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Improved neuroprotection with melatonin-augmented hypothermia versus hypothermia alone in a perinatal asphyxia model
  1. S Faulkner1,
  2. M Chandrasekaran1,
  3. A Bainbridge2,
  4. D Kelen1,
  5. E Powell1,
  6. D Price2,
  7. E Cady2,
  8. X Golay3,
  9. G Raivich1,
  10. N J Robertson1
  1. 1University College London, London, UK
  2. 2University College Hospitals, London, UK
  3. 3Institute of Neurology, Queen Square, London, UK

Abstract

Background Melatonin (N-acetyl-5-methoxytryptamine) is a naturally occurring hormone, an anti-oxidant and cellular pro-survival factor. It is used safely in children with sleep disorders. Beneficial properties of melatonin following brain injury in adult animals have been observed. It is unknown if melatonin augments hypothermic neuroprotection in the developing brain. Proton magnetic resonance spectroscopy (MRS) biomarkers (e.g., lactate/N acetyl asparate – Lac/NAA) are surrogate outcome markers in asphyxiated infants and correlate with cell death.

Aim To determine whether melatonin-augmented hypothermia is more neuroprotective versus hypothermia alone in a piglet model of perinatal asphyxia.

Methods 17 male piglets (<24 h) underwent transient global hypoxia-ischaemia and were randomized to (1) 24 h hypothermia (33.5°C) 2–26 h; or (2) 24 h hypothermia plus 5 mg/kg melatonin infusion started 10 min after resuscitation and 24 h thereafter. 1H MRS (Lac/Creatine (Cr), NAA/Cr and Lac/NAA) in the thalamus (vmFB) and dorsal subcortical white matter voxels were acquired up to 48 h after injury. Area under the Curve (AUC) levels were calculated.

Results Compared to hypothermia alone, post-insult treatment with melatonin combined with hypothermia led to a significant decrease in thalamic Lac/NAA and Lac/Cr AUC (p<0.05, one-sided t-test) in the deep grey matter and increase in NAA/Cr (p<0.05) in the white matter (figure 1).

Abstract 5B.2 Figure 1

Brain metabolite ratios for thalamus (vmFB) (Left) and white matter (WM) (Right). Melatonin +hypothermia reduced Lactate/Cr and Lac/NAA and increased NAA/Cr VERSUS hypothermia (control).

Discussion Combined cooling with melatonin was more neuroprotective than cooling alone in this piglet perinatal asphxya model. Melatonin is a promising candidate for adjunct therapy with cooling in newborn infants with moderate to severe neonatal encephalopathy and may reduce adverse outcome.

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