Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model

Nicola J. Robertson, Stuart Faulkner, Bobbi Fleiss, Alan Bainbridge, Csilla Andorka, David Price, Elizabeth Powell, Lucy Lecky-Thompson, Laura Thei, Manigandan Chandrasekaran, Mariya Hristova, Ernest B. Cady, Pierre Gressens, Xavier Golay, Gennadij Raivich

Research output: Contribution to journalArticle

Abstract

Despite treatment with therapeutic hypothermia, almost 50% of infants with neonatal encephalopathy still have adverse outcomes. Additional treatments are required to maximize neuroprotection. Melatonin is a naturally occurring hormone involved in physiological processes that also has neuroprotective actions against hypoxic-ischaemic brain injury in animal models. The objective of this study was to assess neuroprotective effects of combining melatonin with therapeutic hypothermia after transient hypoxia-ischaemia in a piglet model of perinatal asphyxia using clinically relevant magnetic resonance spectroscopy biomarkers supported by immunohistochemistry. After a quantified global hypoxic-ischaemic insult, 17 newborn piglets were randomized to the following: (i) therapeutic hypothermia (33.5°C from 2 to 26 h after resuscitation, n = 8) and (ii) therapeutic hypothermia plus intravenous melatonin (5 mg/kg/h over 6 h started at 10 min after resuscitation and repeated at 24 h, n = 9). Cortical white matter and deep grey matter voxel proton and whole brain 31P magnetic resonance spectroscopy were acquired before and during hypoxia-ischaemia, at 24 and 48 h after resuscitation. There was no difference in baseline variables, insult severity or any physiological or biochemical measure, including mean arterial blood pressure and inotrope use during the 48 h after hypoxia-ischaemia. Plasma levels of melatonin were 10 000 times higher in the hypothermia plus melatonin than hypothermia alone group. Melatonin-augmented hypothermia significantly reduced the hypoxic-ischaemic- induced increase in the area under the curve for proton magnetic resonance spectroscopy lactate/N-acetyl aspartate and lactate/total creatine ratios in the deep grey matter. Melatonin-augmented hypothermia increased levels of whole brain 31P magnetic resonance spectroscopy nucleotide triphosphate/exchangeable phosphate pool. Correlating with improved cerebral energy metabolism, TUNEL-positive nuclei were reduced in the hypothermia plus melatonin group compared with hypothermia alone in the thalamus, internal capsule, putamen and caudate, and there was reduced cleaved caspase 3 in the thalamus. Although total numbers of microglia were not decreased in grey or white matter, expression of the prototypical cytotoxic microglial activation marker CD86 was decreased in the cortex at 48 h after hypoxia-ischaemia. The safety and improved neuroprotection with a combination of melatonin with cooling support phase II clinical trials in infants with moderate and severe neonatal encephalopathy.

Original languageEnglish (US)
Pages (from-to)90-105
Number of pages16
JournalBrain
Volume136
Issue number1
DOIs
StatePublished - 2013
Externally publishedYes

Fingerprint

Asphyxia
Melatonin
Hypothermia
Induced Hypothermia
Ischemia
Resuscitation
Magnetic Resonance Spectroscopy
Brain Diseases
Thalamus
Lactic Acid
Arterial Pressure
Physiological Phenomena
Neuroprotection
Internal Capsule
Phase II Clinical Trials
Creatine
Putamen
In Situ Nick-End Labeling
Brain
Microglia

Keywords

  • hypoxia-ischaemia
  • melatonin
  • neonatal encephalopathy
  • neuroprotection
  • therapeutic hypothermia

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Robertson, N. J., Faulkner, S., Fleiss, B., Bainbridge, A., Andorka, C., Price, D., ... Raivich, G. (2013). Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain, 136(1), 90-105. https://doi.org/10.1093/brain/aws285

Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. / Robertson, Nicola J.; Faulkner, Stuart; Fleiss, Bobbi; Bainbridge, Alan; Andorka, Csilla; Price, David; Powell, Elizabeth; Lecky-Thompson, Lucy; Thei, Laura; Chandrasekaran, Manigandan; Hristova, Mariya; Cady, Ernest B.; Gressens, Pierre; Golay, Xavier; Raivich, Gennadij.

In: Brain, Vol. 136, No. 1, 2013, p. 90-105.

