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

Robertson, Nicola J., Martinello, Kathryn, Lingam, Ingran, Avdic-Belltheus, Adnan, Meehan, Christopher, Alonso-Alconada, Daniel, Ragab, Sara, Bainbridge, Alan, Sokolska, Magdalena, Tachrount, Mohamed , Middleton, Benita, Price, David, Hristova, Mariya, Golay, Xavier, Soliani Raschini, Annamaria, Aquino, Giancarlo, Pelizzi, Nicola and Facchinetti, Fabrizio (2018) Melatonin as an adjunct to therapeutic hypothermia in a piglet model of neonatal encephalopathy: A translational study. Neurobiology of Disease, 121. pp. 240-251.

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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 and 15 mg/kg/24 h melatonin (proprietary formulation) administered at 2 h and 26 h 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, 2–26 h) and vehicle (HT + V;n = 13); b) HT and 5 mg/kg melatonin over 6 h at 2 h and 26 h after HI (HT + Mel-5;n = 4); c) HT and 15 mg/kg melatonin over 6 h at 2 h and 26 h after HI (HT + Mel-15;n = 13). Intensive care was maintained for 48 h; brain MRS was acquired and cell death (TUNEL) evaluated at 48 h. 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 24 h and 48 h was similar, ATP/phosphate pool was higher for HT + Mel-15 versus HT + V at 24 h (p = 0.038) but not 48 h. A localized reduction in TUNEL positive cell death was observed in the sensorimotor cortex in the 15 mg/kg melatonin group (HT + Mel-15 versus HT + V; p < 0.003) but not in the 5 mg/kg melatonin group (HT + Mel-5 versus HT + V; p = 0.808). Putative therapeutic melatonin levels were reached 8 h after HI (104 increase from baseline; ~15–30 mg/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; 15 mg/kg melatonin started 2 h after HI, given over 6 h, 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.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Robertson, Nicola J.
Martinello, Kathryn
Lingam, Ingran
Avdic-Belltheus, Adnan
Meehan, Christopher
Alonso-Alconada, Daniel
Ragab, Sara
Bainbridge, Alan
Sokolska, Magdalena
Tachrount, Mohamed
Middleton, BenitaB.Middleton@surrey.ac.uk
Price, David
Hristova, Mariya
Golay, Xavier
Soliani Raschini, Annamaria
Aquino, Giancarlo
Pelizzi, Nicola
Facchinetti, Fabrizio
Date : 6 October 2018
DOI : 10.1016/j.nbd.2018.10.004
Copyright Disclaimer : © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Depositing User : Clive Harris
Date Deposited : 14 Jan 2019 11:14
Last Modified : 07 Oct 2019 02:08
URI: http://epubs.surrey.ac.uk/id/eprint/850132

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