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No neuroprotective interventions are currently available. Melatonin (<jats:styled-content style=\"fixed-case\">MLT<\/jats:styled-content>), a potent antioxidant, anti\u2010inflammatory and antiapoptotic agent, offers promise as an intravenous (<jats:styled-content style=\"fixed-case\">IV<\/jats:styled-content>) or transdermal therapy to protect the brain. We aimed to determine the effect of melatonin (<jats:styled-content style=\"fixed-case\">IV<\/jats:styled-content>or transdermal patch) on neuropathology in a lamb model of perinatal asphyxia. Asphyxia was induced in newborn lambs via umbilical cord occlusion at birth. Animals were randomly allocated to melatonin commencing 30\u00a0minutes after birth (60\u00a0mg in 24\u00a0hours;<jats:styled-content style=\"fixed-case\">IV<\/jats:styled-content>or transdermal patch). Brain magnetic resonance spectroscopy (<jats:styled-content style=\"fixed-case\">MRS<\/jats:styled-content>) was undertaken at 12 and 72\u00a0hours. Animals (control n\u00a0=\u00a09; control+<jats:styled-content style=\"fixed-case\">MLT<\/jats:styled-content>n\u00a0=\u00a06; asphyxia n\u00a0=\u00a016; asphyxia+<jats:styled-content style=\"fixed-case\">MLT<\/jats:styled-content>[<jats:styled-content style=\"fixed-case\">IV<\/jats:styled-content>n\u00a0=\u00a014; patch n\u00a0=\u00a04]) were euthanised at 72\u00a0hours, and cerebrospinal fluid (<jats:styled-content style=\"fixed-case\">CSF<\/jats:styled-content>) and brains were collected for analysis. Asphyxia resulted in severe acidosis (<jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content>6.9\u00a0\u00b1\u00a00.0; lactate 9\u00a0\u00b1\u00a02\u00a0mmol\/L) and altered determinants of encephalopathy.<jats:styled-content style=\"fixed-case\">MRS<\/jats:styled-content>lactate:N\u2010acetyl aspartate ratio was 2.5\u2010fold higher in asphyxia lambs compared with controls at 12\u00a0hours and 3\u2010fold higher at 72\u00a0hours (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.05). Melatonin prevented this rise (3.5\u2010fold reduced vs asphyxia;<jats:italic>P<\/jats:italic>\u00a0=\u00a0.02). Asphyxia significantly increased brain white and grey matter apoptotic cell death (activated caspase\u20103), lipid peroxidation (4<jats:styled-content style=\"fixed-case\">HNE<\/jats:styled-content>) and neuroinflammation (<jats:styled-content style=\"fixed-case\">IBA<\/jats:styled-content>\u20101). These changes were significantly mitigated by both<jats:styled-content style=\"fixed-case\">IV<\/jats:styled-content>and patch melatonin. Systemic or transdermal neonatal melatonin administration significantly reduces the neuropathology and encephalopathy signs associated with perinatal asphyxia. A simple melatonin patch, administered soon after birth, may improve outcome in infants affected by asphyxia, especially in low\u2010resource settings.<\/jats:p>","DOI":"10.1111\/jpi.12479","type":"journal-article","created":{"date-parts":[[2018,2,21]],"date-time":"2018-02-21T20:24:44Z","timestamp":1519244684000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Systemic and transdermal melatonin administration prevents neuropathology in response to perinatal asphyxia in newborn lambs"],"prefix":"10.1111","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4000-2110","authenticated-orcid":false,"given":"James D. S.","family":"Aridas","sequence":"first","affiliation":[{"name":"The Ritchie Centre Hudson Institute of Medical Research Clayton Vic. 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Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Ditchfield","sequence":"additional","affiliation":[{"name":"Monash Children's Hospital Monash Health Clayton Vic. Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flora Y.","family":"Wong","sequence":"additional","affiliation":[{"name":"The Ritchie Centre Hudson Institute of Medical Research Clayton Vic. Australia"},{"name":"Monash Children's Hospital Monash Health Clayton Vic. Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rod W.","family":"Hunt","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute Melbourne Vic. Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael C.","family":"Fahey","sequence":"additional","affiliation":[{"name":"The Ritchie Centre Hudson Institute of Medical Research Clayton Vic. Australia"},{"name":"Monash Children's Hospital Monash Health Clayton Vic. Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atul","family":"Malhotra","sequence":"additional","affiliation":[{"name":"The Ritchie Centre Hudson Institute of Medical Research Clayton Vic. Australia"},{"name":"Monash Children's Hospital Monash Health Clayton Vic. Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4506-5233","authenticated-orcid":false,"given":"Euan M.","family":"Wallace","sequence":"additional","affiliation":[{"name":"The Ritchie Centre Hudson Institute of Medical Research Clayton Vic. Australia"},{"name":"Department of Obstetrics and Gynaecology Monash University Clayton Vic. Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graham","family":"Jenkin","sequence":"additional","affiliation":[{"name":"The Ritchie Centre Hudson Institute of Medical Research Clayton Vic. Australia"},{"name":"Department of Obstetrics and Gynaecology Monash University Clayton Vic. 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