Research output: Contribution to journalArticle

Robertson, NJ, Faulkner, S, Fleiss, B, Bainbridge, A, Andorka, C, Price, D, Powell, E, Lecky-Thompson, L, Thei, L, Chandrasekaran, M, Hristova, M, Cady, EB, Gressens, P, Golay, X & Raivich, G 2013, 'Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model', Brain, vol. 136, no. 1, pp. 90-105. https://doi.org/10.1093/brain/aws285
Robertson NJ, Faulkner S, Fleiss B, Bainbridge A, Andorka C, Price D et al. Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain. 2013;136(1):90-105. https://doi.org/10.1093/brain/aws285
Robertson, Nicola J. ; Faulkner, Stuart ; Fleiss, Bobbi ; Bainbridge, Alan ; Andorka, Csilla ; Price, David ; Powell, Elizabeth ; Lecky-Thompson, Lucy ; Thei, Laura ; Chandrasekaran, Manigandan ; Hristova, Mariya ; Cady, Ernest B. ; Gressens, Pierre ; Golay, Xavier ; Raivich, Gennadij. / Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. In: Brain. 2013 ; Vol. 136, No. 1. pp. 90-105.
@article{dcc7ccae0f67441cbdce09b6b19206f9,
title = "Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model",
abstract = "Despite treatment with therapeutic hypothermia, almost 50{\%} of infants with neonatal encephalopathy still have adverse outcomes. Additional treatments are required to maximize neuroprotection. Melatonin is a naturally occurring hormone involved in physiological processes that also has neuroprotective actions against hypoxic-ischaemic brain injury in animal models. The objective of this study was to assess neuroprotective effects of combining melatonin with therapeutic hypothermia after transient hypoxia-ischaemia in a piglet model of perinatal asphyxia using clinically relevant magnetic resonance spectroscopy biomarkers supported by immunohistochemistry. After a quantified global hypoxic-ischaemic insult, 17 newborn piglets were randomized to the following: (i) therapeutic hypothermia (33.5°C from 2 to 26 h after resuscitation, n = 8) and (ii) therapeutic hypothermia plus intravenous melatonin (5 mg/kg/h over 6 h started at 10 min after resuscitation and repeated at 24 h, n = 9). Cortical white matter and deep grey matter voxel proton and whole brain 31P magnetic resonance spectroscopy were acquired before and during hypoxia-ischaemia, at 24 and 48 h after resuscitation. There was no difference in baseline variables, insult severity or any physiological or biochemical measure, including mean arterial blood pressure and inotrope use during the 48 h after hypoxia-ischaemia. Plasma levels of melatonin were 10 000 times higher in the hypothermia plus melatonin than hypothermia alone group. Melatonin-augmented hypothermia significantly reduced the hypoxic-ischaemic- induced increase in the area under the curve for proton magnetic resonance spectroscopy lactate/N-acetyl aspartate and lactate/total creatine ratios in the deep grey matter. Melatonin-augmented hypothermia increased levels of whole brain 31P magnetic resonance spectroscopy nucleotide triphosphate/exchangeable phosphate pool. Correlating with improved cerebral energy metabolism, TUNEL-positive nuclei were reduced in the hypothermia plus melatonin group compared with hypothermia alone in the thalamus, internal capsule, putamen and caudate, and there was reduced cleaved caspase 3 in the thalamus. Although total numbers of microglia were not decreased in grey or white matter, expression of the prototypical cytotoxic microglial activation marker CD86 was decreased in the cortex at 48 h after hypoxia-ischaemia. The safety and improved neuroprotection with a combination of melatonin with cooling support phase II clinical trials in infants with moderate and severe neonatal encephalopathy.",
keywords = "hypoxia-ischaemia, melatonin, neonatal encephalopathy, neuroprotection, therapeutic hypothermia",
author = "Robertson, {Nicola J.} and Stuart Faulkner and Bobbi Fleiss and Alan Bainbridge and Csilla Andorka and David Price and Elizabeth Powell and Lucy Lecky-Thompson and Laura Thei and Manigandan Chandrasekaran and Mariya Hristova and Cady, {Ernest B.} and Pierre Gressens and Xavier Golay and Gennadij Raivich",
year = "2013",
doi = "10.1093/brain/aws285",
language = "English (US)",
volume = "136",
pages = "90--105",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "1",

}

TY - JOUR

T1 - Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model

AU - Robertson, Nicola J.

AU - Faulkner, Stuart

AU - Fleiss, Bobbi

AU - Bainbridge, Alan

AU - Andorka, Csilla

AU - Price, David

AU - Powell, Elizabeth

AU - Lecky-Thompson, Lucy

AU - Thei, Laura

AU - Chandrasekaran, Manigandan

AU - Hristova, Mariya

AU - Cady, Ernest B.

