{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T15:13:28Z","timestamp":1790867608523,"version":"4.1.0"},"reference-count":132,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T00:00:00Z","timestamp":1640995200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Brain and Neuroscience Advances"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p>\n                    In the newborn brain, moderate-severe hypoxia\u2013ischaemia induces glutamate excitotoxicity and inflammation, possibly via dysregulation of candidate astrocytic glutamate transporter ( Glt1) and pro-inflammatory cytokines (e.g. Tnf\u03b1, Il1\u03b2, Il6). Epigenetic mechanisms may mediate dysregulation. Hypotheses: (1) hypoxia\u2013ischaemia dysregulates mRNA expression of these candidate genes; (2) expression changes in Glt1 are mediated by DNA methylation changes; and (3) methylation values in brain and blood are correlated. Seven-day-old rat pups ( n\u2009=\u200942) were assigned to nine groups based on treatment (for each timepoint: na\u00efve ( n\u2009=\u20093), sham ( n\u2009=\u20093), hypoxia\u2013ischaemia ( n\u2009=\u20098) and timepoint for tissue collection (6, 12 and 24\u2009h post-hypoxia). Moderate hypoxic\u2013ischemic brain injury was induced via ligation of the left common carotid artery followed by 100\u2009min hypoxia (8% O\n                    <jats:sub>2<\/jats:sub>\n                    , 36\u00b0C). mRNA was quantified in cortex and hippocampus for the candidate genes, myelin ( Mbp), astrocytic ( Gfap) and neuronal ( Map2) markers (qPCR). DNA methylation was measured for Glt1 in cortex and blood (bisulphite pyrosequencing). Hypoxia\u2013ischaemia induced pro-inflammatory cytokine upregulation in both brain regions at 6\u2009h. This was accompanied by gene expression changes potentially indicating onset of astrogliosis and myelin injury. There were no significant changes in expression or promoter DNA methylation of Glt1. This pilot study supports accumulating evidence that hypoxia\u2013ischaemia causes neuroinflammation in the newborn brain and prioritises further expression and DNA methylation analyses focusing on this pathway. Epigenetic blood biomarkers may facilitate identification of high-risk newborns at birth, maximising chances of neuroprotective interventions.\n                  <\/jats:p>","DOI":"10.1177\/23982128221097568","type":"journal-article","created":{"date-parts":[[2022,5,21]],"date-time":"2022-05-21T02:58:31Z","timestamp":1653101911000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["Regulation of glutamate transport and neuroinflammation in a term newborn rat model of hypoxic\u2013ischaemic brain injury"],"prefix":"10.1177","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4124-2108","authenticated-orcid":false,"given":"Silvia","family":"Pregnolato","sequence":"first","affiliation":[{"name":"Department of Neonatal Neurology, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hemmen","family":"Sabir","sequence":"additional","affiliation":[{"name":"Department of Neonatology and Pediatric Intensive Care, Children\u2019s Hospital, University of Bonn, Bonn, Germany"},{"name":"Department of Pediatrics I\/Neonatology, University Hospital Essen, University Duisburg Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Luyt","sequence":"additional","affiliation":[{"name":"Department of Neonatal Neurology, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kira DA","family":"Rienecker","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy and Rehabilitation Science, University of California San Francisco, San Francisco, CA, USA"},{"name":"Behavioural Genetics Group, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7587-5712","authenticated-orcid":false,"given":"Anthony R","family":"Isles","sequence":"additional","affiliation":[{"name":"Behavioural Genetics Group, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elavazhagan","family":"Chakkarapani","sequence":"additional","affiliation":[{"name":"Department of Neonatal Neurology, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2022,5,20]]},"reference":[{"key":"bibr1-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2009.10.010"},{"key":"bibr2-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-10-24"},{"key":"bibr3-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0900854"},{"key":"bibr4-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-016-0198-1"},{"key":"bibr5-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1533"},{"key":"bibr6-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2011-12-1-r10"},{"key":"bibr7-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"key":"bibr8-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1984.tb05396.x"},{"key":"bibr9-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1010-1045"},{"key":"bibr10-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2011.07.007"},{"key":"bibr11-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(95)00398-A"},{"key":"bibr12-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-199904010-00008"},{"key":"bibr13-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1159\/000346685"},{"key":"bibr14-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.1994.1047"},{"key":"bibr15-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-017-0328-4"},{"key":"bibr16-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1991.tb08163.x"},{"key":"bibr17-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1002\/neu.480230915"},{"key":"bibr18-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