of the human gamma-fibrinogen gene","volume":"19","author":"Albrecht","year":"2007","journal-title":"Cell. Signal."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1002\/ibd.20342","article-title":"Activation of an IL-6: STAT3-dependent transcriptome in pediatric-onset inflammatory bowel disease","volume":"14","author":"Carey","year":"2008","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1007\/s10753-016-0395-2","article-title":"Inhibiting high-mobility group box 1 (HMGB1) attenuates inflammatory cytokine expression and neurological deficit in ischemic brain injury following cardiac arrest in rats","volume":"39","author":"Xu","year":"2016","journal-title":"Inflammation"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Chen, X., Hovanesian, V., Naqvi, S., Lim, Y.-P., Tucker, R., Donahue, J.E., Stopa, E.G., and Stonestreet, B.S. (2017). Systemic infusions of anti-interleukin-1\u03b2 neutralizing antibodies reduce short-term brain injury after cerebral ischemia in the ovine fetus. Brain Behav. Immun.","DOI":"10.1016\/j.bbi.2017.08.002"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.neuroscience.2016.12.051","article-title":"Neutralizing anti-interleukin-1 beta antibodies reduce ischemia-related interleukin-1 beta transport across the blood-brain barrier in fetal sheep","volume":"346","author":"Patra","year":"2017","journal-title":"Neuroscience"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.expneurol.2007.05.005","article-title":"Anti-amyloid beta protein antibody passage across the blood-brain barrier in the SAMP8 mouse model of alzheimer\u2019s disease: An age-related selective uptake with reversal of learning impairment","volume":"206","author":"Banks","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1016\/S0196-9781(02)00261-9","article-title":"Passage of amyloid beta protein antibody across the blood-brain barrier in a mouse model of alzheimer\u2019s disease","volume":"23","author":"Banks","year":"2002","journal-title":"Peptides"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/S0165-5728(01)00242-9","article-title":"Mediated efflux of igg molecules from brain to blood across the blood-brain barrier","volume":"114","author":"Zhang","year":"2001","journal-title":"J. Neuroimmunol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1046\/j.1471-4159.2002.00840.x","article-title":"Expression of the neonatal fc receptor (FCRN) at the blood-brain barrier","volume":"81","author":"Schlachetzki","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/S1474-4422(12)70058-3","article-title":"Tertiary mechanisms of brain damage: A new hope for treatment of cerebral palsy?","volume":"11","author":"Fleiss","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_101","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\u2014Involvement of nerve growth-factor","volume":"15","author":"Strijbos","year":"1995","journal-title":"J. Neurosci."},{"key":"ref_102","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_103","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0304-3940(01)01795-5","article-title":"Interleukin-1 beta exacerbates hypoxia-induced neuronal damage, but attenuates toxicity produced by simulated ischaemia and excitotoxicity in rat organotypic hippocampal slice cultures","volume":"305","author":"Pringle","year":"2001","journal-title":"Neurosci. Lett."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1002\/glia.22320","article-title":"Crosstalk between oligodendrocytes and cerebral endothelium contributes to vascular remodeling after white matter injury","volume":"60","author":"Pham","year":"2012","journal-title":"Glia"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/jcbfm.2008.141","article-title":"Ambivalent aspects of interleukin-6 in cerebral ischemia: Inflammatory versus neurotrophic aspects","volume":"29","author":"Suzuki","year":"2009","journal-title":"J. Cereb. Blood Flow Metabol."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Charriaut-Marlangue, C., Besson, C.V., and Baud, O. (2018). Sexually dimorphic outcomes after neonatal stroke and hypoxia-ischemia. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010061"},{"key":"ref_107","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-ischemia in p3 and p7 rats","volume":"290","author":"Sanches","year":"2015","journal-title":"Neuroscience"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.neuroscience.2013.01.066","article-title":"Early hypoxia-ischemia causes hemisphere and sex-dependent cognitive impairment and histological damage","volume":"237","author":"Sanches","year":"2013","journal-title":"Neuroscience"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"647","DOI":"10.3109\/00207454.2015.1047016","article-title":"Sex differences in brain MRI abnormalities and neurodevelopmental outcomes in a rat model of neonatal hypoxia-ischemia","volume":"126","author":"Huang","year":"2016","journal-title":"Int. J. Neurosci."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1203\/PDR.0b013e3181b1bc34","article-title":"Sex differences in a hypoxia model of preterm brain damage","volume":"66","author":"Mayoral","year":"2009","journal-title":"Pediatr. Res."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Mirza, M.A., Ritzel, R., Xu, Y., McCullough, L.D., and Liu, F.D. (2015). Sexually dimorphic outcomes and inflammatory responses in hypoxic-ischemic encephalopathy. J. Neuroinflamm., 12.","DOI":"10.1186\/s12974-015-0251-6"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1177\/1073858414536468","article-title":"A starring role for microglia in brain sex differences","volume":"21","author":"Lenz","year":"2015","journal-title":"Neuroscientist"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1097\/01.wco.0000162850.44897.c6","article-title":"Therapeutic hypothermia for hypoxic-ischaemic encephalopathy in the newborn infant","volume":"18","author":"Thoresen","year":"2005","journal-title":"Curr. Opin. Neurol."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/8\/6\/101\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:07:40Z","timestamp":1760195260000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/8\/6\/101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,7]]},"references-count":113,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2018,6]]}},"alternative-id":["brainsci8060101"],"URL":"https:\/\/doi.org\/10.3390\/brainsci8060101","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,7]]}}}