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.
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