{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:09:11Z","timestamp":1790809751962,"version":"4.1.0"},"reference-count":72,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T00:00:00Z","timestamp":1606780800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"United Kingdom Department of Health\u2019s National Institute"},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/P025978\/1"],"award-info":[{"award-number":["MR\/P025978\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,16]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>As therapeutic hypothermia is only partially protective for neonatal encephalopathy, safe and effective adjunct therapies are urgently needed. Melatonin and erythropoietin show promise as safe and effective neuroprotective therapies. We hypothesized that melatonin and erythropoietin individually augment 12-h hypothermia (double therapies) and hypothermia + melatonin + erythropoietin (triple therapy) leads to optimal brain protection. Following carotid artery occlusion and hypoxia, 49 male piglets (&amp;lt;48\u2009h old) were randomized to: (i) hypothermia + vehicle (n\u2009=\u200912), (ii) hypothermia + melatonin (20\u2009mg\/kg over 2\u2009h) (n\u2009=\u200912), (iii) hypothermia + erythropoietin (3000\u2009U\/kg bolus) (n\u2009=\u200913) or (iv) tripletherapy (n\u2009=\u200912). Melatonin, erythropoietin or vehicle were given at 1, 24 and 48\u2009h after hypoxia\u2013ischaemia. Hypoxia\u2013ischaemia severity was similar across groups. Therapeutic levels were achieved 3\u2009hours after hypoxia\u2013ischaemia for melatonin (15\u201330 mg\/l) and within 30\u2009min of erythropoietin administration (maximum concentration 10 000 mU\/ml). Compared to hypothermia + vehicle, we observed faster amplitude-integrated EEG recovery from 25 to 30\u2009h with hypothermia + melatonin (P\u2009=\u20090.02) and hypothermia + erythropoietin (P\u2009=\u20090.033) and from 55 to 60\u2009h with tripletherapy (P\u2009=\u20090.042). Magnetic resonance spectroscopy lactate\/N-acetyl aspartate peak ratio was lower at 66\u2009h in hypothermia + melatonin (P\u2009=\u20090.012) and tripletherapy (P\u2009=\u20090.032). With hypothermia + melatonin, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells were reduced in sensorimotor cortex (P\u2009=\u20090.017) and oligodendrocyte transcription factor 2 labelled-positive counts increased in hippocampus (P\u2009=\u20090.014) and periventricular white matter (P\u2009=\u20090.039). There was no reduction in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells with hypothermia + erythropoietin, but increased oligodendrocyte transcription factor 2 labelled-positive cells in 5 of 8 brain regions (P\u2009&amp;lt;\u20090.05). Overall, melatonin and erythropoietin were safe and effective adjunct therapies to hypothermia. Hypothermia + melatonin double therapy led to faster amplitude-integrated EEG recovery, amelioration of lactate\/N-acetyl aspartate rise and reduction in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells in the sensorimotor cortex. Hypothermia + erythropoietin doubletherapy was in association with EEG recovery and was most effective in promoting oligodendrocyte survival. Tripletherapy provided no added benefit over the double therapies in this 72-h study. Melatonin and erythropoietin influenced cell death and oligodendrocyte survival differently, reflecting distinct neuroprotective mechanisms which may become more visible with longer-term studies. Staggering the administration of therapies with early melatonin and later erythropoietin (after hypothermia) may provide better protection; each therapy has complementary actions which may be time critical during the neurotoxic cascade after hypoxia\u2013ischaemia.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaa211","type":"journal-article","created":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T14:44:17Z","timestamp":1606833857000},"source":"Crossref","is-referenced-by-count":44,"title":["Melatonin and\/or erythropoietin combined with hypothermia in a piglet model of perinatal asphyxia"],"prefix":"10.1093","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2004-6650","authenticated-orcid":false,"given":"Raymand","family":"Pang","sequence":"first","affiliation":[{"name":"Department of Neonatology, Institute for Women's Health, University College London, London, 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University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9613-688X","authenticated-orcid":false,"given":"Qin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Institute for Women's Health, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Sokolska","sequence":"additional","affiliation":[{"name":"Department of Medical Physics and Biomedical Engineering, University College London Hospitals, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Torrealdea","sequence":"additional","affiliation":[{"name":"Department of Medical Physics and Biomedical Engineering, University College London Hospitals, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariya","family":"Hristova","sequence":"additional","affiliation":[{"name":"Department 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