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Melatonin as an adjunct to therapeutic hypothermia in a piglet model of neonatal encephalopathy: A translational study

Robertson, NJ; Martinello, K; Lingam, I; Avdic-Belltheus, A; Meehan, C; Alonso-Alconada, D; Ragab, S; ... Facchinetti, F; + view all (2019) Melatonin as an adjunct to therapeutic hypothermia in a piglet model of neonatal encephalopathy: A translational study. Neurobiology of Disease , 121 pp. 240-251. 10.1016/j.nbd.2018.10.004.

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Abstract

Therapeutic hypothermia is only partially protective for neonatal encephalopathy; there is an urgent need to develop treatments that augment cooling. Our objective was to assess safety, efficacy and pharmacokinetics of 5 and15mg/kg/24h melatonin (proprietary formulation) administered at 2h and 26h after hypoxia-ischemia (HI) with cooling in a piglet model. Following moderate cerebral HI, 30 piglets were eligible and randomized to: i) Hypothermia (33.5°C, 2-26h) and vehicle (HT+V;n=13); b) HT and 5mg/kg melatonin over 6h at 2h and 26h after HI (HT+Mel-5;n=4); c) HT and 15mg/kg melatonin over 6h at 2h and 26h after HI (HT+Mel-15;n=13). Intensive care was maintained for 48h; brain MRS was acquired and cell death (TUNEL) evaluated at 48h. Comparing HT+V with HT+Mel-5 and HT+Mel-15, there was no difference in blood pressure or inotropic support needed, brain Lactate/N Acetylaspartate at 24h and 48h was similar, ATP/phosphate pool was higher for HT+Mel-15 versus HT+V at 24h (p=0.038) but not 48h. A localized reduction in TUNEL positive cell death was observed in the sensorimotor cortex in the 15mg/kg melatonin group (HT+Mel-15 versus HT+V; p<0.003) but not in the 5mg/kg melatonin group (HT+Mel-5 versus HT+V; p=0.808). Putative therapeutic melatonin levels were reached 8h after HI (10⁴ increase from baseline; ~15-30mg/L). Mean +SD peak plasma melatonin levels after the first infusion were 0.0014+0.0012 mg/L in the HT+V group, 3.97+1.53 mg/L in the HT+Mel-5 group and 16.8+8.3 mg/L in the HT+Mel-15 group. Protection was dose dependent; 15mg/kg melatonin started 2h after HI, given over 6h, was well tolerated and augmented hypothermic protection in sensorimotor cortex. Earlier attainment of therapeutic plasma melatonin levels may optimize protection by targeting initial events of reperfusion injury. The time window for intervention with melatonin, as adjunct therapy with cooling, is likely to be narrow and should be considered in designing future clinical studies.

Type: Article
Title: Melatonin as an adjunct to therapeutic hypothermia in a piglet model of neonatal encephalopathy: A translational study
DOI: 10.1016/j.nbd.2018.10.004
Publisher version: https://doi.org/10.1016/j.nbd.2018.10.004
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Brain Repair and Rehabilitation
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Metabolism and Experi Therapeutics
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Inst for Women's Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Inst for Women's Health > Maternal and Fetal Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Inst for Women's Health > Neonatology
URI: http://discovery.ucl.ac.uk/id/eprint/10057867
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