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TH is partially effective and adjuvant therapies are needed. Here, we examined whether the antioxidant melatonin (MLT) provides additive benefit with TH, compared to TH alone or MLT alone, to improve recovery from acute encephalopathy in newborn lambs. Immediately before cesarean section delivery, we induced asphyxia in fetal sheep via umbilical cord occlusion until mean arterial blood pressure fell from 55\u00a0\u00b1\u00a03\u00a0mm\u00a0Hg in sham controls to 18\u201020\u00a0mm\u00a0Hg (10.1\u00a0\u00b1\u00a01.5\u00a0minutes). Lambs were delivered and randomized to control, control\u00a0+\u00a0MLT (60\u00a0mg iv, from 30\u00a0minutes to 24\u00a0hours), asphyxia, asphyxia\u00a0+\u00a0TH (whole\u2010body cooling to 35.1\u00a0\u00b1\u00a00.8\u00b0C vs. 38.3\u00a0\u00b1\u00a00.17\u00b0C in sham controls, from 4\u201028\u00a0hours), asphyxia\u00a0+\u00a0MLT, and asphyxia\u00a0+\u00a0TH\u00a0+\u00a0MLT. At 72\u00a0hours, magnetic resonance spectroscopy (MRS) was undertaken, and then brains were collected for neuropathology assessment. Asphyxia induced abnormal brain metabolism on MRS with increased Lactate:NAA (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.003) and reduced NAA:Choline (<jats:italic>P<\/jats:italic>\u00a0=\u00a0.005), induced apoptotic and necrotic cell death across gray and white matter brain regions (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.05), and increased neuroinflammation and oxidative stress (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.05). TH and MLT were independently associated with region\u2010specific reductions in oxidative stress, inflammation, and cell death, compared to asphyxia alone. There was an interaction between TH and MLT such that the NAA:Choline ratio was not significantly different after asphyxia\u00a0+\u00a0TH\u00a0+\u00a0MLT compared to sham controls but had a greater overall reduction in neuropathology than either treatment alone. This study demonstrates that, in newborn lambs, combined TH\u00a0+\u00a0MLT for neonatal encephalopathy provides significantly greater neuroprotection than either alone. These results will guide the development of further trials for neonatal encephalopathy.<\/jats:p>","DOI":"10.1111\/jpi.12744","type":"journal-article","created":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T11:58:07Z","timestamp":1621943887000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Melatonin augments the neuroprotective effects of hypothermia in lambs following perinatal asphyxia"],"prefix":"10.1111","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4000-2110","authenticated-orcid":false,"given":"James DS.","family":"Aridas","sequence":"first","affiliation":[{"name":"Hudson Institute of Medical Research The Ritchie Centre  Clayton Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Yawno","sequence":"additional","affiliation":[{"name":"Hudson Institute of Medical Research The Ritchie Centre  Clayton Vic. Australia"},{"name":"Department of Obstetrics and Gynaecology Monash University  Clayton Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy E.","family":"Sutherland","sequence":"additional","affiliation":[{"name":"Hudson Institute of Medical Research The Ritchie Centre  Clayton Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilias","family":"Nitsos","sequence":"additional","affiliation":[{"name":"Hudson Institute of Medical Research The Ritchie Centre  Clayton Vic. Australia"},{"name":"Department of Obstetrics and Gynaecology Monash University  Clayton Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flora Y.","family":"Wong","sequence":"additional","affiliation":[{"name":"Hudson Institute of Medical Research The Ritchie Centre  Clayton Vic. Australia"},{"name":"Department of Paediatrics Monash University  Clayton Vic. Australia"},{"name":"Monash Children's Hospital Monash Health  Clayton Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rod W.","family":"Hunt","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Monash University  Clayton Vic. Australia"},{"name":"Monash Children's Hospital Monash Health  Clayton Vic. Australia"},{"name":"Murdoch Children's Research Institute  Melbourne Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ditchfield","sequence":"additional","affiliation":[{"name":"Monash Children's Hospital Monash Health  Clayton Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Fahey","sequence":"additional","affiliation":[{"name":"Hudson Institute of Medical Research The Ritchie Centre  Clayton Vic. Australia"},{"name":"Department of Paediatrics Monash University  Clayton Vic. Australia"},{"name":"Monash Children's Hospital Monash Health  Clayton Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atul","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Hudson Institute of Medical Research The Ritchie Centre  Clayton Vic. Australia"},{"name":"Department of Paediatrics Monash University  Clayton Vic. Australia"},{"name":"Monash Children's Hospital Monash Health  Clayton Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4506-5233","authenticated-orcid":false,"given":"Euan M.","family":"Wallace","sequence":"additional","affiliation":[{"name":"Hudson Institute of Medical Research The Ritchie Centre  Clayton Vic. Australia"},{"name":"Department of Obstetrics and Gynaecology Monash University  Clayton Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alistair J.","family":"Gunn","sequence":"additional","affiliation":[{"name":"Department of Physiology School of Medical Sciences University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Jenkin","sequence":"additional","affiliation":[{"name":"Hudson Institute of Medical Research The Ritchie Centre  Clayton Vic. Australia"},{"name":"Department of Obstetrics and Gynaecology Monash University  Clayton Vic. 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