AU - Gressens, Pierre

AU - Golay, Xavier

AU - Raivich, Gennadij

PY - 2013

Y1 - 2013

N2 - Despite treatment with therapeutic hypothermia, almost 50% of infants with neonatal encephalopathy still have adverse outcomes. Additional treatments are required to maximize neuroprotection. Melatonin is a naturally occurring hormone involved in physiological processes that also has neuroprotective actions against hypoxic-ischaemic brain injury in animal models. The objective of this study was to assess neuroprotective effects of combining melatonin with therapeutic hypothermia after transient hypoxia-ischaemia in a piglet model of perinatal asphyxia using clinically relevant magnetic resonance spectroscopy biomarkers supported by immunohistochemistry. After a quantified global hypoxic-ischaemic insult, 17 newborn piglets were randomized to the following: (i) therapeutic hypothermia (33.5°C from 2 to 26 h after resuscitation, n = 8) and (ii) therapeutic hypothermia plus intravenous melatonin (5 mg/kg/h over 6 h started at 10 min after resuscitation and repeated at 24 h, n = 9). Cortical white matter and deep grey matter voxel proton and whole brain 31P magnetic resonance spectroscopy were acquired before and during hypoxia-ischaemia, at 24 and 48 h after resuscitation. There was no difference in baseline variables, insult severity or any physiological or biochemical measure, including mean arterial blood pressure and inotrope use during the 48 h after hypoxia-ischaemia. Plasma levels of melatonin were 10 000 times higher in the hypothermia plus melatonin than hypothermia alone group. Melatonin-augmented hypothermia significantly reduced the hypoxic-ischaemic- induced increase in the area under the curve for proton magnetic resonance spectroscopy lactate/N-acetyl aspartate and lactate/total creatine ratios in the deep grey matter. Melatonin-augmented hypothermia increased levels of whole brain 31P magnetic resonance spectroscopy nucleotide triphosphate/exchangeable phosphate pool. Correlating with improved cerebral energy metabolism, TUNEL-positive nuclei were reduced in the hypothermia plus melatonin group compared with hypothermia alone in the thalamus, internal capsule, putamen and caudate, and there was reduced cleaved caspase 3 in the thalamus. Although total numbers of microglia were not decreased in grey or white matter, expression of the prototypical cytotoxic microglial activation marker CD86 was decreased in the cortex at 48 h after hypoxia-ischaemia. The safety and improved neuroprotection with a combination of melatonin with cooling support phase II clinical trials in infants with moderate and severe neonatal encephalopathy.

AB - Despite treatment with therapeutic hypothermia, almost 50% of infants with neonatal encephalopathy still have adverse outcomes. Additional treatments are required to maximize neuroprotection. Melatonin is a naturally occurring hormone involved in physiological processes that also has neuroprotective actions against hypoxic-ischaemic brain injury in animal models. The objective of this study was to assess neuroprotective effects of combining melatonin with therapeutic hypothermia after transient hypoxia-ischaemia in a piglet model of perinatal asphyxia using clinically relevant magnetic resonance spectroscopy biomarkers supported by immunohistochemistry. After a quantified global hypoxic-ischaemic insult, 17 newborn piglets were randomized to the following: (i) therapeutic hypothermia (33.5°C from 2 to 26 h after resuscitation, n = 8) and (ii) therapeutic hypothermia plus intravenous melatonin (5 mg/kg/h over 6 h started at 10 min after resuscitation and repeated at 24 h, n = 9). Cortical white matter and deep grey matter voxel proton and whole brain 31P magnetic resonance spectroscopy were acquired before and during hypoxia-ischaemia, at 24 and 48 h after resuscitation. There was no difference in baseline variables, insult severity or any physiological or biochemical measure, including mean arterial blood pressure and inotrope use during the 48 h after hypoxia-ischaemia. Plasma levels of melatonin were 10 000 times higher in the hypothermia plus melatonin than hypothermia alone group. Melatonin-augmented hypothermia significantly reduced the hypoxic-ischaemic- induced increase in the area under the curve for proton magnetic resonance spectroscopy lactate/N-acetyl aspartate and lactate/total creatine ratios in the deep grey matter. Melatonin-augmented hypothermia increased levels of whole brain 31P magnetic resonance spectroscopy nucleotide triphosphate/exchangeable phosphate pool. Correlating with improved cerebral energy metabolism, TUNEL-positive nuclei were reduced in the hypothermia plus melatonin group compared with hypothermia alone in the thalamus, internal capsule, putamen and caudate, and there was reduced cleaved caspase 3 in the thalamus. Although total numbers of microglia were not decreased in grey or white matter, expression of the prototypical cytotoxic microglial activation marker CD86 was decreased in the cortex at 48 h after hypoxia-ischaemia. The safety and improved neuroprotection with a combination of melatonin with cooling support phase II clinical trials in infants with moderate and severe neonatal encephalopathy.

KW - hypoxia-ischaemia

KW - melatonin

KW - neonatal encephalopathy

KW - neuroprotection

KW - therapeutic hypothermia

UR - http://www.scopus.com/inward/record.url?scp=84873380508&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873380508&partnerID=8YFLogxK

U2 - 10.1093/brain/aws285

DO - 10.1093/brain/aws285

M3 - Article

VL - 136

SP - 90

EP - 105

JO - Brain

JF - Brain

SN - 0006-8950

IS - 1

ER -