(00)00067-8"},{"key":"bibr19-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1097\/00004647-199601000-00020"},{"key":"bibr20-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1101\/gad.2037511"},{"key":"bibr21-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.31.7.1752"},{"key":"bibr22-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1002\/cne.21667"},{"key":"bibr23-23982128221097568","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2012.00144"},{"key":"bibr24-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/nature09231"},{"key":"bibr25-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/ng1909"},{"key":"bibr26-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/nature11247"},{"key":"bibr27-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5728(85)80063-1"},{"key":"bibr28-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7768-0_4"},{"key":"bibr29-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-24-09235.2000"},{"key":"bibr30-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13200"},{"key":"bibr31-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-3806(01)00303-0"},{"key":"bibr32-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-21-08363.1997"},{"key":"bibr33-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2017-313707"},{"key":"bibr34-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1097\/00004647-199802000-00014"},{"key":"bibr35-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2012.09.001"},{"key":"bibr36-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)17946-X"},{"key":"bibr37-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1097\/MOP.0000000000000591"},{"issue":"10","key":"bibr38-23982128221097568","first-page":"590","volume":"20","author":"Greenberg MVC","year":"2019","journal-title":"Molecular Cell Biology"},{"key":"bibr39-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1136\/bmjpo-2019-000494"},{"key":"bibr40-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/S0303-8467(99)00035-9"},{"key":"bibr41-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-199610000-00015"},{"key":"bibr42-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2015.13"},{"key":"bibr43-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.1993.tb12601.x"},{"key":"bibr44-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.44.27715"},{"key":"bibr45-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.107.499822"},{"key":"bibr46-23982128221097568","doi-asserted-by":"publisher","DOI":"10.3390\/genes7120117"},{"key":"bibr47-23982128221097568","doi-asserted-by":"publisher","DOI":"10.4161\/epi.27648"},{"key":"bibr48-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2004.02968.x"},{"key":"bibr49-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2009.04.012"},{"key":"bibr50-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/ng.298"},{"key":"bibr51-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1111\/gbb.12184"},{"issue":"2013","key":"bibr52-23982128221097568","volume":"2013","author":"Jacobs SE","year":"2013","journal-title":"Cochrane Database of Systematic Reviews"},{"key":"bibr53-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1001\/archpediatrics.2011.43"},{"key":"bibr54-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2018.01.002"},{"key":"bibr55-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3230"},{"key":"bibr56-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-323-40139-5.00062-0"},{"key":"bibr57-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-014-1391-2"},{"key":"bibr58-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/nature14248"},{"key":"bibr59-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2015.10.007"},{"key":"bibr60-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2018-316509"},{"key":"bibr61-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.1995.tb00626.x"},{"key":"bibr62-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2017.10.006"},{"key":"bibr63-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2008.02.011"},{"key":"bibr64-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-014-8764-z"},{"key":"bibr65-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-200201000-00007"},{"key":"bibr66-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"bibr67-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2015.08.021"},{"key":"bibr68-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2017.11.009"},{"key":"bibr69-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.ridd.2019.103508"},{"key":"bibr70-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1159\/000244319"},{"key":"bibr71-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410420310"},{"key":"bibr72-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/561494"},{"key":"bibr73-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1159\/000456658"},{"key":"bibr74-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/0165-3806(94)00177-2"},{"key":"bibr75-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-316-5_4"},{"key":"bibr76-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1177\/1099800419852766"},{"key":"bibr77-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1126\/science.164.3880.719"},{"key":"bibr78-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9378(97)70139-X"},{"key":"bibr79-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/pr.2015.100"},{"key":"bibr80-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22353"},{"key":"bibr81-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2009.188"},{"key":"bibr82-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/nature09230"},{"key":"bibr83-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.devbrainres.2004.06.019"},{"key":"bibr84-23982128221097568","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.00417"},{"issue":"1","key":"bibr85-23982128221097568","first-page":"203","volume":"21","author":"Pu