Systemic and transdermal melatonin administration prevents neuropathology in response to perinatal asphyxia in newborn lambs

James D.S. Aridas, Tamara Yawno, Amy E. Sutherland, Ilias Nitsos, Michael Ditchfield, Flora Y. Wong, Rod W. Hunt, Michael C. Fahey, Atul Malhotra, Euan M. Wallace, Graham Jenkin, Suzanne L. Miller

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Perinatal asphyxia remains a principal cause of infant mortality and long-term neurological morbidity, particularly in low-resource countries. No neuroprotective interventions are currently available. Melatonin (MLT), a potent antioxidant, anti-inflammatory and antiapoptotic agent, offers promise as an intravenous (IV) or transdermal therapy to protect the brain. We aimed to determine the effect of melatonin (IV or transdermal patch) on neuropathology in a lamb model of perinatal asphyxia. Asphyxia was induced in newborn lambs via umbilical cord occlusion at birth. Animals were randomly allocated to melatonin commencing 30 minutes after birth (60 mg in 24 hours; IV or transdermal patch). Brain magnetic resonance spectroscopy (MRS) was undertaken at 12 and 72 hours. Animals (control n = 9; control+MLT n = 6; asphyxia n = 16; asphyxia+MLT [IV n = 14; patch n = 4]) were euthanised at 72 hours, and cerebrospinal fluid (CSF) and brains were collected for analysis. Asphyxia resulted in severe acidosis (pH 6.9 ± 0.0; lactate 9 ± 2 mmol/L) and altered determinants of encephalopathy. MRS lactate:N-acetyl aspartate ratio was 2.5-fold higher in asphyxia lambs compared with controls at 12 hours and 3-fold higher at 72 hours (P <.05). Melatonin prevented this rise (3.5-fold reduced vs asphyxia; P =.02). Asphyxia significantly increased brain white and grey matter apoptotic cell death (activated caspase-3), lipid peroxidation (4HNE) and neuroinflammation (IBA-1). These changes were significantly mitigated by both IV and patch melatonin. Systemic or transdermal neonatal melatonin administration significantly reduces the neuropathology and encephalopathy signs associated with perinatal asphyxia. A simple melatonin patch, administered soon after birth, may improve outcome in infants affected by asphyxia, especially in low-resource settings.

Original languageEnglish
Article numbere12479
Number of pages14
JournalJournal of Pineal Research
Volume64
Issue number4
DOIs
Publication statusPublished - 1 May 2018

Keywords

  • brain injury
  • cell death
  • melatonin
  • neuroprotection
  • oxidative stress
  • perinatal asphyxia
  • radiology
  • transdermal

Cite this

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title = "Systemic and transdermal melatonin administration prevents neuropathology in response to perinatal asphyxia in newborn lambs",
abstract = "Perinatal asphyxia remains a principal cause of infant mortality and long-term neurological morbidity, particularly in low-resource countries. No neuroprotective interventions are currently available. Melatonin (MLT), a potent antioxidant, anti-inflammatory and antiapoptotic agent, offers promise as an intravenous (IV) or transdermal therapy to protect the brain. We aimed to determine the effect of melatonin (IV or transdermal patch) on neuropathology in a lamb model of perinatal asphyxia. Asphyxia was induced in newborn lambs via umbilical cord occlusion at birth. Animals were randomly allocated to melatonin commencing 30 minutes after birth (60 mg in 24 hours; IV or transdermal patch). Brain magnetic resonance spectroscopy (MRS) was undertaken at 12 and 72 hours. Animals (control n = 9; control+MLT n = 6; asphyxia n = 16; asphyxia+MLT [IV n = 14; patch n = 4]) were euthanised at 72 hours, and cerebrospinal fluid (CSF) and brains were collected for analysis. Asphyxia resulted in severe acidosis (pH 6.9 ± 0.0; lactate 9 ± 2 mmol/L) and altered determinants of encephalopathy. MRS lactate:N-acetyl aspartate ratio was 2.5-fold higher in asphyxia lambs compared with controls at 12 hours and 3-fold higher at 72 hours (P <.05). Melatonin prevented this rise (3.5-fold reduced vs asphyxia; P =.02). Asphyxia significantly increased brain white and grey matter apoptotic cell death (activated caspase-3), lipid peroxidation (4HNE) and neuroinflammation (IBA-1). These changes were significantly mitigated by both IV and patch melatonin. Systemic or transdermal neonatal melatonin administration significantly reduces the neuropathology and encephalopathy signs associated with perinatal asphyxia. A simple melatonin patch, administered soon after birth, may improve outcome in infants affected by asphyxia, especially in low-resource settings.",
keywords = "brain injury, cell death, melatonin, neuroprotection, oxidative stress, perinatal asphyxia, radiology, transdermal",
author = "Aridas, {James D.S.} and Tamara Yawno and Sutherland, {Amy E.} and Ilias Nitsos and Michael Ditchfield and Wong, {Flora Y.} and Hunt, {Rod W.} and Fahey, {Michael C.} and Atul Malhotra and Wallace, {Euan M.} and Graham Jenkin and Miller, {Suzanne L.}",
year = "2018",
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language = "English",
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T1 - Systemic and transdermal melatonin administration prevents neuropathology in response to perinatal asphyxia in newborn lambs

AU - Aridas, James D.S.

