{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T12:14:56Z","timestamp":1785500096140,"version":"3.56.0"},"reference-count":57,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T00:00:00Z","timestamp":1581379200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","award":["17\/601"],"award-info":[{"award-number":["17\/601"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009940","name":"Lotto New Zealand","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009940","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001543","name":"Neurological Foundation of New Zealand","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001543","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Recombinant human erythropoietin (rEpo) is neuroprotective in immature animals, but it is unclear whether the combination of high\u2010dose rEpo therapy with therapeutic hypothermia can further improve outcomes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Hypothermia and rEpo independently improved neuronal survival, with greater improvement with hypothermia, and similarly reduced numbers of caspase\u20103 positive cells and reactive microglia after 7\u00a0days recovery.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Hypothermia, but not rEpo, was associated with markedly improved EEG power, whereas both interventions improved recovery of EEG frequency.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>There was no significant improvement in any outcome after combined rEpo and hypothermia compared with hypothermia alone, and of concern, the combination was associated with increased numbers of cortical caspase\u20103\u2010positive cells compared with ischaemia\u2010hypothermia.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These data suggest that the mechanisms of neuroprotection with hypothermia and rEpo overlap and, thus, high\u2010dose rEpo infusion does not appear to be an effective adjunct therapy for therapeutic hypothermia.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Therapeutic hypothermia for hypoxic\u2010ischaemic encephalopathy (HIE) provides incomplete neuroprotection. Recombinant human erythropoietin (rEpo) is neuroprotective in immature animals, but it is unclear whether adjunct rEpo therapy with therapeutic hypothermia can further improve outcomes. Near\u2010term fetal sheep received sham\u2010ischaemia (<jats:italic>n<\/jats:italic>\u00a0=\u00a09) or global cerebral ischaemia for 30\u00a0min (ischaemia\u2010vehicle, <jats:italic>n<\/jats:italic>\u00a0=\u00a08), followed by intravenous infusion of rEpo (ischaemia\u2010Epo, <jats:italic>n<\/jats:italic>\u00a0=\u00a08; 5000\u00a0U\/kg loading dose, then 833.3\u00a0U\/kg\/h), cerebral hypothermia (ischaemia\u2010hypothermia, <jats:italic>n<\/jats:italic>\u00a0=\u00a08), or rEpo plus hypothermia (ischaemia\u2010Epo\u2010hypothermia, <jats:italic>n<\/jats:italic>\u00a0=\u00a08), from 3 to 72\u00a0h post ischaemia. Fetal brains were collected 7\u00a0days after cerebral ischaemia. Cerebral ischaemia was associated with severe neuronal loss and microglial induction in the parasagittal cortex and subcortical regions. Hypothermia reduced overall neuronal loss, cortical caspase\u20103 and reactive microglia in the striatum and cortex, with greater recovery of electroencephalographic (EEG) power and spectral edge (SEF) from 48\u00a0h onwards. rEpo independently improved neuronal survival in the parasagittal cortex, hippocampal CA4 and thalamus, and reduced cortical caspase\u20103 and activated microglia in striatal and cortical areas, with greater SEF from 120\u00a0h onwards. However, ischaemia\u2010Epo\u2010hypothermia did not further improve outcomes compared with ischaemia\u2010hypothermia and was associated with increased numbers of cortical caspase\u20103\u2010positive cells. These findings suggest that although delayed, prolonged treatment with both hypothermia and rEpo are independently neuroprotective, they have overlapping anti\u2010inflammatory and anti\u2010apoptotic mechanisms, such that the delayed, high\u2010dose rEpo infusion for 3\u00a0days did not materially augment neuroprotection with therapeutic hypothermia.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp279131","type":"journal-article","created":{"date-parts":[[2020,1,8]],"date-time":"2020-01-08T05:15:53Z","timestamp":1578460553000},"page":"999-1015","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Non\u2010additive effects of adjunct erythropoietin therapy with therapeutic hypothermia after global cerebral ischaemia in near\u2010term fetal sheep"],"prefix":"10.1113","volume":"598","author":[{"given":"Guido","family":"Wassink","sequence":"first","affiliation":[{"name":"Fetal Physiology and Neuroscience Group Department of 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