Y","year":"2000","journal-title":"AJNR: American Journal of Neuroradiology"},{"key":"bibr86-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-3806(00)00111-5"},{"key":"bibr87-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2016.06.024"},{"key":"bibr88-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1002\/glia.10059"},{"key":"bibr89-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/0887-8994(92)90050-9"},{"key":"bibr90-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.09.011"},{"key":"bibr91-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(94)90038-8"},{"key":"bibr92-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.244"},{"key":"bibr93-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.112.674481"},{"key":"bibr94-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510310103"},{"key":"bibr95-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1101\/gr.091470.109"},{"key":"bibr96-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1111\/apa.14821"},{"key":"bibr97-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcps050929"},{"key":"bibr98-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.7218"},{"key":"bibr99-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-199602290-00006"},{"key":"bibr100-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1101\/gr.104695.109"},{"key":"bibr101-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2009-2441"},{"key":"bibr102-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/S0736-5748(00)00075-7"},{"key":"bibr103-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2015.210"},{"key":"bibr104-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.16-07-02191.1996"},{"key":"bibr105-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.26.6.1093"},{"key":"bibr106-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-015-1937-8"},{"key":"bibr107-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1136\/fn.74.1.F3"},{"key":"bibr108-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1159\/000353948"},{"key":"bibr109-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/506320"},{"key":"bibr110-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1007\/BF00310141"},{"key":"bibr111-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1007\/BF00315011"},{"key":"bibr112-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1186\/s40246-015-0041-3"},{"key":"bibr113-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.1997.tb01522.x"},{"key":"bibr114-23982128221097568","unstructured":"United Nations Inter- agency Group for Child Mortality Estimation (UN-IGME) (2019) Levels & trends in child mortality: Report 2019, estimates developed by the United Nations Inter-agency Group for Child Mortality Estimation. Available at: https:\/\/www.unicef.org\/reports\/levels-and-trends-child-mortality-report-2019"},{"key":"bibr115-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1203\/01.pdr.0000200799.64038.19"},{"key":"bibr116-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00007.2013"},{"key":"bibr117-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.19.2.245"},{"key":"bibr118-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1159\/000085978"},{"key":"bibr119-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0036422"},{"key":"bibr120-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/srep23430"},{"key":"bibr121-23982128221097568","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.12749"},{"key":"bibr122-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-67532-2"},{"key":"bibr123-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1186\/1756-8935-4-1"},{"key":"bibr124-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2009.03.011"},{"key":"bibr125-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181c97d04"},{"key":"bibr126-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-11778-w"},{"key":"bibr127-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1101\/gad.927301"},{"key":"bibr128-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2010.03.030"},{"key":"bibr129-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlx046"},{"key":"bibr130-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1038\/nature12433"},{"key":"bibr131-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20497"},{"key":"bibr132-23982128221097568","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M502581200"}],"container-title":["Brain and Neuroscience Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/23982128221097568","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/23982128221097568","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/23982128221097568","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T13:32:58Z","timestamp":1777383178000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/23982128221097568"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1]]},"references-count":132,"alternative-id":["10.1177\/23982128221097568"],"URL":"https:\/\/doi.org\/10.1177\/23982128221097568","relation":{},"ISSN":["2398-2128","2398-2128"],"issn-type":[{"value":"2398-2128","type":"print"},{"value":"2398-2128","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1]]},"article-number":"23982128221097568"}}