AU - Yawno, Tamara

AU - Sutherland, Amy E.

AU - Nitsos, Ilias

AU - Ditchfield, Michael

AU - Wong, Flora Y.

AU - Hunt, Rod W.

AU - Fahey, Michael C.

AU - Malhotra, Atul

AU - Wallace, Euan M.

AU - Jenkin, Graham

AU - Miller, Suzanne L.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Perinatal asphyxia remains a principal cause of infant mortality and long-term neurological morbidity, particularly in low-resource countries. No neuroprotective interventions are currently available. Melatonin (MLT), a potent antioxidant, anti-inflammatory and antiapoptotic agent, offers promise as an intravenous (IV) or transdermal therapy to protect the brain. We aimed to determine the effect of melatonin (IV or transdermal patch) on neuropathology in a lamb model of perinatal asphyxia. Asphyxia was induced in newborn lambs via umbilical cord occlusion at birth. Animals were randomly allocated to melatonin commencing 30 minutes after birth (60 mg in 24 hours; IV or transdermal patch). Brain magnetic resonance spectroscopy (MRS) was undertaken at 12 and 72 hours. Animals (control n = 9; control+MLT n = 6; asphyxia n = 16; asphyxia+MLT [IV n = 14; patch n = 4]) were euthanised at 72 hours, and cerebrospinal fluid (CSF) and brains were collected for analysis. Asphyxia resulted in severe acidosis (pH 6.9 ± 0.0; lactate 9 ± 2 mmol/L) and altered determinants of encephalopathy. MRS lactate:N-acetyl aspartate ratio was 2.5-fold higher in asphyxia lambs compared with controls at 12 hours and 3-fold higher at 72 hours (P <.05). Melatonin prevented this rise (3.5-fold reduced vs asphyxia; P =.02). Asphyxia significantly increased brain white and grey matter apoptotic cell death (activated caspase-3), lipid peroxidation (4HNE) and neuroinflammation (IBA-1). These changes were significantly mitigated by both IV and patch melatonin. Systemic or transdermal neonatal melatonin administration significantly reduces the neuropathology and encephalopathy signs associated with perinatal asphyxia. A simple melatonin patch, administered soon after birth, may improve outcome in infants affected by asphyxia, especially in low-resource settings.

AB - Perinatal asphyxia remains a principal cause of infant mortality and long-term neurological morbidity, particularly in low-resource countries. No neuroprotective interventions are currently available. Melatonin (MLT), a potent antioxidant, anti-inflammatory and antiapoptotic agent, offers promise as an intravenous (IV) or transdermal therapy to protect the brain. We aimed to determine the effect of melatonin (IV or transdermal patch) on neuropathology in a lamb model of perinatal asphyxia. Asphyxia was induced in newborn lambs via umbilical cord occlusion at birth. Animals were randomly allocated to melatonin commencing 30 minutes after birth (60 mg in 24 hours; IV or transdermal patch). Brain magnetic resonance spectroscopy (MRS) was undertaken at 12 and 72 hours. Animals (control n = 9; control+MLT n = 6; asphyxia n = 16; asphyxia+MLT [IV n = 14; patch n = 4]) were euthanised at 72 hours, and cerebrospinal fluid (CSF) and brains were collected for analysis. Asphyxia resulted in severe acidosis (pH 6.9 ± 0.0; lactate 9 ± 2 mmol/L) and altered determinants of encephalopathy. MRS lactate:N-acetyl aspartate ratio was 2.5-fold higher in asphyxia lambs compared with controls at 12 hours and 3-fold higher at 72 hours (P <.05). Melatonin prevented this rise (3.5-fold reduced vs asphyxia; P =.02). Asphyxia significantly increased brain white and grey matter apoptotic cell death (activated caspase-3), lipid peroxidation (4HNE) and neuroinflammation (IBA-1). These changes were significantly mitigated by both IV and patch melatonin. Systemic or transdermal neonatal melatonin administration significantly reduces the neuropathology and encephalopathy signs associated with perinatal asphyxia. A simple melatonin patch, administered soon after birth, may improve outcome in infants affected by asphyxia, especially in low-resource settings.

KW - brain injury

KW - cell death

KW - melatonin

KW - neuroprotection

KW - oxidative stress

KW - perinatal asphyxia

KW - radiology

KW - transdermal

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U2 - 10.1111/jpi.12479

DO - 10.1111/jpi.12479

M3 - Article

VL - 64

JO - Journal of Pineal Research

JF - Journal of Pineal Research

SN - 0742-3098

IS - 4

M1 - e12479

ER -